Post-transplant lymphoproliferative disorders are one of the critical complications after solid organ transplantation and hematopoietic stem cell transplant. They occurs secondary to uncontrolled B cell proliferation due to EBV infection. B cell gets infection through reactivation or primary infection, the majority of cases are observed in first year after transplantation. On the other hand, PTLD occurs due to T cell proliferation is less commonly and mostly EBV negative.
Epidemiology
Standardized incidence ratio of 10 for non-Hodgkins lymphoma and 4 for Hodgkins lymphoma were reported among SOT. But, incidence of PTLD is 3.2 % in HSCT
Risk factors
1. According to the type of transplant organ.
In solid organ transplant
In kidney transplant, PTLD occurs in 0.8 to 2.5%.
In liver 1 to 5.5 %. In pancreas 0.5 to 5%.
And this variation mainly due to amount of lymphatic tissue in the transplanted organ and the degree of immunosuppression.
2. In hematopoietic stem cell transplant , PTLD incidence is related to the degree of HLA matching and the introduction of T cell depleting agents.
3. Presence of previous exposure to the immunosuppression during treatment of primary renal disease in the native kidney
4. Oncogenic EBV
Pathogenesis
For EBV positive, the development of PTLD can be due to Immunosuppressive decline in the T cell immune surveillance, EBV can integrate into normal B cell program leading to proliferation of these cells , normally, these antigens would trigger a T cell response capable of destruction of most of the EBV infected B cells, however the immune defense mechanism has been compromised in transplant recipients leading to unlimited B cell transformation and the occurrence of lymphoma.
The pathogenesis of PTLD in EBV negative may be due to CMV or another viral infection, prolonged immunosuppression
Classification
Early PTLD is often of diffuse large B cell or other B cell histology
Late PTLD include Burkitt lymphoma and Hodgkins disease
Histological Classification
1. Three non destructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, infectious mononucleosis like PTLD.
2. Polymorphic PTLD
3. Monomorphic PTLD
4. Classic Hodgkins lymphoma like PTLD
Clinical presentation
Non-symptomatic to fulminanting disease with multi-organ failure.
Time to PTLD for different transplant organ
The time to PTLD is longest for the heart recipients and shortest for lung and heart/ lung in pediatric.
Treatment
1.Primary management is reduction of immunosuppression
But in sometimes, it is not feasible due to risk of allograft rejection and loss
2.surgical clearance
3. Antiviral agents
4. Local radiotherapy
5. Intravenous immunoglobulin
6. Chemotherapy
7. Monoclonal antibodies and cytotoxic T cells
Combination of the above modalities lead to better results
Level of evidence:5
review article discussed prevalence ,diagnosis and treatment of PTLD
New therapeutics:
Anti CD30
BTK inhibitors
Check point inhibitors
radioimmunotherapy
this review has discussed the prevalence, clinical clues, prophylactic measures as well as the current and future therapeutic strategies of PTLD.
standardized incidence ratios is the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort). SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients. Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Prophylaxis measures include EBV sero-status of both donor and recipient checking before donor selection. EBV-negative TR is better receiving grafts from EBV-negative donors whenever available. Adjusting immunosuppressive drugs and prophylactic antiviral therapy in potentially high-risk groups should be considered. It is advisable to keep high titers anti-EBV antibodies and to provide preemptive therapy to high-risk recipients after monitoring EBV viral load and allograft function.
The mainstay of primary PTLD management is to ameliorate the immunosuppressive burden. Rituximabhas been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to reduction of immunosuppressants.
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to former modalities.
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells.
Newer therapeutic medications are:
(1) Bruton’s tyrosine kinase inhibition
(2) Inhibition of PI3K and mTORi
(3) Proteasome inhibition
(4) Radioimmunotherapy
(5) Checkpoint inhibitors
(6) Anti-CD30 therapy
Q1: PTLD has been observed among HSCT and SOTs with SIRs of 10 for NHLM and 4 for Hodgkin lymphoma among SOTs. Risk factors: 1-type of SOT (highest in the lung) multiorgan and intestinal 2-Degree of HLA matching and use of lymphocyte-depleting agents and cumulative IS burden
3-EBV positive donors and seronegative recipients in SOT
4-Pediatric patients with two peaks:
A- First year of TX (mostly EBV seropositive)
B- 5-15 years after TX (mostly EBV seronegative
5-Previous exposure to IS.
6-Oncogenic EBV: (LMP-2) perform VCA-IgG before TX to evaluate EBV exposure.
Pathogenesis: In 50% of SOT patients, PTLD is EBV positive infected B cells in immunosuppressed recipient and can escape from T cell destruction and could transform to lymphoma. For EBV negative PTLD hypotheses are: CMV or other infection, prolonged IS, allograft-driven persistent antigenic triggering and hit-and-run hypotheses. EBV positive PTLD are common and mostly B cell proliferating lesions and more common in the first year of TX. Almost 100% of HSCT are EBV positive with lower risk compared to seronegative ones that are less common and mostly are T cell proliferative lesions and less responsive to IS reduction.
Management:
1-IS reduction
2-Rituximab for non-destructive PTLD and polymorphic PTLD and monomorphic large B cell lymphoma-like PTLD.
3-Chemotherapy for: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T cell lymphoma, primary CNS lymphoma and other uncommon lymphoma and B cell PTLD that is non-responsive to IS reduction and rituximab.
4-Other modalities includes:
-Adoptive immunotherapy
-Out patient care with EBV viral load monitoring and regular physical examination
-Other strategies includes: BTK inhibitors, mTOR inhibitors, bortezomib, radio-immunotherapy, checkpoint inhibitors, anti-CD30 therapy.
*Prognosis:
With new treatments, outlook of PTLD has improved. Scoring systems like IPI is effective to determine prognosis.
*Re-transplantation: One to two years disease free survival is necessary after control of PTLD before re-TX with low rate of recurrence. When EBV viral load become absent with long-term antiviral therapy to avoid recurrence.
In addition, basiliximab is the preferred induction therapy. Donor derived PTLDs have a better outcome.
Q2: The level of evidence is 5. It is a review article.
Level 5 evidence :
-PTLD Risk factors:
-SOT
-Allogenic HSCT
-Previous exposure to the immunosuppression during treatment of the primary renal disease in the native kidney.
-EBV
presentation as :
-Pyrexia , neurological manifestation, nodal lesions , gastrointestinal , pulmonary manifestations.
-Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers.
-Management through :RI ,Rituximab therapy, Chemotherapy. and Adoptive immunotherapy , radiotherapy .
-BTK inhibition, inhibition of PI3K and mTOR , proteasome inhibition , radioimmuno-therapy and checkpoint inhibitors .
Post-transplant lymphoproliferative diseases, often known as PTLD, are serious forms of cancer that can develop in patients who have had solid organ transplantation (SOT) or hematopoietic stem-cell transplantation (HSCT). After an Epstein-Barr virus (EBV) infection, whether due to reactivation of the virus or initial infection, the body’s B cells grow excessively, which results in these conditions. The risk of developing PTLD is not uniform across all types of organ transplants; multiorgan and intestine transplants have the highest risk, while kidney transplants have the lowest risk. In allogeneic stem cell transplantation (HSCT), risk factors include the degree of HLA matching and the use of T-cell depleting drugs.
Pathogenesis:
There are multiple pathways involved in the etiology of PTLD; however, in situations where EBV infection is absent, this process is not well understood. The use of immunosuppressive medication can lead to a decrease in T-cell immunosurveillance, which can lead to the development of EBV-positive PTLD. EBV has the ability to integrate itself into the normal programs of B cells, which can then lead to the proliferation and transformation of these cells. The World Health Organization (WHO) has developed a classification system for PTLD. This approach divides the disease into several subtypes, including non-destructive kinds, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin’s lymphoma-like PTLD.
Clinical Presentation:
The clinical manifestations of PTLD are quite diverse, ranging from asymptomatic lesions to fulminating illnesses characterized by the failure of many organs. Fever, weight loss, nodal lesions, troubles with the gastrointestinal tract and the respiratory system, a state similar to infectious mononucleosis, and neurological sickness are common symptoms. The lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract, spleen, tonsils, central nervous system, and salivary glands are some of the body parts that PTLD may affect. The time it takes to reach PTLD varies from organ to organ, with the least time being required for lung and heart transplant patients, especially in pediatric cases, and the longest time being required for adult heart transplant recipients.
Diagnosis and Monitoring:
Streptococcal infections and infectious mononucleosis are two of the conditions that can be considered alternative diagnoses for PTLD. Monitoring for EBV is absolutely necessary for any preemptive therapeutic techniques that are intended to reduce the likelihood of PTLD development. It is essential to utilize both molecular and serological techniques, in addition to monitoring the EBV virus load, in order to make informed judgments regarding the appropriate course of treatment. Selecting the source of the sample, defining unambiguous cutoff values, and selecting the ideal time to start monitoring are all potential pitfalls that can occur during monitoring.
Treatment
Reducing immunosuppression, employing rituximab therapy, providing chemotherapy in some situations, and researching adoptive immunotherapy are all potential treatment methods for PTLD. Reversing PTLD in a considerable number of patients is possible through the reduction of immunosuppression; however, this approach requires careful monitoring of graft function. Standard treatment for certain kinds of PTLD that do not respond to immunosuppression reduction includes the administration of rituximab, which is a monoclonal antibody against CD20. Chemotherapy is recommended for certain kinds of PTLD as well as for patients who do not respond well to rituximab and have reduced immunosuppression.
Conclusion:
Post-transplant lymphoproliferative disorder (PTLD) is a condition that is linked to immunosuppression after transplantation. After the PTLD has been brought under control, there is a need for careful planning of immunosuppression before considering re-transplantation. It is absolutely necessary for hemato-oncologists to be involved in the treatment of patients suffering from PTLD. One possible way to treat PTLD in the future is to look into several targeted medicines, such as inhibitors of Bruton’s tyrosine kinase, PI3K, and mTOR, as well as radioimmunotherapy and checkpoint inhibitors. For the purpose of directing future therapy approaches and having a better understanding of the biology of PTLD, determining the origin of the tumor (donor versus recipient) is absolutely necessary.
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important
malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell
transplant (HSCT), and it develops as a result of uncontrolled B cell proliferation
due to blunted immunological surveillance. B cells may get infected by Epstein-Barr
virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV
infection. The PTLD cases (> 85%) usually occurred in the first post-transplant year. PTLD that due to T-cell proliferation is less commonly and is mostly EBV-negative. Risk factors:
1- Solid Organ Transplantation (SOT):
Estmation in adults from 0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ and intestinal TRs
2- Allogenic HSCT:
High risk mainly with T-cell depleting strategies (relative risk: 8.4-15, and relatively low with the use of non-specific broad lymphocyte depleting agents (T- and B-cells) (relative
risk = 3.1)
3- previous exposure to the immunosuppressive load for treatment of the primary renal disease before transplantation is an unnoticed risk factor for PTLD evolution.
4- Oncogenic EBV: EBV may alter cell growth via several mechanisms:
(1) With lack of immune recognition, EBV may induce highly regulated growth transformation with expression of all of its growth inducing proteins.
(2) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors. (3) EBV induced proliferating cells as well as EBV variant/HLA types combination may permit these proteins to by-pass immune control and go unrecognized.
(4) Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA. Classification:
1- Early PTLD: in which there is positive EBV infection, graft affection, non destructive , less often to be monomorphic subtype extranodal disease, it comprises the majority of PTLD cases.
2- Late onset PTLD: there is frequent EBV negative tumors, common extranodal involvement with less graft involvement .
Both types have the same risk factors and treatment response.
Clinical presentation:
It could be symptomless of fulminant disease with multi-organ failure.
Symptoms include;
Pyrexia (57%)
weight loss (9%)
neurological manifestations (13%)
nodal lesions (38%)
gastrointestinal manifestations (27%),
pulmonary manifestations (15%)
infectious mononucleosis-like syndrome that
could be fulminant (19%)
Allograft dysfunction may ensue due to graft involvement.
Nonspecific symptoms (e.g., fever, asthenia).
The most common sites of PTLD involvement are : Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands. Differential diagnosis: streptococcal infection and infectious mononucleosis TREATMENT OF PTLD :
1- Reduction of immunosuppression drugs can reverse 20%-80% of patients with PTLD
and this includes 50% reduction of calcineurin inhibitors doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF).
Some times withdrawal of all immunosuppressive medications except steroids should be considered in very ill patients.
2- Rituximab therapy
3- Chemotherapy
Indications include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
3- Adoptive immunotherapy
This is done by infusion of donor lymphocytes, to manage PTLD in HSCT patients that is primarily originating from donor cells. Prognosis :
Outcome of PTLD patients has greatly improved owing to the advent of new
lymphoma-specific protocols as well as to the better supportive care.
70% of the PTLD-1 patients had achieved a complete remission with median survival of
approximately 6.6 years.
There is a prognostic scoring system that includes the following: Patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and number of extra-nodal locations.
Post-transplant lymphoproliferative disorders (PTLD) are significant malignancies that occur after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT). These disorders arise from uncontrolled B cell proliferation following Epstein-Barr virus (EBV) infection, either through reactivation or primary infection. The incidence of PTLD varies depending on the type of transplant organ, with multiorgan and intestinal transplants having the highest incidence in SOT, while kidney transplants have the lowest. Risk factors include the degree of HLA matching and the use of T-cell depleting agents in allogenic HSCT.
Pathogenesis:
The pathogenesis of PTLD involves various mechanisms, but in cases without EBV infection, it is less understood. EBV-positive PTLD can develop due to a decline in T-cell immunosurveillance induced by immunosuppressive therapy. EBV can integrate into normal B-cell programs, leading to proliferation and transformation of these cells. PTLD is classified according to the World Health Organization (WHO) classification system, which includes non-destructive types, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin’s lymphoma-like PTLD.
Clinical Presentation:
The clinical presentation of PTLD varies widely, ranging from asymptomatic lesions to fulminating disease with multi-organ failure. Common symptoms include fever, weight loss, nodal lesions, gastrointestinal and respiratory issues, infectious mononucleosis-like syndrome, and neurological illness. PTLD can affect various locations in the body, including lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract, spleen, central nervous system, tonsils, and salivary glands. The time to PTLD varies depending on the transplant organ, being shortest for lung and heart recipients, particularly in pediatric cases, and longest for adult heart recipients.
Diagnosis and Monitoring:
Differential diagnoses for PTLD include streptococcal infections and infectious mononucleosis. EBV monitoring is crucial for preemptive therapy strategies aimed at limiting the risk of PTLD development. Monitoring the EBV viral load and using molecular and serological methods for early detection of EBV are important in guiding therapy decisions. Pitfalls in monitoring include determining the source of the sample, establishing clear cutoff values, and determining the optimal time to start monitoring.
Treatment:
Treatment approaches for PTLD involve reducing immunosuppression, using rituximab therapy, administering chemotherapy in specific cases, and exploring adoptive immunotherapy. Reduction of immunosuppression can reverse PTLD in a significant number of patients but requires close monitoring of graft function. Rituximab, an anti-CD20 monoclonal antibody, is a standard therapy for certain types of PTLD that do not respond to immunosuppression reduction. Chemotherapy is indicated for specific PTLD subtypes and cases unresponsive to rituximab and immunosuppression reduction.
Conclusion:
PTLD is a disease associated with immunosuppression following transplantation. Careful planning of immunosuppression is necessary after PTLD control before considering re-transplantation. The involvement of hemato-oncologists in the management of PTLD patients is crucial. Future strategies for PTLD treatment include exploring various targeted therapies, such as inhibitors of Bruton’s tyrosine kinase, PI3K, and mTOR, as well as radioimmunotherapy and checkpoint inhibitors. The identification of the tumor source (donor vs. recipient) is essential for guiding future therapeutic plans and understanding the biology of PTLD. Level of evidence of this article is V.
PTLD is the second most common malignancy after SOT and HSCT. The highest incidence is recorded in multi-organ transplant and intestinal recipients and the lowest incidence is among renal Tx Recipients.
Risk factors for PTLD:
1- EBV negative recipients.
2- Early occurrence is seen with EBV +ve recipients with later occurrence in EBV -ve recipients.
3- Prolonged exposure to immune-suppression especially in pre-transplant period for primary native kidney disease.
2- Mono-morphic PTLD: either B-cell, T-cell or natural killer cell type.
3- Poly-morphic PTLD: B-cells and T-cells.
4- Classic Hodgkin’s Lymphoma like PTLD.
PTLD treatment options:
1- Reduction of immune-suppression: stop MMF, and Azathioprine, reduce dose of CNI by 50%, monitor graft function.
2- In critically sick patients: stop all immunosuppression except steroids.
3- Rituximab: approved for type 1-3 PTLD not responding to reduction of immune-suppression.
4- Chemotherapy: for Burkitt’s lymphoma, HL, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD resistant to rituximab.
5- Adoptive immunotherapy: EBV specific CTLs for recipient driven or donor-driven PTLD, carries less risk for rejection because of lack of immunosuppression reduction.
Re-transplantation and PTLD recurrence: at least one-year disease free is required after treatment of PTLD before considering re-transplantation because of low recurrence risk. Consider IL-2 antagonist as induction compared to ATG. graft PTLD requires graft nephrectomy which is very curative
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT) and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells may get infected by Epstein-Barr virus (EBV) either by post-transplant viral reactivation; and Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative.
Risk factors
Risk factors are, reportedly, varied according to the type of the transplant organ:
(1) SOT: In adults, the incidence of PTLD has been reported to range from 0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ and intestinal TRs
EBV-positive vs EBV-negative PTLD:
In the light of molecular-genomic data of diffuse large B-cell lymphoma subtype, a range of distinguishing features have been identified to discriminate between EBV+ve and EBV-ve PTLD However, there is a lack of clear distinction between clinical consequences of different EBV serotypes and their response to therapy. Further studies are warranted to recognize more precise molecular-genomic classification of both types.
Clinical presentation: Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure. Salient features: PTLD may present as a local or disseminated disease. In either form, the tumor can behave aggressively in a rapidly progressive manner. Clinical manifestations include Pyrexia (57%), weight loss (9%) neurological manifestations (13%) nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant.
Time to PTLD for different transplanted organs: The time to PTLD is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR. Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology, whereas Burkitt’s lymphoma and Hodgkin’s disease are late events
EBV monitoring for preemptive therapy: The risk of EBV+ve PTLD has been postulated to be related to three factors: Type of transplant organ, time elapsed until diagnosis of post-transplant PTLD and EBV serological status of both recipient and donor before transplant.
An estimation of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy. It has been observed that TR with PTLD usually expresses an increased EBV viral load as compared to PTLD free TR. This higher viral load invites more risk for PTLD evolution.
The mainstay of primary PTLD management is to ameliorate the immunosuppressive burden, so that EBV-specific cellular immunity can be partially restored with no additional risk of acute rejection. RI can reverse 20%-80% of patients with PTLD.
RI plan includes 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF), despite the lack of evidence demonstrating any relation between MMF and PTLD development
With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
Rituximab therapy Rituximab (Rtx) is a potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen, leading to B cell depletion via several mechanisms e.g., phagocytosis (macrophages), complement mediated cytotoxicity, and through natural killer cells (antibody-dependent cell-mediated toxicity)
Of note, CD20-positivity in B-cell PTLD approached 75% of TR in the prospective phase 2 trial (largest subgroup)
Chemotherapy Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
Considering the standard-of-care approaches related to specific histologic features in the rare subtype lymphomas, have mostly improved patient’s outcome
Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells. This situation is in contrast to PTLD developing in TRs of SOT. A robust EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs)
Outpatient care In light of serial follow up of the EBV viral load in identifying the patients at risk and in monitoring the response to therapy, the following steps have been suggested:
(1) Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low-risk groups.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
To summarize
Reduction of immunosuppression is the cornerstone of PTLD management. Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. Chemotherapy is indicated for: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI with variable results. However, “risk-stratified sequential” therapeutic approach seems to be promising. Other modalities may include adoptive immunotherapy and outpatient care. Investigational agents that’re currently under trials have been shown above.
Prognosis Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care. Seventy percent of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years.
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT)[1] , and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells may get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative. The magnitude of cumulative immunosuppressive burden has a crucial role in PTLD evolution[2] . Lymphoma accounts for 21% of all malignancies in SOT recipients as compared to 4% and 5% in immunocompetent individuals, respectively in men and women[3,4] . Clinically, PTLD may manifest either as localized lesion or as systemic disease. Lowering the clinical threshold of PTLD diagnosis is fundamental. Transplant clinicians should be vigilant to this serious disorder. Tissue diagnosis (histopathology) is crucial for PTLD diagnosis, in addition to a clear evidence of EBV DNA, RNA, or protein material[2] . The mainstay of PTLD primary management is reduction of immunosuppression (RI). Complete cessation of the immunosuppressive drugs may be necessary to stop the disease progression. However, RI is not always feasible; a potential risk of allograft loss or graft dysfunction has to be considered particularly for vital organ transplants (e.g., heart transplant). A variety of therapeutic options include surgical clearance, anti-viral agents, local radiotherapy, intravenous immunoglobulin (IVIG), chemotherapeutic agents, monoclonal antibodies and cytotoxic T lymphocytes with variable success[2] . A combination of the above treatment modalities offers better results rather than when used in isolation.
PTLD is a disease of immunosuppression. Recent progress in our understanding of the underlying pathophysiology of PTLD as well as the role of EBV has led to a better management. PTLD recurrence has been rarely reported after re-transplantation that requires careful planning of immunosuppression. An ever-improving moleculargenomic technology has had its impact on upgrading our diagnostic and therapeutic strategies that will be reflected in improved recipient’s outcome. However, close liaison with hemato-oncology team of key importance since the lessons learnt from lymphoma management in the general population can be applied to the management of patients who develop PTLD
What is the level of evidence provided by this article? Level V
INTRODUCTION:
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT).
Occur due to uncontrolled B cell proliferation when infected by EBV either by reactivation or primary infection. Epidemiology of PTLD:
Appear in 1969 for the first time. risk is expressed as “standardized incidence ratios” (SIRs) which is of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) in SOT. Risk factors:
Risk factors vary depending on the type of transplant organ:
SOT: Multiorgan and intestinal transplant has the highest incidence while kidney transplant has the lowest.
Allogenic HSCT: HLA degree of matching and the T cell depleting agents affects the risk, where the more the matching the lower is the risk and the risk was low with broad lymphocyte depleting agents.
EBV negative recipients are more susceptible to develop PTLD, early occurrence is with EBV positive recipients while late occurrence is associated with EBV negative cases.
Immunosuppressive exposure in primary renal disease therapy before transplantation increase immunosuppression burden.
Oncogenic EBV causes growth transformation, initiation of oncogenes, bypass immune control, cell targets, viral and cellular mRNA expression.
Molecular and serological methods together early detection of EBV. Pathogenesis:
50% PTLD in SOT are without EBV infection and those with EBV-positive TRs, the development of PTLD can be due to immunosuppressive-induced decline in the T-cell immunosurveillance. EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells. EBV-positive vs EBV-negative PTLD:
Pathogenesis of PTLD is less evident. Several hypotheses have been postulated. Classification: WHO classification 1) Non-destructive: Plasmocytic; florid Follicular; infectious mononucleosis-like. 2) Polymorphic PTLD: B cells in maturing stages, T cells. 3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell type. 4) classic Hodgkin’s lymphoma-like PTLD. Clinical presentation:
Variable presentation – asymptomatic lesions to fulminating disease with multi-organ failure.
Fever (57%), weight loss (9%), nodal lesions (38%), gastrointestinal (27%), respiratory (15%) and infectious mononucleosis-like syndrome (19%), neurological illness (13%).
Common locations: Lymph nodes, liver, lung, kidney, bone marrow, GI Tract, spleen, CNS, tonsils and salivary glands
Time to PTLD: shortest for Lungs and heart + Lung in pediatric recipients; longest for adult heart recipients. Differential diagnosis:
A. Streptococcal infections
B. Infectious mononucleosis EBV monitoring for preemptive therapy:
1) strategies to limit the risk of PTLD development:
2) Reduction Immunosuppression, Rituximab, Adoptive T cell (EBVST)
3) viral load correlates with increases risk of PTLD
4) EBV Viral load is mandatory to start and monitoring therapy
5) Cell free plasma EBV-DNA correlates better marker of EBV activity
Pitfalls – source of sample, cut off value, time to start monitoring not clear Prophylaxis:
Better for EBV-negative people to receiving grafts from EBV-negative donors. Keeping high titres of anti-EBV antibodies (IVIG / Cyto-Gam administration)
High-risk cases – monitoring EBV viral load; rising titres à reduction of immunosuppression with close monitoring of allograft function. TREATMENT OF PTLD: Reduction of Immunosuppression (RI):
1) Stop MMF, and AZT and 50% reduction of CNI dose.
2) Reverse PTLD in 20%-80% of patients.
3) Need to monitor graft function – 37% Ac Rejection observed
4) Critically ill patients – withdraw all IS except steroid (low dose Prednisone). Rituximab (Rtx) therapy:
Chimeric anti-CD20 mab : binds to CD-20 antigen (expressed on 75% B cell) àB cell depletion
Approved standard therapy for WHO- type1-3 of PTLD, not responding to RI.
Retuxi Monotherapy – Overall response rate (ORR) 44%-79%; Complete remission (CR) in 20%-55% cases
With 4 additional doses of 3 weekly-Rtx – CR rises to 34%-60.5%
PTLD-1 trial: CR 25% after standard induction + augmented by 4 doses of 3 weekly Rtx (low-risk group). Chemotherapy:
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI. Adoptive immunotherapy:
A robust EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs) Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD. A variety of recent approaches e.g., adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells” and Tac-resistant, engineered CTLs has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load. Future strategies:
1) Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib)
2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]
3) Proteasome inhibition (Bortezomib)
4) Radioimmunotherapy, (Yibritumomab, tiuxetan)
5) Checkpoint inhibitors (Pembrolizumab, nivolumab)
6) Anti-CD30 therapy (Brentuximab vedotin)
Their efficacy remains to be validated via randomized controlled trials. Re-transplantation and PTLD recurrence:
one-year disease free survival is necessary after control of PTLD before re-transplantation.
ATG vs IL-2 receptor antagonists: IL2 first priority
the lowest safe dosages monitored by target trough levels should be considered.
MMF can be included safely in the immunosuppressive protocols with no more added risk.
mTOR inhibitors: Their role in PTLD development remains debatable.
Graft PTLD: Usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative.
Origin of PTLD (donor vs recipient): Identification of the tumor source is crucial for future therapeutic plans and recognition of the biology of the next PTLD. CONCLUSION:
PTLD is a disease of immunosuppression.
PTLD recurrence is rare after re-transplantation and needs careful planning of immunosuppression.
Hemato-oncologist should be involved in the management of PTLD patients.
INTRODUCTION Post-transplant lymphoproliferative disorders (PTLD) are a serious malignancy that can occur after solid organ transplantation (SOT) or hematopoietic stem-cell transplantation (HSCT). The disorder develops due to uncontrolled B cell proliferation, often triggered by Epstein-Barr virus (EBV) infection. The incidence of PTLD varies depending on the type of transplant, with the highest incidence observed in lung and intestinal TRs. PTLD can manifest as either localized lesions or systemic disease. Reduction of immunosuppression is the mainstay of PTLD primary management, although this is not always feasible due to the risk of allograft loss or graft dysfunction. Other treatment options include surgical clearance, anti-viral agents, local radiotherapy, intravenous immunoglobulin, chemotherapeutic agents, monoclonal antibodies, and cytotoxic T lymphocytes. PTLD incidence has been increasing in recent years, likely due to improved diagnostic technology, older donors and recipients, and new immunosuppressive strategies. EBV may alter cell growth via several mechanisms, and molecular testing is essential for early detection of infection.
PATHOGENESIS The pathogenesis of post-transplant lymphoproliferative disorders (PTLD) is attributed mainly to Epstein-Barr virus (EBV) infection, which can integrate into normal B-cell program and lead to B-cell transformation. In EBV-positive transplant recipients, PTLD development is due to a decline in T-cell immune surveillance induced by immunosuppression. However, as many as 50% of PTLD cases in SOT are not accompanied by EBV infection. The pathogenesis of PTLD in EBV-negative patients is less evident, and several hypotheses have been postulated, including prolonged immunosuppression and allograft-driven persistent antigenic triggering. T-cell subtype PTLD, which is usually EBV-negative, is a rare tumor that presents with dissimilar manifestations to those of T-cell lymphoma in immunocompetent subjects. Further studies are needed to identify more precise molecular-genomic classification of both types of PTLD.
CLASSIFICATION It includes nondestructive, polymorphic, monomorphic, and classic Hodgkin’s lymphoma-like types based on histopathological features. PTLD can manifest as a localized or disseminated disease and present with nonspecific symptoms such as fever, weight loss, neurological and gastrointestinal manifestations, and nodal lesions. An allograft dysfunction may also occur due to graft involvement. PTLD diagnosis is crucial in transplant recipients, and the threshold for diagnosis should be lowered.
The most common sites of PTLD involvement are lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract, spleen, central nervous system, tonsils, and salivary glands. PTLD can be discriminated from lymphomas in immunocompetent patients based on gene-expression profiles and immunohistochemical staining.
The presence of EBV infection is not necessary for PTLD diagnosis, but it is mandatory to assess the EBV-encoded RNA in-situ hybridization.
DIFFERENTIAL DIAGNOSIS PTLD can be diagnosed according to WHO 2017 Classification, but there is a lack of consistency due to missing criteria such as EBV sero-status, molecular-genomic data, and transplant organ type. PTLD may present with a variety of symptoms, and an associated high EBV viral load should raise suspicion. Differential diagnoses include streptococcal infections and Infectious mononucleosis. Preemptive therapy strategies for PTLD are based on monitoring EBV viral load and recognizing risk factors such as donor and recipient EBV sero-status.
TREATMENT OF PTLD
Post-transplant lymphoproliferative disorder (PTLD) is a rare but serious complication of solid organ transplantation. The main cause of PTLD is Epstein-Barr virus (EBV) infection in immunocompromised transplant recipients. The treatment of PTLD mainly involves ameliorating the immunosuppressive burden and restoring EBV-specific cellular immunity. Reduction of immunosuppressive burden (RI)
The reduction of immunosuppressive burden involves a 50% reduction in calcineurin inhibitors (CNI) doses and withdrawal of antimetabolites. RI can reverse 20%-80% of patients with PTLD, and acute rejection rates of 37% have been observed in some trials. Rituximab therapy
Rituximab is a monoclonal antibody that binds to the CD20 antigen, leading to B cell depletion. Rituximab is approved for three types of PTLD and has shown an overall response rate of 44%-79%. Adding 4 doses of rituximab can raise the rate of complete remission to 34%-60.5%. Chemotherapy
Chemotherapy is indicated for Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to rituximab and RI. The standard-of-care approaches related to specific histologic features in rare subtype lymphomas have mostly improved patient outcomes.
Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients. Expanded EBV-specific CTLs have been an effective therapeutic option in autologous as well as in donor-derived PTLD. Outpatient care
Outpatient care involves serial follow-up of the EBV viral load in identifying patients at risk and monitoring response to therapy. It also involves a comprehensive clinical picture that includes EBV viral load assessment, physical examination, radiology testing, and monitoring allograft function. The therapeutic options should be tailored as per multidisciplinary team discussion.
Post-transplant lymphoproliferative disorder (PTLD) is a severe complication following organ transplantation, particularly in patients who are receiving long-term immunosuppressive therapy. It is a disease of immunosuppression and can result in malignancy of lymphoid cells. This article provides an overview of the management and prognosis of PTLD.
The reduction of immunosuppression is the primary method for managing PTLD. Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. Chemotherapy is indicated for Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI. Other modalities may include adoptive immunotherapy and outpatient care. Investigational agents that are currently under trials have also been shown to be effective.
PROGNOSIS:
The outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as better supportive care. The IPI is a prognostic scoring system that includes patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and number of extra-nodal locations. A French registry system also relies primarily upon patient’s age, serum creatinine concentration, LDH level, PTLD localization, and histopathologic criteria. However, it is not superior to the IPI. The PTLD-1 trial has settled the prognostic validity of IPI. Hypoalbuminemia is a robust prognostic factor. CD20-positivity in PTLD indicates a poorer outcome.
PTLD RECURRENCE:
Feasibility of re-transplantation after successful management of PTLD has been reported in particular cases; however, one-year disease-free survival is necessary after control of PTLD before re-transplantation. Recommendations to limit the possibility of PTLD recurrence include time to retransplant, EBV, the role of immunosuppression, induction therapy, maintenance immunosuppression, monoclonal gammopathy, and the origin of PTLD.
CONCLUSION:
Recent progress in understanding the underlying pathophysiology of PTLD and the role of EBV has led to better management. PTLD recurrence has been rarely reported after re-transplantation, which requires careful planning of immunosuppression. The ever-improving molecular-genomic technology has had its impact on upgrading diagnostic and therapeutic strategies that will be reflected in improved recipient’s outcome.
Post-transplant lymphoproliferative disorders (PTLD) are lymphoid and/or plasmacytic proliferations that occur in the setting of solid organ or allogeneic hematopoietic cell transplantation as a result of immunosuppression. They are among the most serious and potentially fatal complications of transplantation. Majority of PTLD cases(≥ 85%) are usually observed in first year post transplant year.
Risk factors-
1)Type of SOT- In adults, the incidence of PTLD has been reported to range from 0.8%2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and 20% in multi-organ and intestinal Transplant.
2)Degree of immunosuppression — The degree of immunosuppression has long been considered a major determinant of the development of PTLD. In particular, the degree of T cell immunosuppression appears to be more important than the degree of immunosuppression overall, due to the impairment of EBV-specific T cell-mediated immunity.
3)EBV serostatus — There is an increased risk of PTLD among EBV-negative recipients of EBV-positive donor organs. the incidence rate of PTLD for EBV-seronegative recipients is around 24 times higher than that for EBV-seropositive recipients. PTLD may be more common in children, because a higher percentage of children is EBV-seronegative prior to transplantation .
4)Time since transplant-The risk of PTLD also varies with time post-transplant.The highest lymphoma rate was observed during the first year post-transplant.
. 5)Other Risks- Some additional risk factors for PTLD include a history of pretransplant malignancy and fewer HLA matches and CMV seromismatch
EBV positive vs EBV negative PTLD- Around 30 % of PTLD are EBV negative.EBV positive PTLD is observed mostly during 1st year post transplant , in comparison EBV negative PTLD observed later.EBV positive PTLD are mostly B cell proliferation and CD20+ whereas EBV negative PTLD are mostly CD20 negative (T cells proliferation). EBV negative PTLD have poor prognosis in comparison to EBV positive PTLD.
Four general types of PTLD have been described in transplant recipients:
●Early lesion (ie, plasmacytic hyperplasia and infectious mononucleosis-like PTLD) – This presents as an infectious mononucleosis-type acute illness characterized by polyclonal B cell proliferation with no evidence to suggest malignant transformation.
●Polymorphic PTLD – Polymorphic PTLD are polyclonal or monoclonal lymphoid infiltrates that demonstrate evidence of malignant transformation but do not meet all of the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients.
.Classic Hodgkin PTLD-Classic Hodgkin lymphoma-like PTLD is the least common form of PTLD. Biopsy of involved tissue should fulfill the criteria required for the diagnosis of classic HL .
Clinical feature-
PTLD may present as a local or disseminated disease. In either form, the tumor can behave aggressively in a rapidly progressive manner. Clinical manifestations include: Pyrexia (57%) weight loss (9%), neurological manifestations (13%) nodal lesions (38%) gastrointestinal manifestations (27%),pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant (19%).An allograft dysfunction may ensue due to graft involvement. Lowering the threshold for PTLD diagnosis is crucial, as TR may present with nonspecific symptoms (e.g., fever, asthenia). An associated high EBV viral load by PCR should make one suspect PTLD. The most common locations of PTLD involvement are as follows-Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
Prophylaxis and Treatment-
Antiviral prophylaxis — Ganciclovir inhibits EBV replication in vitro..Many transplant center uses prophylaxis in High-risk patients (eg, donor EBV-positive, recipient EBV-negative) and uses a minimum of 100 days of intravenous ganciclovir (6 to 10 mg/kg per day).
EBV monitoring for preemptive therapy– While many transplant recipients demonstrate a modestly increased EBV viral load in the peripheral blood post-transplant, the vast majority of patients with EBV-positive PTLD will demonstrate a more marked elevation in the EBV viral load. Many transplant centers incorporate EBV monitoring into the routine evaluation of patients at high risk for PTLD and preemptively treat at the time of viral reactivation.Most centers administer preemptive rituximab therapy for patients at high risk of EBV-associated PTLD if titre of EBV rises significantly.
Initial management is largely dependent upon the type of PTLD:
•Early lesions – For most patients with early lesions, we suggest reduction of immunosuppression alone rather than in combination with other therapies Other agents are generally reserved for those patients with residual disease despite reduced immunosuppression or for those who cannot tolerate reduction of immunosuppression.
•Polymorphic PTLD – For most patients with polymorphic PTLD that expresses CD20 (CD20+ PTLD), we suggest the use of rituximab in addition to reduction of immunosuppression, as tolerated, rather than reduction of immunosuppression alone or this combination with chemotherapy .
•Monomorphic PTLD – For patients with monomorphic CD20+ PTLD, we suggest the use of rituximab, either alone or in combination with chemotherapy in addition to reduction of immunosuppression . Single agent rituximab may be considered for patients who have minimal symptoms and for those who are not candidates for initial chemotherapy. All other patients with CD20+ PTLD are offered rituximab plus combination chemotherapy, administered concurrently or sequentially. Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with combination chemotherapy plus reduction of immunosuppression. Surgery is reserved for patients with complications such as perforation or obstruction.
•Classic Hodgkin lymphoma-like PTLD – Classic Hodgkin lymphoma-like PTLD is the least common form of PTLD and there is a paucity of data regarding management. For most patients with classic Hodgkin lymphoma-like PTLD we suggest management with chemotherapy with or without radiation therapy according to protocols used for classic Hodgkin lymphoma.
●There is a paucity of information concerning mortality of patients with PTLD. Although the prognosis varies with clonality and extent of disease, published series suggest overall survival rates ranging between 25 to 35 percent. Mortality with monomorphic PTLD and T cell PTLD are higher.
INTRODUCTION:
PTLD remains a considerable concern is post-transplant patients accounting for 1/5th of all post-transplant cancers. Majority are B cell associated secondary to EBV infection. Increased vigilance and early detection is crucial.
First described in 1969, now higher incidence is being noted with better diagnostic technology with a standardized incidence ratio of 10 (non-Hodgkin) and 4 (Hodgkin) PTLD. Risk factors include transplanted organ, induction and maintenance immunosuppression (T cell depleting agents), EBV status of donor and recipient pre-transplant, age of recipient and EBV infection.
EBV infected B cells remain the cornerstone of pathogenesis combined with immunosuppression related reduction in T cell activity. For EBV negative PTLD many theories are postulated but none proven.
PTLD is a diagnosis requiring tissue confirmation with histopathology and immunophenotyping, as the treatment and outcomes depend on the histopathological subtype. The sub-types include 1. Non-destructive, 2. Polymorphic, 3. Monomorphic, 4. Classical Hodgkin lymphoma. Staging should be done as for normal population.
Variable presentation can be found. B-symptoms are common. Graft dysfunction should be assessed. Differentials include bacterial and other viral infections. EBV monitoring by PCR is not validated as there are no clear cut off values and no standard testing interval is defined. However for high risk cases preemptive strategy should be utilized. Prophylaxis in the form of EBV serology of both recipient and donor at time of donor selection should be routine practice and EBV negative recipient should get graft from EBV negative donor. Treatment of PTLD includes 1) Reduction in Immunosuppressive therapy 2) Rituximab 3) Chemotherapy and 4) Adoptive Immunotherapy.
1. Reduction in immunosuppression
It remains the cornerstone of PTLD management as reducing the immunosuppression can lead to activation of EBV specific T cells. This is achieved by stopping antimetabolite and reducing CNI by 50%, while monitoring for rejection.
2. Rituximab
B cell PTLD has 75% positivity for CD 20 antigen. Rituximab is a monoclonal antibody against CD-20 positive cells. Rituximab has been approved as standard therapy for 3 subtypes of PTLD (non-destructive, polymorphic and monomorphic DLBCL). Addition of Rituximab to the reduction of immunosuppressive therapy has been shown to achieve complete remission in 1/4th of cases.
3. Chemotherapy
PTLD subtypes unresponsive to RI and Rituximab are indications for chemotherapy including Burkitts, Hodgkin, Peripheral T cell, Primary CNS lymphomas. Standard regime of R-CHOP is widely used and safe provided toxicities are monitored and managed. Up to 88% response rate and 70% complete remission rates have been achieved.
4. Adoptive Immunotherapy
T cells targeting EBV infected B cells by Donor lymphocyte infusion or CTLs are in use for resistant cases.
Regular monitoring during treatment for both toxicities and response should be done. This includes 1) Viral load monitoring 2) Screening for toxicities of therapy 3) Monitoring for rejection 4) MDT involvement.
A few experimental therapies have been suggested but no robust evidence is available for their use.
The prognosis of PTLD has improved markedly with 70% complete remission rates achieved. This is in large part due to better supportive acre and better management of treatment related toxicities. The use of prognostic scoring systems is also helping improve outcomes by identifying high risk cases.
Re-transplantation after successful remission and disease free interval of 1-2 years, however certain modification in induction and maintenance immunosuppression needs to be kept in mind. What is the level of evidence provided by this article?
Level V
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Introduction
This article discusses the clinical evidence, measures, and strategies for treating Post-Transplantation Lymphoproliferative Disorders (PTLD). PTLD are the disorders that occur due to immunosuppression after Solid Organ Transplantation.
Discussion
The primary management of PTLD includes reduction of immunosuppression (RI). A combination of methods is considered to treat PTLD instead of an isolated method because administration of immunosuppressants cannot be completely ceased. These methods are discussed in this article.
Only 50% of PTLD is not caused by EBV infections. However the clinical consequences of different EBV serotypes require further studies to recognize molecular genome classification of both types. According to WHO PTLD can be categorized as non-destructive PTLD, polymorphic PTLD, monomorphic PTLD and Hodgkin’s lymphoma-like PTLD.
The manifestation of PTLD clinically varies widely from symptomless lesions to fulminating disease with multi-organ failure.
Heart transplant recipients take the longest to develop PTLD while the shortest is lung and lung/heart in paediatric recipients.
To monitor pre-emptive PTLD therapy, an estimation of viral load through PCR amplification of peripheral blood EBV DNA is mandatory. PTLD patients express increased EBV viral load.
EBV sero-status of donor and recipient is to be recognized before donor selection.
Immunosuppressive burden reduction is the primary objective of PTLD treatment. RI involves reducing calcineurin inhibitors by 50%. Allograft function should be monitored during RI trial for early rejection manifestations.
Rituximab (Rtx) binds to CD-20 antigen leading to B-cell depletion.
Uncommon lymphomas and B-cell PTLD lymphomas which are unresponsive to RI and Rtx are considered for immunochemotherapy.
EBV-specific cytotoxic lymphocytes (CTLs) induce a EBV-specific cellular immune response.
Outpatient care included weekly monitoring for high-risk TRs and monthly followed by three-monthly monitoring for low-risk TRs. Increase in viral load indicates progression. EBV viral load assessment includes comprehensive clinical picture like radiology and physical examination. Balance in PTLD management and allograft rejection avoidance is crucial. Multidisciplinary teams (MDTs) should discuss therapeutic options.
Lymphoma-specific protocols with the support of better supportive care has greatly improved PTLD patients’ outcomes.
Recommendations for reducing PTLD recurrences include 12 -24 months from remission should be given for new transplant, monitoring of EBV, immunosuppression monitoring, induction therapy, monoclonal gammopathy and origin of PTLD.
Conclusion
PTLD management has significantly improved since the understanding of pathophysiology and the role of EBV. Molecular genomic technology has aided in building management strategies. A close liaison of MDT with haemato-oncology team plays a vital role in successfully management of PTLD and recurrence.
· Post transplant lymphoproliferative disorder is a malignancy caused by uncontrolled B cell proliferation due to blunted immunological surveillance.
· B cells can be infected by EBV through post-transplant reactivation, primary EBV infection, or environmental exposure.
· PTLD is most common in the first post-transplant year, while T-cell proliferation is less common.
· PTLD is a serious disorder requiring tissue diagnosis and evidence of EBV DNA, RNA, or protein material.
Epidemiology of PTLD:
PTLD has been recognized in both SOT and HSCT since 1969. PTLD prevalence has increased due to better diagnostic technology, older donors, increased awareness, new immunosuppressive strategies, and HSCT.
Risk factors:
Risk factors vary depending on the type of transplant organ.
1- SOT: In adults, 0.8%-2.5% in kidney transplant recipients (KTR),
• 0.5%-5.0% in pancreatic TRs,
• 1.0%-5.5% in liver TRs,
• 2.0-8.0% in heart TRs,
• 3.0-10.0% in lung TRs,
• ≤ 20% in multi-organ and intestinal TRs
2- Allogenic HSCT: PTLD incidence is related to HLA matching and T-cell depletion.
3- Immunosuppressive load exposure during primary renal illness is a risk factor for the development of PTLD.
4- Oncogenic EBV: EBV may alter cell growth via:
• Lack of immune recognition,
• Induction of the potent oncogenes
• EBV-induced proliferating cells as well as EBV variant/HLA types.
• Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA
Pathogenesis:
Role of EBV:
Recent reports suggest that as many as 50% of PTLD in SOT are not accompanied by EBV infection
• For EBV-positive TRs, EBV can integrate into normal B-cell programs, Defences by compromised T-cells in TRs lead to uncontrolled transformation and lymphoma.
• EBV-negative patients Pathogenesis of PTLD is less evident. Several hypotheses have been postulated like
• CMV
• Another viral infection,
• Prolonged
• Immunosuppression,
• Allograft-driven persistent antigenic triggering,
• Hit-and-run hypothesis
Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure. It may present as a local or disseminated disease.
It includes :
• Pyrexia (57%)
• Weight loss (9%)
• Neurological manifestations (13%)
• Nodal lesions (38%)
• Gastrointestinal manifestations (27%)
• Pulmonary manifestations (15%).
• Infectious mononucleosis-like syndrome that could be fulminant (19%)
Differential diagnosis:
In TRs with pyrexia, pharyngitis, and cervical lymphadenopathy, should be taken into consideration.
Prophylaxis:
• In some populations that are very susceptible to developing PTLD, preemptive treatment should be taken into consideration.
• Donor and recipient EBV serostatus should be known before choosing a donor, and EBV-negative donors ideally better to be used for EBV-negative TR
• Achieving the lowest immunosuppressive load clinically feasible.
• IVIG/CytoGam injection to maintain high titers of anti-EBV antibodies is also advised.
TREATMENT OF PTLD
Reduce Immunosuppression:
The reduction of the immunosuppressive load is the cornerstone of basic PTLD therapy, Rituximab therapy
Rituximab is an effective chimeric anti-CD20 monoclonal antibody that binds to CD-antigen and causes B cell depletion through a variety of mechanisms. Chemotherapy
Indications:
• Burkitt’s lymphoma,
• Hodgkin’s lymphoma,
• Peripheral T-cell lymphoma,
• Primary CNS lymphoma and other uncommon lymphomas,
• B-cell PTLD unresponsive to Rtx and RI Adoptive immunotherapy
EBV-specific CTLs are a potent treatment in both donor- and recipient-derived PTLD, but GVHD is the main danger. Future strategies
• Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib).
• Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)
• Proteasome inhibition[83] (Bortezomib).
• Radioimmunotherapy. (90Yibritumomab, tiuxetan).
• Checkpoint inhibitors (Pembrolizumab, nivolumab).
• Anti-CD30 therapy (Brentuximab vedotin).
Prognosis:
IPI is a prognostic scoring system that includes the following:
• Patient’s age,
• Performance attitude,
• Current stage,
• Lactate dehydrogenase (LDH),
• Number of extra-nodal locations.
Using univariate analysis, poor prognostic criteria have been postulated that include the following:
• Monoclonality,
• Negative EBV serology,
• Primary CNS involvement,
• Tumour originated from T-cell, performance status ≥ 2,
• Chemotherapy-based therapy (plus RI),
• Multiple involved locations
Re-transplantation and PTLD recurrence:
• The feasibility of re-transplantation after successful management of PTLD has been reported, but one-year disease-free survival is necessary.
• Retransplantation after the PTLD cure remains controversial due to the re-exposure of immunosuppression.
• To limit the possibility of PTLD recurrence, the following recommendations are worth noting:
Time to retransplant:
· EBV positivity,
· Low/absent EBV viral load,
· Close monitoring,
· Anti-viral therapy,
· Role of immunosuppression.
Conclusion:
• PTLD is a disease of immunosuppression, with improved understanding and management.
• Moleculargenomic technology has improved diagnostic and therapeutic strategies to reduce PTLD recurrence.
• Rare reports of PTLD recurrence following re-transplantation necessitate cautious immunosuppressive planning.
INTRODUCTION;. Post-transplant lymphoproliferative disorders (PTLD) are lymphoid and/or plasmacytic proliferations that occur as a result of immunosuppression in the setting of solid organ or allogeneic hematopoietic cell transplantation. These conditions lie along a continuum of disease and are categorized by the World Health Organization PTLD classification system . PTLDs are among the most serious complications of transplantation.
PTLD epidemiology PTLD incidence is 3.2% in HSCT recipients and it’s recognition has increased due to advanced technology, increase of the donor and recipient age and new immunosuppressive regimens as well as haploidentical HSCT. Risk factors -SOT: Multiorgan and intestinal transplant has the highest incidence while kidney transplant has the lowest. -Allogenic HSCT: HLA degree of matching and the T cell depleting agents affects the risk, where the more the matching the lower is the risk and the risk was low with broad lymphocyte depleting agents. EBV negative recipients are more susceptible to develop PTLD, early occurrence is with EBV positive recipients while late occurrence is associated with EBV negative cases. -Immunosuppressive exposure in primary renal disease therapy before transplantation increase immunosuppression burden. -Oncogenic EBV causes growth transformation, initiation of oncogenes, bypass immune control, cell targets, viral and cellular mRNA expression. Molecular and serological methods together early detection of EBV Pathogenesis 50% of PTLD are EBV negative with unclear specific pathogensis. In EBV positive cases ,defective T cell surveillance through immunosuppressives is implicated. EBV-positive vs EBV-negative PTLD There is no clear difference but some differences can be noted EBV negative: has features similar to diffuse large B-cell lymphoma in immunocompetent patients, mostly T cell lesion of germinal B cell center type ,less prevalent , common with seronegative SOT in pediatrics. EBV positive :is more common , of B cell origin of non germinal center type ,prevalent with HSCT Early versus Late onset PTLD Early onset represent the majority of PTLD cases ,it is usually associated with EBV positive cases, with graft involvement and is non destructive , donor derived ,less common to be Monomorphic subtypes and bortezomib can be useful after allogeneic HSC also Induction therapy has a role. Late onset is less prevalent ,mostly EBV negative with extra nodal involvement more than graft affection, with high incidence of late onset Hodgkin’s lymphoma after allogeneic HSCT and cumulative immunosuppressives have an important role.
Clinical presentation: variable presentation – asymptomatic lesions to fulminating disease with multi-organ failure. Fever (57%), weight loss (9%), nodal lesions (38%), gastrointestinal (27%), respiratory (15%) and infectious mononucleosis-like syndrome (19%), neurological illness (13%). Common locations: Lymph nodes, liver, lung, kidney, bone marrow, GI Tract, spleen, CNS, tonsils and salivary glands Time to PTLD: shortest for Lungs and heart + Lung in paediatric recipients; longest for adult heart recipients Prophylactic measures: better for EBV-negative people to receiving grafts from EBV-negative donors. Keeping high titres of anti-EBV antibodies (IVIG / Cyto-Gam administration) High-risk cases – monitoring EBV viral load; rising titres à reduction of immunosuppression with close monitoring of allograft function Pre-emptive strategies to limit the risk of PTLD development: – Reduction Immunosuppression, Rituximab, Adoptive T cell (EBVST) – viral load correlates with increases risk of PTLD – EBV Viral load is mandatory to start and monitoring therapy – Cell free plasma EBV-DNA correlates better marker of EBV activity Pitfalls – source of sample, cut off value, time to start monitoring not clear
TREATMENT OF PTLD 1. Reduction of Immunosuppression (RI) – Stopping antimetabolites (MMF, AZT); 50% reduction of CNI dose – reverse PTLD in 20%-80% of patients – Need to monitor graft function – 37% Ac Rejection observed – Critically ill patients – withdraw all IS except steroid (low dose Prednisone) EBV positive disease responds better than EBV negative cases No response to RI observed in – old age (>50years), bulky disease (>7cm); advanced stage (Ann-Arbor III/IV) 2- Rituximab (Rtx) therapy: Chimeric anti-CD20 mab : binds to CD-20 antigen (expressed on 75% B cell) àB cell depletion Approved standard therapy for WHO- type1-3 of PTLD, not responding to RI. Retuxi Monotherapy – Overall response rate (ORR) 44%-79%; Complete remission (CR) in 20%-55% cases With 4 additional doses of 3 weekly-Rtx – CR rises to 34%-60.5% PTLD-1 trial: CR 25% after standard induction + augmented by 4 doses of 3 weekly Rtx (low-risk group). 3- Chemotherapy Indications: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma; Lymphoma & B-cell PTLD unresponsive to Retuxi + RI Incomplete / no response to Retuxi monotherapy –> 4 cycles of R-CHOP-21 given every 3 wks, with G-CSF support; ORR 88%; CR of 70% at end of therapy. Risk-stratified sequential therapeutic approach Rtx weekly x 4cycles –> response assessment at 2-4 weeks good response –> 4 more doses of Rtx at 3wks interval poor response –> R-CHOP-21 with supportive care and G-CSF Reduced Immunosuppression + Stratified Sequential Chemo-therapy is considered the standard of care for Polymorphic and Monomorphic DLBL-like PTLD (regardless to EBV status) after SOT. Selection in to poor risk group depending on presence of risk factors (type of allograft type, response to Rtx and performance status) formed the basis of PTLD-2 trial. 4- Adoptive immunotherapy Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD. GVHD can be the complication 5- Outpatient care Serial monitoring of viral load, allograft function, physical examination and imaging – to optimize balance between PTLD management and avoidance of allograft acute rejection is crucial. 6. Future strategies: newer therapeutic medications – their efficacy remains to be validated via RCT. (1) Bruton’s TKI – (Ibrutinib) – used in GVHD and allograft rejection; in DLBCL 2. A Inhibition of PI3K – Idelalisib 2. B mTORi – SRL and Everolimus – role in PTLD controversial (3) Proteasome inhibition (Bortezomib) – in early presented PTLD post allogeneic HSCT (4) Radioimmunotherapy, (90Yibritumomab, Tiuxetan) – small pilot trial (5) Checkpoint inhibitors (Pembrolizumab, nivolumab): Cytotoxic T lymphocyte associated antigen 4 pathway: recommended in clinical trials, (6) Anti-CD30 therapy (Brentuximab Vedotin) – CD30 expressed in 85% PTLD; limited clinical experience (only case reports). Re-transplantation and PTLD recurrence · 12 to 24 mo after complete PTLD remission · Epstein–Barr nuclear antigen IgG positivity · Low/absent EBV viral load is recommended at the time of re-transplantation · persistently high EBV viral load – Anti-viral therapy: Gancyclovir long-term prophylaxis · T cell-depleting agents should be excluded from induction strategies (IL-2R blocker first choice) · Triple therapy (CNI, MMF and steroids) in lowest safe dosage
What is the level of evidence provided by this article?
1. Please summarise this article SUMMARY: This is a systematic review,discussed prevalence, clinical clues, prophylactic measures as well as the current and future therapeutic strategies. Introduction: PTLD is a disease of over-immunosuppression Lack of T-cell led immune surveillance results in uncontrolled B cell proliferation EBV-infection is triggering factor – primary infection (EBV-positive donor to EBV-negative recipient), or late reactivation due to cumulative immunosuppression Lymphoma account for 21% of all malignancies in SOT recipients Epidemiology: SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients. Reported incidence of PTLD in 3.2% of HSCT, 1-2% of SOT 85% PTLD occurs within 1 yr post-transplant; Second peak at 5-15 yrs Risk factors: (1) SOT: lymphatic tissue in allograft (highest in small intestine 20%, Lungs 3-10%, heart 2-8%, lowest in kidney 0.8-2.5%) and the degree of immunosuppression (cumulative immunosuppression level) (2) Allogenic HSCT: HLA matching à consequent T-cell depleting Induction used (3) Prior immunosuppression treatment of primary disease in native kidney (4) Oncogenic EBV – induction of LMP1, LMP2 oncogene Pathogenesis: EBV+ : immunosuppression-induced decline in the T-cell mediated immune surveillance EBV negative (50% PTLD in SOT) – CMV & other Viral infections, prolonged immunosuppression, allograft-driven persistent antigenic trigger, hit & run hypothesis Histopathological (WHO) classification of PTLD: (1) Non-destructive: Plasmacytic; florid Follicular; infectious mononucleosis-like (2) Polymorphic PTLD: B cells in maturing stages, T cells, (3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell type (4) classic Hodgkin’s lymphoma-like PTLD EBV infection could be currently seen in almost all non-destructive PTLD, in > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD, and in only 50% of monomorphic PTLD. Cell of origin: (Gene-expression profile and IHC) – EBV+ve cases are mostly non-germinal center B-cell type; EBV-ve cases are more of “germinal center B-cell type EBV-encoded RNA (EBER) in-situ hybridization assessment is mandatory for all the cases, although presence of EBV infection is not necessary for PTLD diagnosis. Clinical presentation: variable presentation – asymptomatic lesions to fulminating disease with multi-organ failure. Fever (57%), weight loss (9%), nodal lesions (38%), gastrointestinal (27%), respiratory (15%) and infectious mononucleosis-like syndrome (19%), neurological illness (13%). Common locations: Lymph nodes, liver, lung, kidney, bone marrow, GI Tract, spleen, CNS, tonsils and salivary glands Time to PTLD: shortest for Lungs and heart + Lung in paediatric recipients; longest for adult heart recipients Prophylactic measures: better for EBV-negative people to receiving grafts from EBV-negative donors. Keeping high titres of anti-EBV antibodies (IVIG / Cyto-Gam administration) High-risk cases – monitoring EBV viral load; rising titres à reduction of immunosuppression with close monitoring of allograft function Pre-emptive strategies to limit the risk of PTLD development: – Reduction Immunosuppression, Rituximab, Adoptive T cell (EBVST) – viral load correlates with increases risk of PTLD – EBV Viral load is mandatory to start and monitoring therapy – Cell free plasma EBV-DNA correlates better marker of EBV activity Pitfalls – source of sample, cut off value, time to start monitoring not clear TREATMENT OF PTLD 1. Reduction of Immunosuppression (RI) – Stopping antimetabolites (MMF, AZT); 50% reduction of CNI dose – reverse PTLD in 20%-80% of patients – Need to monitor graft function – 37% Ac Rejection observed – Critically ill patients – withdraw all IS except steroid (low dose Prednisone) EBV positive disease responds better than EBV negative cases No response to RI observed in – old age (>50years), bulky disease (>7cm); advanced stage (Ann-Arbor III/IV) 2- Rituximab (Rtx) therapy: Chimeric anti-CD20 mab : binds to CD-20 antigen (expressed on 75% B cell) àB cell depletion Approved standard therapy for WHO- type1-3 of PTLD, not responding to RI. Retuxi Monotherapy – Overall response rate (ORR) 44%-79%; Complete remission (CR) in 20%-55% cases With 4 additional doses of 3 weekly-Rtx – CR rises to 34%-60.5% PTLD-1 trial: CR 25% after standard induction + augmented by 4 doses of 3 weekly Rtx (low-risk group). 3- Chemotherapy Indications: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma; Lymphoma & B-cell PTLD unresponsive to Retuxi + RI Incomplete / no response to Retuxi monotherapy –> 4 cycles of R-CHOP-21 given every 3 wks, with G-CSF support; ORR 88%; CR of 70% at end of therapy. Risk-stratified sequential therapeutic approach Rtx weekly x 4cycles –> response assessment at 2-4 weeks
good response –> 4 more doses of Rtx at 3wks interval
poor response –> R-CHOP-21 with supportive care and G-CSF Reduced Immunosuppression + Stratified Sequential Chemo-therapy is considered the standard of care for Polymorphic and Monomorphic DLBL-like PTLD (regardless to EBV status) after SOT. Selection in to poor risk group depending on presence of risk factors (type of allograft type, response to Rtx and performance status) formed the basis of PTLD-2 trial. 4- Adoptive immunotherapy Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD. GVHD can be the complication 5- Outpatient care Serial monitoring of viral load, allograft function, physical examination and imaging – to optimize balance between PTLD management and avoidance of allograft acute rejection is crucial. 6. Future strategies: newer therapeutic medications – their efficacy remains to be validated via RCT. (1) Bruton’s TKI – (Ibrutinib) – used in GVHD and allograft rejection; in DLBCL 2. A Inhibition of PI3K – Idelalisib 2. B mTORi – SRL and Everolimus – role in PTLD controversial (3) Proteasome inhibition (Bortezomib) – in early presented PTLD post allogeneic HSCT (4) Radioimmunotherapy, (90Yibritumomab, Tiuxetan) – small pilot trial (5) Checkpoint inhibitors (Pembrolizumab, nivolumab): Cytotoxic T lymphocyte associated antigen 4 pathway: recommended in clinical trials, (6) Anti-CD30 therapy (Brentuximab Vedotin) – CD30 expressed in 85% PTLD; limited clinical experience (only case reports). Re-transplantation and PTLD recurrence
· 12 to 24 mo after complete PTLD remission
· Epstein–Barr nuclear antigen IgG positivity
· Low/absent EBV viral load is recommended at the time of re-transplantation
· persistently high EBV viral load – Anti-viral therapy: Gancyclovir long-term prophylaxis · T cell-depleting agents should be excluded from induction strategies (IL-2R blocker first choice) · Triple therapy (CNI, MMF and steroids) in lowest safe dosage
2. What is the level of evidence provided by this article?
– Not levelled
incidence
SIR is 10 for non hdgkins and 4 for hodgkins lymphoma
two peaks – FIRST aroun 1 yr and SECOND at 10-15 yrs
risk factors
organ depending on amount of lymphatic tissue in it so small intestine is highes and kidney is lowest
cummulative immunosuppression(IS) level – hish risk with more IS
more with T cell depletion
pathology
EBV positice case – non germinal type B cell lymphoma
EBV neg cases of PTLD- germinal type B cell lymphoma
symptoms
asyptomatic
LN enalrgement
systemic symptoms like weight loss or fever
organ specific symptoms
mutiorgan failure
EBV monitering in transplant recipient as preemptive therapy for PTLD
more viral load increases the risk of PTLD
cell free plasma DNA EBV is best
souce of sample and cut off is not clear
prevention of PTLD
always accept EBV negative graft for EBV negative recipient
IS to be kept at lower level
CMV reactivation should also lead to reduction of IS
TREATMENT
reduction of IS – stop antimetabolites, 50% reductioon or more in CNI
reverese 20-80% of PTLD cases
assess the response in 2-4 week
EBV positive cases show more response to reduction in IS
RETUXIMAB(Rtx) BINDS TO cd20 AND LEAD TO DEPLETION OF B cell
recommanded for all three types of PTLD except hodgkin lymphoma type
25% COMPLETE RESPONSE afetr Rtx weekly 4 doses followed by 3weekly 4 doses- LOW RISK GROUP (ptld1 TRIAL)
ABOVE GROUP HAS BETTER SURVIVAL CHANCES COMAPRED TO complete remission with
Rtx followed by CHOP
CHEMOTHARPAAY
for burkits lymphoma, hodgkins lymphoma, CNS lesion , uncommon lymphoma , cases not responding to Rtx
chemo to be used with supportive care and G-CSF to prevent complications
Risk-stratified sequential therapeutic approach
Post Rtx – assess the respone
good response – 4 more doses of Rtx
poor response – RCHOP with supportive care and G-CSF
this also for the basis for PTLD-2 trial where two groups are radamised based on type of allograft , response to Rtx and performance status – level 1 eveidence
Adaptive immunotherapy
in PTLD after stem cell transplant – EBV specific cytotoxic T cell can give traansfused to generate T cell response
GVHD can be the complication
Summary
Post-transplant lymphoproliferative disorders (PTLD) develop as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells may get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The mainstay of PTLD primary management is reduction of immunosuppression (RI). A potential risk of allograft loss or graft dysfunction has to be considered particularly for vital organ transplants (e.g., heart transplant).
In adults, the incidence of PTLD has been reported to range from 0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ and intestinal TRs[9,10] (Figure 1). These figures suggest that the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors
The magnitude of increased risk of PTLD can be graded as follows: (1) HSCT (zero in patients who received cyclophosphamide for GVHD and > 20% with selective T-cell depletion); (2) Umbilical-cord transplantation (4%-5%); (3) Transplant from unrelated donors (4%-10%); and (4) Transplant from matched, related donors (1%-3%)
Considering the improving patient and allograft survival, two peaks of PTLD incidence have been observed, first peak: In the first post-transplant year (mostly EBV seropositive), and, second peak: Usually present 5-15 years after transplant (mostly EBV seronegative)
50% PTLD in SOT are not accompanied by EBV infection. Pathogenesis
For EBV-positive TRs, the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immunosurveillance. EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells. Normally, these antigens would trigger a T-cell response capable of destruction of most of the EBV-infected B cells. This immune defense mechanism has been compromised in TRs leading to unlimited Bcell transformation and the evolution of lymphoma. In PTLD in EBV-negative patients several hypotheses have been postulated e.g., CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes. EBV-positive vs EBV-negative PTLD
Further studies are warranted to recognize more precise molecular-genomic classification of both types and would help to define best therapeutic strategies, Classification
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD.
Gene-expression profile and immunohistochemical
1-germinal center” B cell (EBV-ve)
2-Non–germinal” center B cell (EBV+ve cases )
Despite wide-spread application of preemptive monitoring of peripheral-blood EBV viral load, it seems to be devoid of any diagnostic benefit Clinical feature
Pyrexia (57%)
nodal lesions (38%)
gastrointestinal manifestations (27%)
infectious mononucleosis-like syndrome (19%)
pulmonary manifestations (15%)
neurological manifestations (13%)
weight loss (9%)
allograft dysfunction
Management MDT approach
Prevention
Primarily, EBV sero-status of both donor and recipient should be recognized before donor selection.
EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
A fine-tuning the immunosuppressive burden to as low as clinically possible.
Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression.
Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function RI
Compared to EBV positive disease, the EBV negative cases are less responsive to RI
However, a complete lack of response to RI has been observed in old, aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV) Rituximab
It has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI Chemotherapy
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI Adoptive immunotherapy
A robust EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs) Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD. A variety of recent approaches e.g., adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells” and Tac-resistant, engineered CTLs has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load. Future strategies
(1) Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib)
(2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]
(3) Proteasome inhibition (Bortezomib)
(4) Radioimmunotherapy, (Yibritumomab, tiuxetan)
(5) Checkpoint inhibitors (Pembrolizumab, nivolumab)
(6) Anti-CD30 therapy (Brentuximab vedotin)
Their efficacy remains to be validated via randomized controlled trials. Re-transplantation and PTLD recurrence
one-year disease free survival is necessary after control of PTLD before re-transplantation.
ATG vs IL-2 receptor antagonists: IL2 first priority
the lowest safe dosages monitored by target trough levels should be considered.
MMF can be included safely in the immunosuppressive protocols with no more added risk.
mTOR inhibitors: Their role in PTLD development remains debatable.
Graft PTLD: Usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative.
Origin of PTLD (donor vs recipient): Identification of the tumor source is crucial for future therapeutic plans and recognition of the biology of the next PTLD.
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
INTRODUCTION
· Post-transplant lymphoproliferative disorders (PTLD) develop as a result of uncontrolled B cell proliferation due to blunted immunological surveillance.
· B cells may get infected by EBV either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure
· Lymphoma accounts for 21% of all malignancies in SOT recipients
· Clinically, PTLD may manifest either as localized lesion or as systemic disease
· The mainstay of PTLD primary management is reduction of immunosuppression (RI).
· A variety of therapeutic options include surgical clearance, anti-viral agents, local radiotherapy, intravenous immunoglobulin (IVIG), chemotherapeutic agents, monoclonal antibodies and cytotoxic T lymphocytes with variable success
Risk factors
(1) SOT: the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors
(2) Allogenic HSCT: incidence is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant
(3) Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney
(4) Oncogenic EBV
Pathogenesis
· PTLD development was attributed mainly to EBV infection, however, recent reports suggest that as many as 50% PTLD in SOT are not accompanied by EBV infection
· For EBV-positive TRs, the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immunesurveillance.
Classification: depending mainly on histopathological classification:
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD. (2) Polymorphic PTLD. (3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). And (4) classic Hodgkin’s lymphoma-like PTLD
Clinical presentation: Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Salient features: Pyrexia (57%), weight loss (9%), neurological manifestations (13%), nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant (19%)
The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands
Time to PTLD for different transplanted organs: is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR
EBV monitoring for preemptive therapy: preemptive strategies to limit the risk of PTLD development:
RI, rituximab therapy, and adoptive transfer of EBV-specified T cells.
Prophylaxis:
· EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
· Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
· monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function have been also recommended
TREATMENT OF PTLD
1-RI
· RI can reverse 20%-80% of patients with PTLD
· RI includes 50% reduction of calcineurin inhibitors doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil.
· With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered
· EBV negative cases are less responsive to RI than EBV positive disease
· A complete lack of response to RI has been observed in patients > 50 years, bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV)
2- Rituximab (Rtx) therapy
· Rtx indicated in: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
· The overall response to Rtx monotherapy in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases
3- Chemotherapy
· Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
· Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy, with overall response rate approached 88%
4- Adoptive immunotherapy
Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD
5- Outpatient care
(1) Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial. (5) Therapeutic options should be tailored as per multidisciplinary team discussion.
(6) The initial therapeutic step is RI or cessation of immunosuppression
6- Future strategies: (1) Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib) (2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]; SRL and everolimus (3) Proteasome inhibition (Bortezomib) (4) Radioimmunotherapy, (90Yibritumomab, tiuxetan) (5) Checkpoint inhibitors (Pembrolizumab, nivolumab): Cytotoxic T lymphocyteassociated antigen 4 pathway: recommended only in clinical trials. And (6) Anti-CD30 therapy (Brentuximab vedotin)
Re-transplantation and PTLD recurrence
Recommendations to limit the possibility of PTLD recurrence:
(5) Time to retransplant: Approximately two years of time should elapse after successful PTLD management
(6) EBV: The following recommendations is currently suggested in the literature: (a) TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation. (b) Low/absent EBV viral load is recommended at the time of retransplantation. (c) Close monitoring of TRs with persistently high EBV viral load is advised. (d) Anti-viral therapy
(7) Role of immunosuppression: Retransplantation after PTLD cure remains controversial due to the re-exposure of immunosuppression
(8) (4) Induction therapy: The following agents are considered:
(a) ATG vs IL-2 receptor antagonists: ATG induction significantly triggers the risk of lymphoma evolution as compared to other agents
(b) Rituximab in induction therapy: inhibit EBV proliferation within lymphocytes, consequently limiting the risk of PTLD development
(9) Maintenance immunosuppression:
(a) Triple therapy (CNI, MMF and steroids): consider lowest safe dose
(b) MMF can be included safely in the immunosuppressive protocols with no more added risk
(c) mTOR inhibitors: Their role in PTLD development remains debatable.
(d) Graft PTLD usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative
(10)Monoclonal gammopathy complete resolution is an obvious indicator of complete remission of PTLD
(11)Origin of PTLD: a better outcome in TRs with “donor” lymphomas.
CONCLUSION
· PTLD is a disease of immunosuppression
· PTLD recurrence is rare after re-transplantation and needs careful planning of immunosuppression
· Hemato-oncologist should be involved in the management of PTLD patients
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation and hematopoietic stem-cell transplant and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance.
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT. Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population. Role of EBV 50% of PTLD in post kidney transplant are EBV +ve. EBV cause abnormal b cell proliferation because of the inability of t cell to destruct the infected EBV -B cells because of the immunosuppression the EBV -ve PTLD may be explained by another viral infection like CMV or prolonged immunosuppression. PTLD is a disease of immunosuppression, with improved understanding and management. • Moleculargenomic technology has improved diagnostic and therapeutic strategies to reduce PTLD recurrence. • Rare reports of PTLD recurrence following re-transplantation necessitate cautious immunosuppressive planning.
What is the level of evidence provided by this article?
level 3
INTRODUCTION
· PTLD is a malignancy caused by uncontrolled B cell proliferation due to blunted immunological surveillance.
· B cells can be infected by EBV through post-transplant reactivation, primary EBV infection, or environmental exposure.
· PTLD is most common in the first post-transplant year, while T-cell proliferation is less common.
· PTLD is a serious disorder requiring tissue diagnosis and evidence of EBV DNA, RNA, or protein material. Epidemiology of PTLD
PTLD has been recognized in both SOT and HSCT since 1969. PTLD prevalence has increased due to better diagnostic technology, older donors, increased awareness, new immunosuppressive strategies, and HSCT.
Risk factors
Risk factors vary depending on the type of transplant organ.
1- SOT: In adults, 0.8%-2.5% in kidney transplant recipients (KTR),
• 0.5%-5.0% in pancreatic TRs,
• 1.0%-5.5% in liver TRs,
• 2.0-8.0% in heart TRs,
• 3.0-10.0% in lung TRs,
• ≤ 20% in multi-organ and intestinal TRs
2- Allogenic HSCT: PTLD incidence is related to HLA matching and T-cell depletion.
3- Immunosuppressive load exposure during primary renal illness is a risk factor for the development of PTLD.
4- Oncogenic EBV: EBV may alter cell growth via:
• Lack of immune recognition,
• Induction of the potent oncogenes
• EBV-induced proliferating cells as well as EBV variant/HLA types.
• Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA Pathogenesis Role of EBV:
Recent reports suggest that as many as 50% of PTLD in SOT are not accompanied by EBV infection
• For EBV-positive TRs, EBV can integrate into normal B-cell programs, Defenses by compromised T-cells in TRs lead to uncontrolled transformation and lymphoma.
• EBV-negative patients Pathogenesis of PTLD is less evident. Several hypotheses have been postulated like
• CMV
• Another viral infection,
• Prolonged
• Immunosuppression,
• Allograft-driven persistent antigenic triggering,
• Hit-and-run hypothesis Classification:
WHO 2017 Classification,
• Three nondestructive PTLDs: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
• Polymorphic PTLD.
• Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
• Classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure. It may present as a local or disseminated disease.
It includes :
• Pyrexia (57%)
• Weight loss (9%)
• Neurological manifestations (13%)
• Nodal lesions (38%)
• Gastrointestinal manifestations (27%)
• Pulmonary manifestations (15%).
• Infectious mononucleosis-like syndrome that could be fulminant (19%)
Differential diagnosis:
In TRs with pyrexia, pharyngitis, and cervical lymphadenopathy, should be taken into consideration.
Prophylaxis:
• In some populations that are very susceptible to developing PTLD, preemptive treatment should be taken into consideration.
• Donor and recipient EBV serostatus should be known before choosing a donor, and EBV-negative donors ideally better to be used for EBV-negative TR
• Achieving the lowest immunosuppressive load clinically feasible.
• IVIG/CytoGam injection to maintain high titers of anti-EBV antibodies is also advised.
TREATMENT OF PTLD Reduced Immunosuppression:
The reduction of the immunosuppressive load is the cornerstone of basic PTLD therapy,
Rituximab therapy
Rituximab is an effective chimeric anti-CD20 monoclonal antibody that binds to CD-antigen and causes B cell depletion through a variety of mechanisms. Chemotherapy
Indications:
• Burkitt’s lymphoma,
• Hodgkin’s lymphoma,
• Peripheral T-cell lymphoma,
• Primary CNS lymphoma and other uncommon lymphomas,
• B-cell PTLD unresponsive to Rtx and RI
Adoptive immunotherapy
EBV-specific CTLs are a potent treatment in both donor- and recipient-derived PTLD, but GVHD is the main danger.
Prognosis:
IPI is a prognostic scoring system that includes the following:
• Patient’s age,
• Performance attitude,
• Current stage,
• Lactate dehydrogenase (LDH),
• Number of extra-nodal locations.
Using univariate analysis, poor prognostic criteria have been postulated that include the following:
• Monoclonality,
• Negative EBV serology,
• Primary CNS involvement,
• Tumor originated from T-cell, performance status ≥ 2,
• Chemotherapy-based therapy (plus RI),
• Multiple involved locations
Re-transplantation and PTLD recurrence
• The feasibility of re-transplantation after successful management of PTLD has been reported, but one-year disease-free survival is necessary.
• Retransplantation after the PTLD cure remains controversial due to the re-exposure of immunosuppression.
• To limit the possibility of PTLD recurrence, the following recommendations are worth noting: Time to retransplant,
· EBV positivity,
· Low/absent EBV viral load,
· Close monitoring,
· Anti-viral therapy,
· Role of immunosuppression.
Conclusion:
• PTLD is a disease of immunosuppression, with improved understanding and management.
• Moleculargenomic technology has improved diagnostic and therapeutic strategies to reduce PTLD recurrence.
• Rare reports of PTLD recurrence following re-transplantation necessitate cautious immunosuppressive planning.
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches Introduction: PTLD are one of the most common malignancy post SOT& HSC. Immunosuppression & EBV infection are the main factors by controlled proliferation of B cells EBV infection be by reactivation of the virus post-transplant or primary via the infected graft or environmental exposure majority of PTLD(85%) developed in the 1st year. PTLD can be due to T cell proliferation this is less common & EBV negative. diagnosis based on a high level of suspicion presence of tissue histopathology & evidence of EBV DNA, RNA or protein material positivity. The incidence of lymphoma post-transplantation 21% of all malignancies in post-SOT compared to 4-5 % in immunocompetent individuals. Options of management are reduction or cessation of immunosupressions surgical intervention , antivirals IV IG, local radiotherapy monoclonal AB & cytotoxic T lymphocytes graft dysfunction has to be considered. Risk factors : – Incidnence of PTLDs is lower in PKT in comparison to others with highest for HSCT & intestine ( dgteee of immunosuppressions & amount of lymphatic tissue are key factors) – Previous exposure of immunosuppression before transplantation is a risk factor – Oncogenic effect of EBV Pathogenesis: – Role of EBV 50% of PTLD in PKT are EBV +ve. EBV cause abnormal b cell proliferation because of the inability of t cell to destruct the infected EBV -B cells because of the immunosuppression the EBV -ve PTLD may be explained by another viral infection like CMV or prolonged immunosuppression hit & run hypothesis. c/p : – Ranging from asymptomatic to fulminant multiorgan failure & may be localized or disseminated. – High level of suspicion is very important for diagnosis. – Pyrexia ,weight ,loss GIT involvement graft dysfunction & neurological manifestations, and IMN picture especially in the presence of high titre of EBV PCR is the most salient features. Prophylaxis : – EBV -ve recipients are better to receive a graft from EBV -ve donors whenever available. – Reactivation of other viruses like CMV or BK should trigger initiation of reduction of immunosuppression as viral replication might indicate overimmunosuppression . – Maintenance of high titer of anti-EBV AB by IV IG /cytoGam also is recommended. – Monitoring of viral load in a high-risk case & considering pre impetive RI with rising titer & close monitoring of graft function is also recommended. Treatment : 1- RI : – Reduction of immunosuppression by 50% reduction of CNI dose & withdrawal of antimetabolites is the mainstay of primary management. It can revere 20-80% of PTLD. Holding all immunosuppression apart from glucocorticoid should be considered in critically ill patients. – Re-evaluating of the lymphoma staging after 2-4 weeks along with graft function. – EBV +ve are more responders. – Poor response is shown in old age >50 ys, bulky lesion >7 cm & advanced stages of the disease (Ann-Arbor stage III /IV) 2-rituximab: – Monoclonal chimeric antibody against CD20, which is positive in 75% of PTLD patients. – 375 mg/m2 body surface area weekly for 4 doses + RI. 3-chemotherapy: – CHOP regimen every 3 weeks for 4 cycles. The overall response to R-CHOP reached 88%. – Indications: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI. 4- adoptive immunotherapy: Infusion of donor cytotoxic t-lymphocytes. the major risk is GVHD. 5- future strategies: Bortezomib & radioimmunotherapy. >>poor prognostic criteria are EBV negativity, primary CNS involvement, monoclonality, T-cell origin, multiple organ involvement & chemotherapy-based therapy +RI. Retransplantaion: – Re transplantation after successful management of PTLD can be done with some precautions : 1- 1-2 year disease free survival before retransplantation 2- TR should experience EBV IgG before retransplantation 3- Low or absent EBV load 4- Long term Anti-Viral therapy by ganciclovir is recommended. 5- Exclude T-cell depleting agents from induction immunosuppression, IL-2 receptor antagonists are the 1st priority. 6- Rituximab may be used as an element of desensitization regimen 7- Lowest safest doses of maintaince immunosuppresice medications with MMF can be used safely
1- One of the commonest malignancies post SOT , it happens because of uncontrolled proliferation of B-cell in reaction to poor immune response, two key factors are present; immunosuppression medications burden and infection with EBV which infect B-cells, this infection could be reactivation from or primary infection of the patient or from the donor himself, so reduction of immunosuppression is a key for management and to hold immunosuppression in some cases to save the life of the patient.
2- SIR standardized incidence ratio is the incidence of the disease in specific population (like transplant population) divided on the incidence of disease in general population.
3- Risk factors:
a- Amount of lymphatic tissue in an allograft and the degree of immunosuppression; the lowest incidence in the kidney 0.8-2.5%, and the highest in multi-organ and intestine transplantation reaches 20%.
b- Degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant; type of induction therapy is a key in the early developed PTLD, the one that develops late PTLD is determined by cumulative immunosuppressive burden, and EBV is responsible for early PTLD in the 1st year post-transplant, as well as the incidence of PTLD in pediatrics is higher because of increased risk of primary EBV infection.
c- Previous exposure to the immunosuppressive medication as a treatment of the primary renal disease in the native kidney may be not a risk factor for PTLD.
d- EBV it infects B-cells and integrate into it leads to proliferation, this may be due to blunted T-cell response, this leads to development of lymphoma, sometimes there PTLD with negative EBV , and this may be due to the degree of immunosuppression and other viruses like CMV, HHV-8, EBV positive PTLD happens in the first year post-transplant and negative EBV happens in the late post-transplant after 1 year and may be at 10 years post-transplant.
4- Classification of PTLD:
a- Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
b- Polymorphic PTLD.
c- Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
d- classic Hodgkin’s lymphoma-like PTLD
5- clinical manifestations:
a- localized or disseminated
b- rapid progressive disease
c- Pyrexia, weight loss, neurological manifestations, nodal lesions, gastrointestinal manifestations, pulmonary manifestations, and infectious mononucleosis-like syndrome that could be fulminant.
d- allograft dysfunction
e- Most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
f- High clinical suspicion with positive EBV PCR can confirm the diagnosis of PTLD.
g- Can be differentiated from other conditions based on clinical symptoms like infectious mononucleosis and streptococcal infection.
h- Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology; whereas Burkitt’s lymphoma and Hodgkin’s disease are late.
i- EBV+ve PTLD is related to three factors: Type of transplant organ, time elapsed until diagnosis of post-transplant PTLD and EBV serological status of both recipient and donor before transplant.
j- The preemptive therapy by IVIG should be considered in high-risk groups for developing PTLD. Furthermore, monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function have been also recommended.
6- Treatment of PTLD:
a- RI reduction of immunosuppression can reverse 20-80% of PTLD and the plan is reduction of CNI by 50% and holding of azathioprine/MMF and continue steroid, and of course, in life threating condition holding of all immunosuppression is highly recommended, EBV negative cases are less responsive to RI than EBV positive cases, there is a complete lack of response to RI in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease.
b- Rituximab therapy Rtx it is anti-CD20 monoclonal antibody leads to B-cell depletion, it is considered as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
c- Chemotherapy: it is recommended in Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI. It is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).
d- Adoptive immunotherapy; infusion of donor cells.
7- Prognosis; prognostic scoring system that includes the following: Patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and number of extra-nodal locations. Another scoring system has been also given in a French registry system that relies primarily upon patient’s age, serum creatinine concentration, LDH level, PTLD localization, and histopathologic criteria.
8- Re-transplantation and PTLD recurrence:
a- To limit the possibility of PTLD recurrence: 1- Time to retransplant: Approximately two years of time should elapse after successful PTLD management.
b- EBV: The following recommendations is currently suggested:
1- transplant recipient TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation.
2- Low/absent EBV viral load is recommended at the time of retransplantation.
3- Close monitoring of TRs with persistently high EBV viral load is advised.
4- Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence. Ganciclovir has been suggested for this purpose.
c- Role of immunosuppression: Retransplantation after PTLD cure remains controversial due to the re-exposure of immunosuppression.
d- Induction therapy:
1- ATG (antibody depleting agents) should be avoided, and basiliximab is recommended.
2- Rituximab as induction therapy may be used as desensitization agent in high risk patient.
e- Maintenance immunosuppression:
1- Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered.
2- mTOR inhibitors: Their role in PTLD development remains debatable.
3- graft nephrectomy is curative in graft PTLD.
f- Monoclonal gammopathy: monoclonal gammopathy may indicate incompletely remitted PTLD, its complete resolution is an obvious indicator of complete remission.
g- Origin of PTLD (donor vs recipient):
Please summarize this article Post-transplantation Lyphoproliferative disorder is complication of uncontrolled B cell proliferation due to irregularities in immune system secondary to immunosuppression drugs and post- transplant viral reactivation. Usually those secondary to EBV infection related PTLD, they present in first year after transplantation. According to this article post SOT this accounts around 21% all cancers, with significant cancer related mortality. However, it has association with age, type of immunosuppression, dose, and duration. Although, the renal transplant having the lowest incident, while the intestinal transplant has highest incidence up-to 20%.
Epidemiology of PTLD; PTLD was described initially in 1969 by Penn et al. Since then it was observed in both SOT and HSCT both. The good thing is better diagnostic technology, newer approaches in treatment and awareness of this disorder. The reported incidence of PTLD in HSCT recipient is around 3.2% in multicenter studies.
Risk factors; The key factors are lymphatic tissue in allograft, EBV infection and reactivation, positive donor and negative recipient, Burden and duration of immunosuppression, And also type of graft, the most common association with intestinal transplantation and very rarely with renal transplantation that is 0.8% to 2.5%. Impaired immune surveillance would be a explanation for infection associated malignancy, while role of immunosuppression, its duration, dosages, varies with different immunosuppression. The data shows the seronegative recipient for EBV associated PTLD are more vulnerable to develop PTLD 10-75%. Prevalence of PTLD is more in children population.
Pathogenesis; EBV infects the B-cells and become dormant form, when there is depressed immune system there is reactivation and leading abnormal proliferation and transformation of B-cell and different type’s malignancies. There are other associated viral infection can cause proliferation of clones of B-cells like EBV infection. Other hypothesis like hit and run hypothesis, graft driven persistent antigenic triggering, prolonged immunosuppression.
Classification; Classification depends on early and late onset PTLD. WHO 2017 classification is categories mainly based on histopathological classification that is gene- expression profile and immunohistochemical staining. 1. Nondestructive PTLD, 2. Polymorphic PTLD, 3. Monomorphic PTLD, and 4. Classic Hodgkin lymphoma like PTLD.
Treatment; Reduction of immunosuppression, cyclosporine up-to 50%, stop antimetabolites. If no response switch to rituximab ( a monoclonal antibody CD20 inhibitors, Second line chemotherapy not responding to rituximab like CHOP. For refractory disease Adaptive immunotherapy, Radiotherapy, Antiviral treatment, Supportive care.
Future strategies; . Protease inhibitor, . Inhibition of PI3K and mTORi, . Radio immunotherapy, . Checkpoint inhibitors, . Anti-CD30 inhibitors. Prognosis; The current advances in awareness in treatment has improved the survival disease free and has decreased mortality. The patients who has achieved remission the median survival is approximately 6.6 years. CD20 positive PTLD has poor prognosis. Using different scoring system like IPI, PTLD-I, II and others postulated the poor prognostic factors like native for EBV-associated PTLD, monoclonality, primary CNS involvement, T-cell associated origin, performance status >2, extended disease, need of second line chemotherapy.
Retransplantation; Re-transplantation with all consideration carries a good response and low risk of PTLD recurrence if EBV IgG positive and prophylactic antiviral therapy. Can be considered if in remission and no disease after two years of treatment. EBV virus load should be monitored, and prophylactic antiviral should be started. Induction in second transplantation should not be done with ATG. Immunosuppression should be with lowest dosages.
Two main risk factors of PTLD are: Firstly, the cumulative immunosuppressive burden, and secondly, the oncogenic impact of the Epstein-Barr virus. The latter is a key pathognomonic driver of PTLD evolution.
The treatment of PTLD includes reduction of immunosuppression, rituximab therapy, either isolated or in combination with other chemotherapeutic agents, adoptive therapy, surgical intervention, antiviral therapy and radiotherapy.
The key step in the management of PTLD is to reduce the immunosuppressive load.
B cells may get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year.
Clinically, PTLD may manifest either as localized lesion or as systemic disease.
Tissue diagnosis (histopathology) is crucial for PTLD diagnosis, in addition to a clear evidence of EBV DNA, RNA, or protein material.
The mainstay of PTLD primary management is reduction of immunosuppression (RI). Complete cessation of the immunosuppressive drugs may be necessary to stop the disease progression.
The increased risk is expressed as “standardized incidence ratios” (SIRs) i.e., the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort).
a reported incidence of PTLD in 3.2% of HSCT recipients has been observed in multicenter studies.
(1) SOT: In adults, the incidence of PTLD has been reported to range from 0.8%-2.5% in kidney transplant recipients (KTR)
(2) Allogenic HSCT: PTLD incidence is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant.
The role of immunosuppressive agents is less clear due to variability in timing, duration, and dosage in different immunosuppressive strategies.
A number of PTLDs in allogeneic HSCT are donor-driven (EBV-infected lymphocytes) and are usually observed in 1 st post-transplant year, with almost 100% being EBV positive.
Compared to EBV seropositive TRs, the seronegative patients in SOT are more vulnerable to develop PTLD with an increased estimated risk of 10-75
Considering the improving patient and allograft survival, two peaks of PTLD incidence have been observed, first peak: In the first post-transplant year (mostly EBV seropositive), and, second peak: Usually present 5-15 years after transplant (mostly EBV seronegative).
previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution.
Oncogenic EBV: EBV may alter cell growth via several mechanisms: (1) With lack of immune recognition, EBV may induce highly regulated growth transformation with expression of all of its growth inducing proteins. (2) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors. (3) EBV induced proliferating cells as well as EBV variant/HLA types combination may permit these proteins to by-pass immune control and go unrecognized. And (4) Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA
Pathogenesis
Role of EBV: For decades, PTLD development was attributed mainly to EBV infection, however, recent reports suggest that as many as 50% PTLD in SOT are not accompanied by EBV infection
EBV monitoring for preemptive therapy: The risk of EBV+ve PTLD has been postulated to be related to three factors: Type of transplant organ, time elapsed until diagnosis of post-transplant PTLD and EBV serological status of both recipient and donor before transplant
Compared to the reliability of EBV DNA via peripheral-blood mononuclear cells, the “cell-free plasma EBV DNA” has been reported as a better marker of EBV activity
Primarily, EBV sero-status of both donor and recipient should be recognized before donor selection
Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered. Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
RI can reverse 20%-80% of patients with PTLD.
RI plan includes 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF), despite the lack of evidence demonstrating any relation between MMF and PTLD development . With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
Compared to EBV positive disease, the EBV negative cases are less responsive to RI
However, a complete lack of response to RI has been observed in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV
However, Rtx has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. The overall response to Rtx monotherapy (375 mg/m 2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases.
. Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5%. In the PTLD-1 trial (prospective, multicenter trial including post-SOT PTLD), the complete remission rate approached 25% after standard induction augmented by another four doses of 3 weekly Rtx (low-risk patients).
The complete response can be interpreted as three associated benefits: Better overall survival, extended time to progression, and better progression-free survival.
Furthermore, in comparison with the group of TRs with complete remission with Rtx followed by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), the low-risk group in the cohort receiving risk-stratified sequential expressed longer disease-free survival at 3 year, despite no change in overall survival.
More recent prospective trial PTLD-2 is registering TRs with the “risk stratification” based on the following parameters: Type of the allograft, response to Rtx therapy, and international prognostic index (IPI) scoring
Chemotherapy
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
In all CD20+ve subtypes (75% or more), Rtx should be included.
Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells. This situation is in contrast to PTLD developing in TRs of SOT
summarize
Reduction of immunosuppression is the cornerstone of PTLD management. Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and, monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. Chemotherapy is indicated for: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI with variable results. However, “risk-stratified sequential” therapeutic approach seems to be promising. Other modalities may include adoptive immunotherapy and outpatient care. Investigational agents that’re currently under trials have been shown above.
III. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Please summarise this article
INTRODUCTION
Post-transplant lymphoproliferative disorders (PTLD), are malignancies occurring post solid organ transplantation (SOT) or hematopoietic stem cell transplant (HSCT). Lymphomas account for 20% of all cancers in SOT patients as compared to 4-5% among immunocompetent individuals.
PTLD develops as a consequence of blunted immunological surveillance resulting in uncontrolled B cell proliferation. The B cells get infected by EBV either by post-transplant viral reactivation or primary EBV infection through the donated organ or through environmental exposure. Most cases occur within the first-year post-transplant. PTLD due to abnormal T cell proliferation is less common and is mostly EBV-negative. PTLD can present as either a localized lesion or as a systemic disease. In addition to EBV DNA, RNA and protein material, tissue diagnosis is key in the diagnosis of PTLD.
The cumulative immunosuppressive burden plays a key role in PTLD. The mainstay of treatment is reduction in immunosuppression (RIS) although this comes with a potential risk graft or dysfunction or loss. Complete cessation of immunosuppressive medication can be attempted with an aim to stop disease progression.
Other treatment modalities include: – surgical intervention, local radiotherapy, antiviral therapy, chemotherapeutic agents, intravenous immunoglobulin (IVIG), monoclonal antibodies, cytotoxic T lymphocytes (CTLs). Combined therapies offer better outcomes compared to monotherapy.
Epidemiology of PTLD
There has been an increase in the incidence of PTLD in both SOT and HSCT patients since 1969 when the first 5 cases of PTLD were reported.
Risk factors
– type of organ transplanted – incidence of PTLD is lowest among kidney transplant recipients and highest in multi-organ and intestinal transplant recipients
– degree of HLA matching
– use of T-cell depleting induction strategies
– cumulative immunosuppressive burden
– donor type i.e., donor-driven EBV-infected lymphocytes
– EBV seronegative transplant recipients
– prior exposure to immunosuppression in the management of the primary kidney disease
– oncogenic EBV
Pathogenesis
Immunosuppressive-induced decline in T-cell immune-surveillance results in development of PTLD among EBV-positive transplant recipients. EBV infects the B cells leading to abnormal proliferation and transformation of the B cells and evolution into a lymphoma.
Several hypotheses have been suggested among EBV-negative transplant recipients i.e., CMV or other viral infections, prolonged immunosuppression, hit-and-run hypothesis, graft-driven persistent antigenic triggering. T-cell subtype PTLD is usually EBV-negative whereas B-cell subtype is EBV-positive.
Classification
– Early and late onset PTLD
· Early PTLD is often associated with EBV positivity, graft involvement, less often extra-nodal disease, non-destructive PTLD, less often monomorphic subtype, higher prevalence
· Late onset PTLD is associated with EBV negative tumors, less graft involvement, extra-nodal disease, high incidence of late onset Hodgkin’s after allogeneic HSCT, elevated LDH levels, lower prevalence
The patients can be asymptomatic or have non-specific symptoms but can also present with sudden, severe symptoms with multi-organ failure.
Salient features
– PTLD can present as a local or disseminated disease, which can be aggressive and rapidly progressive
– Pyrexia, nodal lesions, gastrointestinal symptoms, fulminant infectious mononucleosis-like syndrome, pulmonary manifestations, neurological symptoms, weight loss
– Graft dysfunction
– Common locations of PTLD involvement include: – lymph nodes, GIT, liver, lung, CNS, bone marrow, kidney, spleen, tonsils, salivary glands
Longest in heart transplant recipients and shortest among lung and heart/ lung paediatric transplant recipients.
Early PTLD is of diffuse large B-cell or other B-cell lymphomas histology, on the other hand, Burkitt’s lymphoma and Hodgkin’s disease are associated with late PTLD.
EBV monitoring for preemptive therapy
Factors associated with the risk of EBV-positive PTLD: –
– Type of organ transplanted
– Time elapsed until diagnosis of post-transplant PTLD
– Donor and recipient pre-transplant EBV serological status
Estimation EBV viral load via PCR amplification of peripheral blood EBV DNA is essential in monitoring preemptive PTLD therapy. High viral loads are associated with increased risk for PTLD evolution.
Drawbacks in this preemptive monitoring strategies: –
– Unclear cut-off values
– Sources of samples are not universal
– Absence of set standard points of time to perform the monitoring
Preemptive strategies put into place to limit the risk of development of PTLD in SOT and HSCT recipients include: –
– Reduction in immunosuppression
– Rituximab therapy
– Adoptive immunotherapy i.e., adoptive transfer of EBV-specific T cells
Prophylaxis
Determine the pre-transplant EBV status of the donor and recipient. An EBV-negative transplant recipient should receive a graft from EBV-negative donors.
Adjust the immunosuppressive burden to the lowest possible and safe level
Reactivation of other viruses e.g., CMV, BKV indicates over-immunosuppression and should prompt a reduction in the immunosuppression dose
Preemptive/ prophylactic antiviral therapy should be offered to high-risk patients
Maintain high titers of anti-EBV antibodies via administration of IVIG/ CytoGam
Monitor EBV viral load in high-risk patients, if rising titers are noted then consider preemptive reduction in immunosuppression and close monitoring of the graft function
TREATMENT OF PTLD
· Reduction of immunosuppression (RI)
RI helps restore EBV-specific cellular immunity without any additional risk of acute rejection
RI strategies involve 50% reduction in CNI doses in addition to withdrawal of antimetabolites.
In critically ill cases, withdrawal of all immunosuppressive drugs except corticosteroids can be considered.
Due to the early response to RI, PTLD patients should be reassessed within 2-4 weeks.
Graft function should be monitored so as to recognize any signs of early rejection.
EBV-negative cases are less responsive to RI when compared to EBV-positive disease.
Risk factors associated with complete lack of response to RI: –
o Old age (>50 years)
o Bulky lesions (>7cm)
o Advanced disease (Ann Arbor stage III/ IV)
· Rituximab therapy
Rituximab is indicated as a standard therapeutic agent in the following types of PTLD: –
o Non-destructive PTLD
o Polymorphic PTLD
o Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI
Rituximab is given weekly for 4 weeks in addition to RI. An additional four does of 3 weekly rituximab can be given to patients who fail to achieve complete remission.
· Chemotherapy
Indications for immunochemotherapy include: –
o Burkitt’s lymphoma
o Hodgkin’s lymphoma
o Peripheral T-cell lymphoma
o Primary CNS lymphoma
o Other uncommon lymphomas
o B-cell PTLD unresponsive to rituximab and RI
RI should be considered in view of the immunosuppressive effect of chemotherapeutic agents and their toxicity.
Ritxumab should be included in all CD20+ subtypes.
Proper supportive care and G-CSF administration has improved the outcomes in chemotherapy treated patients.
Chemotherapy treatment options include: –
o Weekly rituximab for 4 weeks followed by CHOP every 3 weeks and G-CSF support
o Four cycles of R-CHOP given every 3 weeks with G-CSF support for patients who do not respond to rituximab monotherapy i.e., risk-stratified sequential therapeutic approach
RI and risk-stratified sequential therapy are considered as the standard of care for polymorphic and monomorphic diffuse large B-cell lymphoma-like PTLD post-SOT regardless of EBV status.
· Adoptive immunotherapy
This therapy involves infusion of donor lymphocytes to manage PTLD that is primarily originating from donor cells post-HSCT. On the other hand, in SOT recipients, the EBV-specific immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs). Expanded EBV-specific CTLs can be used in both autologous (recipient-derived PTLD) and donor-derived PTLD. Engineered CTLs can be used with no need to reduce the immunosuppressive burden. GVHD is the major risk associated with adoptive immunotherapy.
Outpatient care
– Weekly monitoring of EBV viral titers should be done in high-risk cases.
– Initial monthly monitoring then 3-monthly monitoring for low-risk patients.
– A viral drop indicates response to therapy while persistently high or continuous rise in viral load denotes disease development or progression.
– Serial physical examination, radiological assessment and graft function monitoring should also be carried out.
– Aim at a favorable balance between avoidance of rejection and management of PTLD.
– Multidisciplinary team should be engaged to tailor a regimen for the patients
Future strategies
The efficacy of these strategies is yet to be validated via RCTs.
o Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib)
o Inhibition of PI3K (Idelalisib) and mTORi (sirolimus, everolimus)
o Proteosome inhibition (Bortezomib)
o Radioimmunotherapy (90Yibritumomab, tiuxetan)
o Checkpoint inhibitors (Pembrolizumab, nivolumab)
o Anti-CD30 therapy (Brentuximab vedotin)
Summary
Reduction of immunosuppression is the mainstay of treatment in PTLD
Indications for rituximab: –
· Non-destructive PTLD, Polymorphic PTLD and Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI
Indications for chemotherapy: –
· Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and B-cell PTLD not responding to Rituximab/ RI
Risk-stratified sequential therapeutic approach seems to be gaining favor.
Other therapeutic options include adoptive immunotherapy.
Prognosis
Better supportive care and presence of new lymphoma-specific protocols has greatly improved the outcomes among PTLD patients.
Various prognostic scoring systems have been used to assess patient’s prognostic attitude in aggressive lymphoma.
Indicators of poor prognosis include: –
A period of one-year disease free survival is necessary after control of PTLD before considering re-transplantation.
Measures to reduce the possibility of PTLD recurrence – the following should be considered: –
– Allow 2 years to elapse after successful PTLD management before re-transplanting.
– Aim for a low/ absent EBV viral load at the time of re-transplantation.
– The transplant recipient should have EBV nuclear antigen IgG positivity – an anti-EBV marker of robust cytotoxic response.
– Close monitoring of transplant recipients with high EBV viral load
– Offer long-term prophylactic antiviral therapy (e.g., Ganciclovir) and serial EBV viral load checks to reduce incidence of PTLD recurrence.
– RI/ withdrawal has been the standard in management of PTLD.
– Avoid ATG-based induction regimens since ATG has been shown to trigger the risk of lymphoma evolution.
– Rituximab can be used to inhibit EBV proliferation within the lymphocytes hence limiting development of PTLD.
– Avoid intense maintenance immunosuppression to allow recovery of the immune system and promote evolution of the anti-EBV cytotoxic lymphocyte which will in turn impair EBV-triggered B-cell proliferation. Use the lowest safe dosages and monitor the trough levels. MMF does not seem to have any added risk in regard to PTLD evolution. Role of mTORi in PTLD remains debatable.
What is the level of evidence provided by this article?
Level V – narrative article
PTLD;CURRENT CONCEPTS AND FUTURE THERAPEUTIC STRATEGIES
INTRODUCTION; PTLD is common post transplant and results from uncontrolled B cell proliferation from low immunity post transplant.B Cell +VE PTLD occurs in 1st year post transplant while B Cell -VE later.
PTLD has varied presentations either locally or systemically.
Mainstay tx is RI which has to be balanced to avert graft dysfunction.Other treatment options include ; SX,antiviral medications,DXT,IVIG,Chemo & Monoclonal abs
EPIDEMIOLOGY. SIRS of 10 (NHL) and 4 % among SOT compared to 3.2% in HSCT recipients have been reported.
RISK FACTORS. 1.SOT -Amount of lymphatic tissue in allograft (0.8-2.5% in KTR and less than 20% in multiorgan and intestinal TR) -Degree of immunosuppression.
2.Allogeneic HSCT. -Level of HLA matching with addition of T cell depleting agents before transplant e.g In HSCT – 0 in those who had CYC for GVHD and more than 20% with T cell depletion. -Seronegative patients in SOT > seropositive pts in SOT in getting PTLD,this explains why more paediatrics than adults get PTLD. -1ST peak -1 yr post transplant ; EBV +VE. -2ND pEAK- 5-15 yrs post transplant ; EBV -VE.
3.Previous exposure to immunosuppressive meds for primary underlying kidney diseas is a risk factor for dev of PTLD.
4.Oncogenic EBV. -EBV that’s oncogenic is not recognized by the immune system and thus leads to unregulated proliferation of growth inducing proteins. -This also stimulates potent oncogenes;LMP1& LMP2. -They also induce proliferation of cell + EBV +VE variant/HLA types that will stimulate malignant transformation.
PATHOGENESIS.
-In EBV +VE TR,PTLD is secondary to immunosuppressive meds that impair T cell immune syaytem allowing the EBV infected B cells to proliferate unchecked and be malignant. -For EBV -VE TR,pathogenesis is unclear but other factors e.g CMV,prolonged immunosuppressive meds may lead to PTLD development.
EBV +VE vs EBV -VE PTLD. -EBV +VE PTLD is mostly B cell,more common in 1st 1 yr post transplant and has less risk of PTLD while EBV -VE PTLD is mostly common in the 2nd peak,5-15 yrs post transplant,is mostly T cell and has more risk of developing PTLD -The clinical consequences of this distinction is not clear.
CLASSIFICATION;WHO 2017
-Non destructive PTLD-Plasmacytic hyperplasia,follicular hyperplasia and infectious mononucleosis like PTLD. -Polymorphic PTLD. -Monomorphic PTLD. -Classic HL like PTLD. -EBV +VE cases are mostly non germinal centre B cell types while EBV -VE cases are mostly germinal centre B cell types.
CLINICAL PRESENTATION.
-Local or disseminated. -Pyrexia,wt loss,CNS symptoms,nodal lesions,GI manifestations,Pulmonary manifestations and infectious mononucleosis like syndrome. -Common location ; LN,liver,pulmonary,renal,bone marrow,GI tract,spleen,CNS & Salivary glands.
DDX
-Strep infection. -Infectious mononucleosis.
Time to PTLD for transplanted organs.
-Longest in cardiac recipients. -Shortest;Pulmonary and cardiac in paediatric TR. -Early PTLD ; DLBC or other B cell lymphoma. -Late PTLD;Burkitts,HL.
EBV Monitoring for preemptive therapy;
-VL monitoring via PCR – TR with PTLD has increased EBV VL compared to PTLD free TR.The downside of VL monitoring is lack of clear cut off values,lack of universal source of samples and finally lack of standard points of time to monitor. -Cell free plasma EBV DNA is a better marker of EBV activity.
Prophylaxis;
-EBV -VE TR should, when possible get donations from EBV -VE donor. -Immunosuppressive meds should be kept at the lowest possible dose to maintain graft function. -RI should be done once CMV and BK have been detected. -Prophylactic meds should be administered to those at highest risk of PTLD. -Monitor viral loads in those at highest risk of PTLD. -Pre-emptive RI should be done with increasing titres and graft function monitored.
TREATMENT. 1.RI
-This is the mainstay treatment aimed at restoring immunity against EBV.It involves; > 50% CNI reduction + withdrawal of anti metabolites.In critically ill,all immunosuppressive medication with exception of steroids are withdrawn. -With RI graft function is monitored and pt restaged every 2-4 weeks. -Pts predisposed to no response to RI ; >50 yrs,bulky lesions > 7cm and those with Ann Arbor stage ¾
2.RITUXIMAB.
-This is a CD 20 Monoclonal antibody that acts by depleting B cells in treating PTLD. -Used in; >Non destructive PTLD. >Polymorphic PTLD. >Monomorphic PTLD. -Given as 375 mg/m2 weekly for 4 weeks with upto 20-55% CR being recorded.When combined with RI,It gives better results – 34-60.5% CR -Addition of another 4 doses of RTX increases CR by upto 25% -R – CHOP is associated with a longer disease free survival at 3 yrs.
3.CHEMOTHERAPY.
INDICATIONS; a.Burkitts lymphoma. b.HL. c.Peripheral T cell lymphoma. d.Primary CNS lymphoma. e.B Cell PTLD not responsive to RTX + RI. f.Rare lymphoma. -In all CD 20+VE subtypes RTX should be added on treatment. -Addition of G CSF decreases infection rate and mortality in those on chemotherapy.Anti PCP therapy should be considered on those on chemo.
4.ADOPTIVE IMMUNOTHERAPY.
-Despite GVHD ,donor lymphocyte infusion has shown good results in PTLD in HSCT pts and not PTLD in TRs of SOT. -Expanded EBV specific CTL have shown good results in autologous (Recipient + donor derived)PTLD.
5.OUTPATIENT CARE.
-Weekly monitoring of EBV VL in at high risk patients,monthly and later 3 monthly in at low risk pts. -Persistent high titres or rising VL indicate aggressive or progressive dx. -Serial PE,Imaging and monitoring of graft function. -Balance PTLD tx and graft function to avoid rejection. -MDT directed therapeutic options. -Stepwise approach;RI/cessation of immunosuppressive meds and then individual pt directed therapeutic options.
-Poor prognostic factors ; Hypoalbuminemia,monoclonality,EBV -VE,primary CNS Involvement,T cell tumor, ECOG>2, and more than x1 involved location.
RETRANSPLANT AFTER PTLD RECURRENCE.
-1yr needed of disease free state before it is considered. -Atleast 2 yrs should lapse before transplant after successful PTLD tx. -Prolonged antiviral prophylaxis with serial EBV viral markers needed to reduce incidence of recurrence. -RTX and IL2R antagonists can be considered as part of retransplant induction meds to decrease PTLD development. -Lowest safest doses of immunosuppressive meds should be given to decrease risk of PTLD.
1. Please summarise this article
This narrative review published in the World Journal of Transplantation in 2020 provides a broad overview of our current understanding of post-transplantation lymphoproliferative disorders (PTLD). The key messages are outlined below:
When do transplant recipients develop PTLD?
Solid organ transplant recipients, or patients who have undergone hematopoietic stem-cell transplant are at significantly increased risk of developing a lymphoproliferative disorder compared to the general population. The authors highlight the majority of PTLD cases are linked to abnormal B cell proliferation, with Epstein-Barr virus (EBV) infection playing a key role in the aetiology. The source of EBV infection may come from either post-transplant viral reactivation or primary infection (donor organ or environmental exposure). There is a spike in the incidence of such cases in the first year after transplantation, when exposure to potent immunosuppression (with its impact on immunological surveillance) is at its peak. Meanwhile, cases of PTLD driven by T cell proliferation rather than abnormal B cell proliferation tend to be associated with the absence of detectable EBV infection but are a much rarer phenomenon and more likely to occur later in the post-transplantation course.
Peaks in incidence of PTLD
1. First 1 year after transplantation
EBV infection plays a key role in aetiology of many of these cases
2. 5-15 years after transplantation
Patients may be EBV seronegative in such cases
3. Late PTLD >20 years after transplantation
Increasing number of cases- possibly relating to increased recipient age/survival +/- cumulative immunosuppression burden What are the risk factors for developing PTLD?
Analysis of standardised incidence ratios (SIRS) reveals that transplant recipients have a 10 and 4 times greater risk of developing Non-Hodgkin’s lymphoma and Hodgkin’s lymphoma respectively, compared to the general population.
The authors summarise the main risk factors which can predispose organ transplant recipients to PTLD:
· Type of organ (with possible link to lymphatic tissue burden from donor organ and intensity of immunosuppression protocol required). Multi-organ and intestinal transplants infer a significantly higher risk than pancreas and kidney transplants
· Impaired immune surveillance as a direct consequence of potent immunosuppression places patients at higher risk of infection-related malignancies. This is particularly relevant to patients who may be EBV seronegative at the time of transplantation, such as paediatric recipients
· Previous exposure to immunosuppressive treatments e.g. renal transplant recipients who previously received potent immunosuppression to treat the primary disease affecting their native kidneys
· Epstein-Barr virus (EBV) infection plays a key role in the aetiology of many cases of PTLD including via the induction of potent oncogenes such as LMP1 and LMP2 which may be present in the donor organ alongside other pathways for triggering abnormal cell proliferation. It is imperative to ascertain donor and recipient EBV sero-status prior to transplantation
The authors acknowledge the 2017 World Health Organisation (WHO) classification according to histopathology, and describe the trends in EBV infection in such cases
Non-destructive PTLD
– Plasmacytic hyperplasia
– Florid follicular hyperplasia
– Infectious-mononucleosis-like
Almost 100% of cases associated with detectable current EBV infection
Polymorphic PTLD
>90% cases associated with detectable current EBV infection
Monomorphic PTLD
– B cell type
– T cell type
– Natural Killer cell type
50% cases associated with detectable current EBV infection
Hodgkin’s lymphoma-like PTLD
>90% cases associated with detectable current EBV infection
How might a patient with PTLD present clinically?
The key message here is that, in the context of increased risk in this specific population, clinicians should remain vigilant and have a low threshold for investigating for potential PTLD. PTLD may affect one or multiple organs, and may or may not be associated with impaired allograft function depending on the particular organ involvement. The disease may be localised or disseminated but local disease does not infer more benign disease and either form may be rapidly progressive.
Key symptoms may include:
· Fever (commonest)
· Loss of energy
· Weight loss
· Lymphadenopathy
· Change in bowel habit
· Neurological symptoms including change in behaviour or seizures
What are the current treatment strategies for PTLD?
The authors summarise the current treatment approaches for PTLD.
1. Reduction in immunosuppression (RI)
This is the first and most important step.
Usually includes 50% reduction of calcineurin inhibitor and withdrawal of antimetabolite (azathioprine, MMF)
This approach is likely to produce the best results in EBV-positive disease
Careful monitoring for any signs of acute rejection is warranted
In some cases, RI alone may be an effective treatment
2. Rituximab
Rituximab is an anti-CD20 monoclonal antibody leading to B cell depletion
Can be used for:
1. non-destructive PTLD
2. polymorphic PTLD
3. monomorphic diffuse large B-cell lymphoma-like PTLD with incomplete response to RI
Often given as an infusion on a weekly basis for 4 weeks (induction) +/- further less frequent doses
3. Chemotherapy
Can be used for:
1. Burkitt’s lymphoma
2. Hodgkin’s lymphoma
3. Peripheral T cell lymphoma
4. Primary CNS lymphoma
5. B-cell PTLD not responding to above steps
Outcomes have improved following recognition of the need for GCSF administration and PJP prophylaxis
4. Adoptive immunotherapy
Has been shown to be of benefit in hematopoietic stem-cell transplant recipients where donor lymphocytes are infused which are programmed to facilitate an adequate response to EBV
What might be the future treatment options for PTLD?
At the conclusion to this review paper the authors briefly touch upon emerging treatments which are yet to undergo robust randomised controlled trials but which may form part of our future treatments
1. Bruton’s tyrosine kinase inhibition
2. Inhibition of PI3K and mTORi
3. Proteasome inhibitors
4. Radioimmunotherapy
5. checkpoint inhibitors
6. Anti-CD30 therapy
Can patients be re-transplanted after PTLD
The authors discuss the important question regarding whether a patient may be re-transplanted following PTLD. They highlight that this is possible but must be given very careful consideration, especially in light of the re-exposure to immunosuppression which will be required. The timing of any potential further transplant is crucial: it is imperative the patient has at least 1 year disease-free survival following successful treatment of their PTLD, although many clinicians will advise waiting 2 years before the patient receives another transplant. The recipient should also have: EBV IgG antigen positivity beforehand, a low/absent EBV viral load at the time of re-transplantation, close monitoring of those with higher EBV viral load and long-term prophylaxis (Ganciclovir).
2. What is the level of evidence provided by this article?
This article is a narrative review rather than systematic review. It provides a good summary of the topic but is a lower level of evidence than a systematic review as the search methods/decisions to include/exclude papers are not explicit and therefore may be more prone to bias. The review in itself is detailed with 104 references but one cannot ascertain how comprehensive this is. In addition, the topic is broad rather than specific- this has the advantage of providing the reader with a good opportunity to understand key concepts for this large topic but is likely to be at the expense of finer details (e.g. specific exploration of trials within areas of this topic).
Introduction:
PTLD is common and account 21% from cancer post transplant and main cause are immunosuppressive therapy and reactivation of infection mainly EBV and treatment by reducing immunosuppressive therapy or stop immunosuppressive drug ti prevent progression of cancer.
Epidemiology of PTLD:
Prevalence of PTLD disease increase because increase awareness to PTLD disorders especially in increase new advent of immunosuppressive therapy and old age of donor and recipient and new diagnostic modalities to detect PTLD.
Risk factors:
Solid organ transplant
HSCT
Oncogenic of EBV
Previous exposure to immunosuppressive agents in treatment of primary kidney disease.
Clinical picture:
It’s varying from symptomless to fulminating multi organ damage
Main features is low grade fever, weight loss, neurological manifestations and nodal lesions gastrointestinal manifestations, pulmonary manifestations, and infectious mononucleosis-like syndrome and allograft dysfunction may ensue due to graft involvement. PTLD is associated high EBV viral load by PCR.
The most common locations of PTLD involvement are Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract, spleen, central nervous system, tonsils and salivary glands.
Differential diagnosis:
Presence of fever/ pharyngitis and lymphadenopathy should be role out PTLD
IMM
Streptococcal infection.
Time of PTLD in transplant patients :
Early PTLD is always B cell lymphoma
Late is associated with Burkitt’s lymphoma and Hodgkin’s disease.
Treatment of PTLD:
Reduce calcinurine inhibitors to half and stop azathioprine and MMF
Continuous steroid dose
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen against B cell.
Chemotherapy
Indication of chemotherapy is Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and B-cell PTLD unresponsive to Rituximab.
Adaptive immunotherapy:
Infusion of donor lymphocytes is mainly to manage PTLD in HSCT patients which primarily originating from donor cells. However there is risk of GVHD.
Prognosis:
Outcome of PTLD patients has been improved due to advent of new lymphoma-specific protocols and better supportive care.
Compete remission reach to 70%. with average survival rate is 6.6 years.
What is the level of evidence provided by this article?
Introduction:
PTLD develops as a result of uncontrolled B cell proliferation due to a blunted immunologic surveillance. B cells may get infected by EBV by post viral reactivation or through the donated organ or via environmental exposure. It is most commonly observed during the first year after transplantation. It accounts for 21% of all malignancies in SOT recipients, and 4% in immunocompetent patients. The mainstay of management is RIS, and there are various other treatment modalities including surgical clearance, anti-viral agents, local radiotherapy, IVIG, chemotherapy, monoclonal antibodies and cytotoxic T lymphocytes. These have shown varying amounts of success, and usually work better when in combination.
Epidemiology and Risk Factors
In SOT recipients, the incidence of PTLD ranges from 0.8 to 10% depending on the organ transplanted. The risk is highest in multi organ transplant and intestinal transplant and lowest for kidney transplant
The risk factors of PTLD in allogenic HSCT included a higher risk in umbilical-cord transplantation and transplant from unrelated donors compared to transplant from related donors.
Recent reports suggest that approximately 50% of PTLD may be accompanied by EBV infection. This may be due to immunosuppressive-induced decline in the T-cell immune surveillance.
The other risk factors include:
Age: Incidence is highest in the pediatric population
Cumulative immunosuppressive exposure
Classification
The classification of PTLD can be categorized according to the WHO 2017 classification, as follows:
Clinical Presentation
PTLD presents in many forms. It may present as lesions with no symptoms to fulminating disease with multi-organ failure. It may present as a local or disseminated disease. Patients may present with pyrexia, weight loss, neurological manifestations, nodal lesions, gastrointestinal manifestations, pulmonary manifestations and infectious mononucleosis-like syndrome.
Treatment
Reducing the immunosuppression in the mainstay of PTLD management. It involves reducing CNIs by 50% and withdrawal of antimetabolites (e.g. azathioprine and MMF). The patients need to be restaged in 2-4 weeks and the allograft function needs to be monitored. Lack of response to immune suppression reduction has been noted in older patients, patients with bulky lesions and advanced stages of the disease.
Rituximab is a monoclonal antibody that binds to CD 20 antigen leading to B cell depletion. Rituximab has been approved as a standard therapeutic agent, for PTLD, for three types as per the WHO classification mentioned previously:
Non-destructive PTLD
Polymorphic PTLD
Monomorphic diffuse large B-cell lymphoma-like PTLD, not responding to decreased immune suppression.
It has been shown that rituximab, followed by chemotherapy (CHOP) has a longer disease-free survival at 3 years.
Infusion of donor lymphocytes, to achieve adoptive immunity, has been shown to manage PTLD in NSCT patients that is originally from donor cells. However, this treatment modality has a risk of GVHD development.
Summary
The main management involves the reduction of immune suppression. Rituximab treatment is indicated in non-destructive PTLD, polymorphic PTLD and monomorphic diffuse large B-cell lymphoma-like PTLD, not responding to decreased immune suppression. Chemotherapy is indicated for Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and B-cell PTLD that is not responsive to immune suppression reduction.
Retransplant
Patients can undergo re-transplantation after successful PTLD treatment, to limit the possibility of PTLD recurrence, some recommendations should be considered: Time to re-transplant
Awaiting approximately 2 years after successful PTLD management EBV
Low/absent EBV viral load is recommended at time of re-transplantation, with continuous monitoring and antiviral treatment Role of immune suppression
It has been noted that PTLD is a disease of post-transplant immune suppression, hence reduction of immune suppression is the cornerstone of management. MMF is safe to be used in re transplant regimen. The role of mTOR inhibitors in PTLD is debatable Induction therapy
IL2 receptor agonists, rituximab Maintenance immune suppression
Its important to maintain the lowest safe doses of CNIs. MMF can be included in the maintenance ISS protocol Monoclonal gammopathy
Its important to confirm clearance of monoclonal gammopathy to reduce the risk of recurrence Origin of PTLD
Identifying the tumor source is crucial for determining future therapeutic plans
Level of Evidence
This is a narrative review: Level V
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation. It develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative. Important Risk factors:
-In Solid Organ Transplant : the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors therefore it is highest in intestinal, ht, lung transplant compared with kidneys.
-Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney.
-Oncogenic EBV: EBV may alter cell growth via several mechanisms:
-EBV may induce highly regulated growth transformation.
Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
-EBV induced proliferating cells may permit these proteins to by-pass immune control
-Growth alterations with the right levels of expression of cell targets
Treatment of PTLD :
1- Reduction of immunosuppression: the cornerstone of management. 2- Rituximab :
it is indicated in the following types:
a- Non-destructive PTLD.
b- Polymorphic PTLD.
c- Monomorphic diffuse large B-cell lymphoma -like PTLD that is not responsive to reduction of immunosuppression. 3- Chemotherapy: it is indicated in the following types :
a- Burkitt’s lymphoma.
b- Hodgkin’s lymphoma.
c- peripheral T- cell lymphoma.
d- 1ry CNS lymphoma.
e- B-cell PTLD that is not responding to either reduction of immunosuppression or Rituximab. 4- Other modalities:
a- adaptive immunotherapy.
b- outpatient care.
c- risk-stratified sequential therapeutic approach.
d- anti-viral therapy.
e- Radiotherapy. Re-transplantation and PTLD recurrence:
To limit the possibility of PTLD recurrence:
Time to re-transplant: Approximately two years of time should elapse after successful PTLD management. Level of study evidence: V
( Narrative review article)
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation. It develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative.
Important Risk factors:
-In Solid Organ Transplant : the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors therefore it is highest in intestinal, ht, lung transplant compared with kidneys.
-Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney.
-Oncogenic EBV: EBV may alter cell growth via several mechanisms:
-EBV may induce highly regulated growth transformation. Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors. -EBV induced proliferating cells may permit these proteins to by-pass immune control -Growth alterations with the right levels of expression of cell targets
1- Reduction of immunosuppression: the cornerstone of management.
2- Rituximab : it is indicated in the following types:
a- Non-destructive PTLD.
b- Polymorphic PTLD.
c- Monomorphic diffuse large B-cell lymphoma -like PTLD that is not responsive to reduction of immunosuppression.
3- Chemotherapy: it is indicated in the following types :
a- Burkitt’s lymphoma. b- Hodgkin’s lymphoma. c- peripheral T- cell lymphoma. d- 1ry CNS lymphoma. e- B-cell PTLD that is not responding to either reduction of immunosuppression or Rituximab.
Transplant recipients are at high risk of developing malignancy especially, after solid organ transplant. Skin malignancy are the most common followed by PTLD. PTLD spectrum include benign proliferation of lymphoid tissues to frank malignancy.
The main risk factors of PTLD include, cumulative immunosuppressive burden, and secondly, the oncogenic impact of the Epstein-Barr virus. The main treatment option of PTLD include, reduction of immunosuppression, rituximab therapy, either isolated or in combination with other chemotherapeutic agents, adoptive therapy, surgical intervention, antiviral therapy and radiotherapy.
Pathogenesis
EBV positive PTLD
It can be due to immunosuppressive-induced decline in the T-cell immune surveillance. EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells. The immune defence mechanism has been compromised in TRs leading to unlimited B cell transformation and the evolution of lymphoma.
EBV negative PTLD
It can be due to CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis
Categories of PTLD
These include-
plasmacytic hyperplasia
Mono Morphic
Polymorphic
Classical Hodgkin lymphoma
Clinical Presentations.
These include , Pyrexia , weight loss, neurological manifestations , nodal lesions, gastrointestinal manifestations , pulmonary manifestations and infectious mononucleosis-like syndrome that could be fulminant. An allograft dysfunction may ensue due to graft involvement.
Treatment
The options include-
Reduction of immune suppression
For early stage , low risk cases antimetabolites can be stopped. CNI can be reduced by 30-50%. Patient should be monitored until complete remission is achieved.
Rituximab
Rituximab is a monoclonal anti-CD20 antibody that has become a standard of care in patients with polymorphic PTLD, or monomorphic DLBCL-like PTLD, who are unresponsive to initial RIS. Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) (with Deauville ≤ 3) after four cycles of weekly standard-dose Rituximab.
Chemotherapy
If remission is not achieved with Rituximab alone or with disease progression R -CHOP every three weeks should be given with total of 4 cycles. In addition GCSF and Prophylaxis for P Jerovecii should be given.
Adoptive immunotherapy
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD. If available, autologous or allogeneic EBV-directed CTLs should be considered in patients with R/R EBV-positive PTLD
Retransplantation
It can be considered 2 years post treatment and remission.
EPV viral load should be assessed and use of Gancylovir and anti EPV agent
ATG should be avoided in induction phase
Rituximab can be used during induction
Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered
What is the level of evidence provided by this article?
· Response to therapy Patient survival 65% and 46%, (In adult heart/lung tx)[1,45] 53% and 41% (In adult heart/lung tx)[1,45].
Role of immun-osuppression Induction therapy has a role Cumulative immunosuppression is crucial
· Prevalence Majority of PTLD cases Less prevalentSafety and efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen every 3 wk and G-CSF support have been elucidated in the PTLD-1 trial.
A risk-stratified sequential therapeutic approach has been admitted in the second part of this trial as follows: Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with. G-CSF support in cases with no complete response to isolated Rtx therapy.
Overall response rate approached 88%, with 70% of cases with any response achieved a complete response at the end of therapeutic program.
Considering an excellent outcome reported of this trial, a reduction of the immunosuppressive load and risk-stratified sequential therapy are widely considered the standardized care of polymorphic and monomorphic diffuse large B-cell lymphoma-like PTLD after SOT
· Adoptive immunotherapyTo achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells.
This situation is in contrast to PTLD developing in TRs of SOT.
A robust EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs).
The major risk of this therapeutic modality, is GVHD development.
Expanded EBV-specific CTLs have been an effective therapeutic option in autologous as well as in donor-derived PTLD.
A variety of recent approaches e.g., adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells” and Tac-resistant, engineered CTLs has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load.
· Outpatient careIn light of serial follow up of the EBV viral load in identifying the patients at risk and in monitoring the response to therapy, the following steps have been suggested.
Monitoring of EBV viral titers in higher risk patients.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
The latter does not necessarily correlate with PTLD status.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
· Early PTLD Late PTLDGeneral criteria Diffuse large B-cell or other B-cell lymphoma Burkitt’s lymphoma and Hodgkin’s disease are late events.
Specific tumorigenic events e.g., C-myc translocations are restricted to late PTLDs. Time to PTLD Shortest for lung, heart/lung TR. PTLD is quite frequent in liver TR (Late PTLD beyond 5 yr is rare, immunosuppression can be tapered/hold due to tolerance).
Longest for the heart TR and at risk for late PTLD even > 10 yr after trans-plantation.
Distinct criteria B-cell origin, almost exclusively EBV+ve, reflecting reduced immunosurv-eillance as major pathogenetic factor.
Resembles tumors with distinct pathogenetic alterations and nodal appearance.
Role of immunos-uppression Induction therapy has a role.
More likely to develop graft rejection and switch to Tac before
· Cumulative immunosuppression is crucialTx: Transplantation; TR: Transplant recipient; PTLD: Post-transplant lymphoproliferative disorders; EBV: Epstein-Barr virus; HSCT: Haplo-identical allogeneic hematopoietic stem-cell transplant; LDH: Lactate dehydrogenase.
Initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality
· Future strategiesA list of newer therapeutic medications has been proposed.
Their efficacy remains to be validated via randomized controlled trials. Bruton’s tyrosine kinase (BTK) inhibition. Virtually active in GVHD and allograft rejection; remarkably active in activated B cells (ABC) type diffuse large B cell lymphoma (DLBCL).
(2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]; SRL and everolimus: Evident – in vitro evidence – of involved pathways; mTORi have robust immunosuppressive impact, introduction in PTLD therapy still controversial.
(6) Anti-CD30 therapy (Brentuximab vedotin): Expression of CD30 in 85% of all PTLD subtypes; the given effects is only limited to case reports
· To summarizeReduction of immunosuppression is the cornerstone of PTLD management. Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and, monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
IPI is a prognostic scoring system that includes the following: Patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and number of extra-nodal locations.
Another scoring system has been given in a French registry system that relies primarily upon patient’s age, serum creatinine concentration, LDH level, PTLD localization, and histopathologic criteria.ATG induction significantly triggers the risk of lymphoma evolution as compared to other agents The latter agents, may provide two benefits, first, a lower risk of PTLD development, and, second, TRs are more amenable to avoid long-term excessive immunosuppression after retransplantation.
Clinical clues about the origin of lymphoma cell line is an important therapeutic guide in using cytotoxic Tcell infusions in PTLD management
· FindingsOverall response rate approached 88%, with 70% of cases with any response achieved a complete response at the end of therapeutic program
· CONCLUSIONRecent progress in our understanding of the underlying pathophysiology of PTLD as well as the role of EBV has led to a better management. PTLD recurrence has been rarely reported after re-transplantation that requires careful planning of immunosuppression.
An ever-improving moleculargenomic technology has had its impact on upgrading our diagnostic and therapeutic strategies that will be reflected in improved recipient’s outcome.
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT)
Risk factor
1-Type of solid organ transplant · In adults, the incidence of PTLD is 0.8%- 2.5% in kidney transplant recipients And 1.0%-5.5% in liver TRs,
2- Allogenic HSCT
· T-cell depleting agents prior to transplant. Higher risk,
With lower risk with the use of non-specific broad lymphocyte depleting agents (T- and B-cells) · the type of induction therapy has a role in development early PTLD, and late PTLD is largely determined by cumulative immunosuppressive burden.
(3) the presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease
(4) Oncogenic EBV: EBV may alter cell growth via several mechanisms:
Pathogenesis
Role of EBV: · 50% PTLD in SOT are not accompanied by EBV infection · For EBV-positive TRs, the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immune- surveillance. · EBV can integrate into normal B-cell program leading to proliferation and transformation which should be destructed by T-cell response EBV POSITIVE VS NEGATIVE
Not prognostic/predictive of response to therapy EBV positive PTLD
Fewer genomic abnormalities
Mostly B-cell proliferative lesions
More common (first peak) EBV NEGATIVE
hare many genomic/ transcriptmic features
Mostly T-cell proliferative
Less common
Early PTLD.
EBV positivity
Graft involvement
Less often: Extranodal disease Nondestructive
Induction therapy has a role
Majority of PTLD cases Late onset PTLD
Frequent EBV negative
Less graft involvement
Extra-nodal disease: more common
Cumulative immunosuppression is crucial Less prevale Classification 1. plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD. 2. Polymorphic PTLD. 3. Monomorphic PTLD 4. classic Hodgkin’s lymphoma-like PTLD Clinical presentation:
PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Prophylaxis:
EBV sero-status of both donor and recipient before donor selection.
EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
A fine-tuning the immunosuppressive burden to as low as clinically possible.
TREATMENT OF PTLD 1-Reduction of immunosuppression · The mainstay of primary PTLD management is to ameliorate the immunosuppressive · 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate Rituximab · Rtx is a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. · The overall response to Rtx monotherapy in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases[
Chemotherapy
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells. Outpatient care 1. Weekly monitoring of EBV viral titers in higher risk patients. 2. Monthly monitoring initially followed by three monthly monitoring for low risk groups. 3. viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression. 4. Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. 5. Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial. 6. Therapeutic options should be tailored as per multidisciplinary team discussion. 7. An the initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality Re-transplantation and PTLD recurrence · To limit the possibility of PTLD recurrence the following is recommended (1) Time to retransplant: Approximately two years of time after successful PTLD management. (2) .. EBV.
(a) TR should experience Epstein–Barr nuclear antigen IgG positivity before retransplantation.
(b) Low/absent EBV viral load is recommended at the time of retransplantation.
(c) Close monitoring of TRs with persistently high EBV viral load is advised.
(d) Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load (3) Role of immunosuppression:
· it is the magnitude of immunosuppressive intensity that is the fundamental trigger for PTLD evolution.
· Retransplantation after PTLD cure remains controversial due to the re-exposure of immunosuppression.
(4) Induction therapy:
· The T cell-depleting agents should be excluded from the induction strategies (5) Maintenance immunosuppression:
· the potential risk of PTLD development should not interfere with our choice of proper immunosuppressive regimen
· Triple therapy (CNI, MMF and steroids), the lowest safe dosages monitored by target trough levels should be considered.
· MMF can be included safely in the immunosuppressive protocols with no more added risk 6) Monoclonal gammopathy:
complete resolution is an obvious indicator of complete remission. (7) Origin of PTLD
(donor vs recipient): Identification of the tumor source is crucial for future therapeutic plans and recognition of the biology of the next PTLD,
Post-transplant lymphoproliferative disease PTLD:
The most common malignancy in solid organ transplantation SOT with incidence of 25% in comparison to non-transplant population of 2-4 %.
Two major related factors are intertwined in provoking malignant transformation, immunosuppression and EBV.
its peak incidence is in the first-year post-transplant, around 85%, 15% is encountered after that.
Its predominantly B-lymphocyte mediated in the majority of cases, almost all of the first post operative year cases are EBV positive, B-lymphocytes PTLD. T-lymphocyte PTLD is non EBV related. PTLD spectrum : might be simple lymphoid proliferation to lymphoma.
Clinical presentation is either localized or systemic with protean features entailing extra vigilance and low threshold for diagnosis of PTLD by treating physician. Risk factors:
Several risk factors were observed in context of PTLD, including. 1} SOL. it was noted that, higher incidence was related to certain organs, such as multiple organs transplantation and Intestinal transplantation as the most common relevant context. As a role of thumb, the bigger and multiple organs transplanted, the vastest lymphatic tissues would be transferred. Hence, PTLD was more prevalent in Intestine, liver and lung transplant than kidney s, which is the least reported to be associated with PTLD. 2} Induction with lymphocyte depleting agent:
In situation when T lymphocytes depleted with ATG during induction, or as part of treatment of ACMR, B lymphocytes are imbalanced to T lymphocytes which keep it in check and inhibit its over-proliferation. When, the patient receives antilymphocyte medications that deplete both of the lineage B and T lymphocytes, less risk would be reported. 3} Previous transplant or glomerular disease treated with immunosuppression. 4}EBV:
Sero-negative recipient with positive donor is link to higher risk of PTLD. As the acute infective status is a major trigger for robust lymphocytic spread .
The other way of infection is reactivation. Treatment:
Minimization of immunosuppression RIS, is the cardinal policy of therapy with withdrawal of MMF and AZA and reducing the dose of CNi,
Rituximab and chemotherapy might be implemented.
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. INTRODUCTION. PTLD is one of the most common malignancy post solid organ transplant which is mainly due to multi-factorial causes such as long term immunosuppressive therapy, viral infection such as EBV which lead to uncontrolled B cell proliferation, tissue biopsy is considered the gold standard of diagnosis and the corner stone of treatment is to reduce the immunosuppression with Rituximab and other chemotherapy but still no definitive therapy that carries the best prognosis. Epidemiology of PTLD. It is accounts about 10% of all solid organ transplantation, 1-2% of kidney transplantation and considered the most common malignancy in children with SOT. There are many risk factors for PTLD such as EBV infection, immunosuppressive drugs, Age, length of time post-transplant, ethnic origin, CMV and other viral infections and recipient or donor origin-PTLD. Pathogenesis. EBV play a role in developing PTLD as it leads to proliferation and transformation of B cell with loss of apoptosis, especially with decline in the T-cell immune surveillance due to immunosuppressive state. Pathogenesis of PTLD in EBV-negative patients is less evident and have many theories such as CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run theory as EBV commences the pathogenic process leading to the development of PTLD and then disappeared. Classification. WHO 2017 Classification (1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD. (100%associated with EBV). (2)Polymorphic PTLD. (90% associated with EBV). (3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). (50% associated with EBV). (4) classic Hodgkin’s lymphoma-like PTLD.( (90% associated with EBV). Clinical presentation. No specific symptoms for PTLD, the classic symptoms of weight loss, sweats and fever can still occur often with symptoms of the related organ involved rather than lymphadenopathy. CNS involvement occurs in 30% of PTLD (1% in Non-Hodgkin lymphoma in the general population) and graft involvement is 30%. Prophylaxis: -EBV-negative TR is better receiving grafts from EBV-negative donors whenever available. -Balanced immunosuppressive medications. -Reduction of Immunosuppressive medications with viral re-activation. -Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered. Treatment:- 1-Reduction of immunosuppression . RI can reverse 20%-80% of patients with PTLD, especially decreasing CNI group and withdrawal of antimetabolites such as azathioprine or Mycophenolate mofetil (MMF) and With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered, we should monitor the graft function, to detect any manifestation of acute rejection. 2-Rituximab therapy. Rituximab is a chimeric m Ab mouse-human against CD20 and most PTLDs express CD20 but 20 to 30% of all PTLD are CD20 negative and the overall response to Rtx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases. Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5%. 3-Chemotherapy. Indications of Immune chemotherapy include: Burkett’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI. Safety and efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen every 3 wk and G-CSF support have been elucidated in the PTLD-1 sequential treatment (ST) trial. The PTLD-2 sequential treatment (ST) trial demonstrated the efficacy of Rituximab monotherapy for those who are low-risk and respond well to the rituximab monotherapy and those who are at higher risk or non-responders will receive sequential chemotherapy (CHOP). The response rate approached 88%, with 70% of cases with any response achieving a complete response at the end of the therapeutic programme. 4-Adoptive immunotherapy.
Strong EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes and the major risk of this therapeutic modality is GVHD development. 5-Outpatient care.
1-Monitoring of EBV viral titers weekly, in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
2-Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
3-Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
4-Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
5-Therapeutic options should be tailored as per multidisciplinary team discussion.
6-The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality. Re-transplantation and PTLD recurrence.
One-year disease free survival is necessary after control of PTLD before re-transplantation.
There are strategies that limit the recurrence of PTLD after re-transplant such as waiting two years after successful PTLD management, TR should experience Epstein–Barr nuclear antigen IgG positivity before retransplantation, Low/absent EBV viral load is recommended at the time of retransplantation with close monitoring of TRs with persistently high EBV viral load is advised.
Regarding the immunosuppression, ATG induction significantly triggers the risk of lymphoma evolution as compared to other agents, using of triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered. Future strategies.
1. Bruton’s tyrosinekinase (BTK) inhibition (Ibrutinib)
2. Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]; SRL and everolimus
3. Proteasome inhibition (Bortezomib)
4. Radioimmunotherapy , (90Yibritumomab, tiuxetan)
5. Checkpoint inhibitors (Pembrolizumab, nivolumab)
6. Anti-CD30 therapy (Brentuximab vedotin) CONCLUSION.
PTLD is one of the serious complications post KTX, need high suspicion for diagnosis and most of cases related to EBV and mainly respond to reduction of immunosuppression , re-transplant with special consideration carries a good response and low risk of PTLD recurrence.
Level of evidence: V (a narrative review article).
Post-transplant lymphoproliferative disorders (PTLD) are one of the essential malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT), and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells may get infected by Epstein-Barr virus (EBV) either by:
(1) Post-transplant viral reactivation.
(2) Primary EBV infection
Risk factors:
(1) SOT
(2) Allogenic HSCT
(3) the presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution
(4) Oncogenic EBV
Pathogenesis:
EBV-positive TRs, the development of PTLD can be attributed to the immunosuppressive-induced decline in the T-cell immune surveillance. EBV can integrate into regular B-cell programs leading to the proliferation
and transformation of these cells
EBV-positive vs. EBV-negative PTLD::
T-cell subtype PTLD (usually EBV-ve) is a rare tumor and presents with manifestations that are dissimilar to those of T-cell lymphoma in immune-competent subjects.
Classification:
(1) Three nondestructive PTLDs: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD
Clinical presentation:
Pyrexia (57%), weight loss (9%), neurological manifestations (13%), nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%), and infectious mononucleosis-like syndrome that could be fulminant (19%)
Differential diagnosis::
Streptococcal infections or Infectious mononucleosis.
Time to PTLD for different transplanted organs: The time to PTLD is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR
EBV monitoring for preemptive therapy:
An estimation of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy.
Prophylaxis:
Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function have also been recommended.
TREATMENT OF PTLD:
RI reduced immunosuppressive medication
Rituximab therapy
Chemotherapy.
Adoptive immunotherapy
Outpatient care:
: (1) Weekly monitoring of EBV viral titers
(2) While viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression
(3) Serial physical examination,
(4) Optimum balance between PTLD management and avoidance of acute allograft rejection is crucial
(5) Therapeutic options should be tailored as per multidisciplinary team discussion
(6) The initial therapeutic step is RI or cessation of immunosuppression
Future strategies:
(1) Bruton’s tyrosine kinase (BTK) inhibition
(2) Inhibition of PI3K and mTOR
(3) Proteasome inhibition
(4) Radioimmunotherapy
(5) Checkpoint inhibitors.
(6) Anti-CD30 therapy
Prognosis
The outcome of PTLD patients has significantly improved owing to the advent of new lymphoma-specific protocols as well as the better supportive care
transplant recipients including those of kidney recipients are at a high risk of lymphoproliferative disorders that range from benign proliferation of lymphoid tissues to frank malignancy with aggressive behavior.
there are 2 main risk factors for post-transplant lymphoproliferative disorders (PTLD) :
1- the cumulative intensive immunosuppression.
2- the oncogenic virus, EBV
for the last 2 decades, a significant progress has been achieved for the diagnosis and management of PTLD.
the management include the following :
1- Reduction of immunosuppression: the cornerstone of management. 2- Rituximab : it is indicated in the following types:
a- Non-destructive PTLD.
b- Polymorphic PTLD.
c- Monomorphic diffuse large B-cell lymphoma -like PTLD that is not responsive to reduction of immunosuppression. 3- Chemotherapy: it is indicated in the following types :
a- Burkitt’s lymphoma.
b- Hodgkin’s lymphoma.
c- peripheral T- cell lymphoma.
d- 1ry CNS lymphoma.
e- B-cell PTLD that is not responding to either reduction of immunosuppression or Rituximab. 4- Other modalities:
a- adaptive immunotherapy.
b- outpatient care.
c- risk-stratified sequential therapeutic approach.
d- anti-viral therapy.
e- Radiotherapy.
What is the level of evidence provided by this article?
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Introduction
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation. It develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative.
The immunosuppressive burden has an important role in PTLD evolution. Lymphoma presents 21% of all malignancies in SOT recipients as compared to 4% and 5% in immunocompetent individuals. Tissue diagnosis is crucial for PTLD diagnosis, in addition to clear evidence of EBV DNA, RNA.
The mainstay of PTLD primary management is reduction of immunosuppression. Complete cessation of the immunosuppressive drugs may be necessary to stop the disease progression. However, RI is not always feasible; a potential risk of allograft loss or graft dysfunction has to be considered particularly for vital organ transplants.
Another therapeutic options include surgical excision, anti-viral agents, local radiotherapy, intravenous immunoglobulin (IVIG), chemotherapeutic agents, monoclonal antibodies and cytotoxic T lymphocytes with variable success.
Clinical presentation: Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Salient features: PTLD may present as a local or disseminated disease. Clinical manifestations include: Pyrexia, weight loss, neurological manifestations, nodal lesions, gastrointestinal manifestations, pulmonary manifestations and infectious mononucleosis-like syndrome that could be fulminant.
An associated high EBV viral load by PCR should make one suspect PTLD. The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
Prophylaxis: Primarily, EBV serostatus of both donor and recipient should be recognized before donor selection. EBV-negative candidates is better receiving grafts from EBV-negative donors whenever available. A fine-tuning the immunosuppressive burden to as low as clinically possible. Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression. Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
TREATMENT OF PTLD:
The mainstay of primary PTLD management is reduction of immunosuppression. Reduction of immunosuppression can reverse 20%-80% of patients with PTLD. It is plan includes 50% reduction of calcineurin inhibitors doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil, despite the lack of evidence demonstrating any relation between MMF and PTLD development.With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
Rituximab therapy:
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen, leading to B cell depletion. Rituximab has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification:
(1) Non destructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. (375 mg/m2 body-surface area, weekly for 4 wk.
Chemotherapy Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and reduction of immunosuppression.
Adoptive immunotherapy Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells.
Re-transplantation and PTLD recurrence Feasibility of re-transplantation after successful management of PTLD has been reported in particular cases; however, one-year disease free survival is necessary after control of PTLD before re-transplantation.
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches Epidemiology
SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma). On the other hand, a reported incidence of PTLD in 3.2% of HSCT recipients has been observed in multicenter studies
Risk factors
(1) SOT: the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors therefore it is highest in intestinal, ht, lung transplant compared with kidneys.
(2) Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney.
(3) Oncogenic EBV: EBV may alter cell growth via several mechanisms:
A) EBV may induce highly regulated growth transformation.
B) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
C) EBV induced proliferating cells may permit these proteins to by-pass immune control
D) Growth alterations with the right levels of expression of cell targets
Pathogenesis EBV-positive TRs: the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immune surveillance and hence this immune defence mechanism compromised, B cell undergoes unlimited transformation and the evolution of lymphoma. PTLD in EBV-negative hypotheses: CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes. ( Table 1)
Clinical presentation:
Clinical pic: varies from vary from symptomless lesions to fulminating disease. 50 % fever and nodal lesions, 25 % GI and IMN, 10 % Wt loss, neuro and pulmonary
Onset: Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology; whereas Burkitt’s lymphoma and Hodgkin’s disease are late events.
EBV monitoring for preemptive therapy:
The risk of EBV+ve PTLD relatd to Type of transplant organ, time elapsed until diagnosis of post-transplant PTLD and EBV serological status of both recipient and donor before transplant.
An estimation of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy. It has been observed that TR with PTLD usually expresses an increased EBV viral load as compared to PTLD free TR. This higher viral load invites more risk for PTLD evolution. Pitfalls: cut-off values are not clear, sources of samples are not universal, absence of standard points of time to perform the monitoring that reflected poor positive and negative predictive of EBV viral load.
“Cell-free plasma EBV DNA” has been reported as a better marker of EBV activity
Preemptive strategies: RI, rituximab therapy, and adoptive transfer of EBV specified T cells for high-risk group of PTLD patients (not defined)
Prophylaxis:
EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
A fine-tuning the immunosuppressive burden to as low as clinically possible.
Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression. High risk groups: Preemptive/prophylactic antiviral therapy, Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam, monitoring EBV viral load, preemptive RI with rising titers, and close monitoring of allograft function have been also recommended .
TREATMENT OF PTLD
RI: RI plan includes 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF). TR can be restaged within two to four weeks in contrary to lymphoma staging in immunocompetent patients. Acute rejection rate of 37%. Less response with EBV -ve cases. Complete lack of response observed in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV)
Rituximab therapy standard ttt for the following stages: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. Chemotherapy: for the following: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI Adoptive immunotherapy: Infusion of donor lymphocytes, to achieve adoptive immunotherapy. Has risk of GVHD.
Outpatient care
(1) High risk: weekly monitor. Low risk: Monthly then every three monthly
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
Prognosis: 70 % complete remission with median survival 6.6 years. IPI is a prognostic scoring system that includes the following: age, performance attitude, stage, LDH, and number of extra-nodal locations.
Re-transplantation and PTLD recurrence
To limit the possibility of PTLD recurrence the following recommendations are worth noting: 1- Time to retransplant: Approximately two years of time should elapse after successful PTLD management. 2- EBV:
· TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation.
· Low/absent EBV viral load is recommended at the time of retransplantation.
· Close monitoring of TRs with persistently high EBV viral load is advised.
· Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence . Ganciclovir has been suggested for this purpose. 3- Role of immunosuppression: RI/withdrawal of immunosuppression has been the cornerstone of PTLD management. Induction therapy:
– ATG vs IL-2 receptor antagonists: The T cell-depleting agents should be excluded from the induction strategies with IL-2 receptor antagonists appeared to have the first priority.
– Rituximab in induction therapy: Rtx may be introduced as an element of desensitization regimen in high-risk TR.
Maintenance immunosuppression: Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered. MMF: Considering the safety of MMF in regard to PTLD evolution, MMF can be included safely in the immunosuppressive protocols with no more added risk. mTOR inhibitors: Their role in PTLD development remains debatable. These agents may inhibit the development of lymphomas in vitro, but their clinical application in human still warrant the proper evidence. 4- Graft PTLD: Is very intriguing and usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative. 5- Monoclonal gammopathy: Whilst the presence of monoclonal gammopathy may indicate incompletely remitted PTLD, its complete resolution is an obvious indicator of complete remission.
6- Origin of PTLD (donor vs recipient): better outcome in TRs with “donor” lymphomas, it is an important therapeutic guide in using cytotoxic T cell infusions in PTLD management.
Introduction: Post-transplant lymphoproliferative disorders (PTLD), are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT). Occurs due uncontrolled B cell proliferation due to blunted immunological surveillance. EBV infects B cell by: (1) Post-transplant viral reactivation. (2) through the donated organ or environmental.
Risk factors: 1. Solid organ transplantation: more common in multiorgan transplantation, thoracic transplants and intestinal Tx. 2. Allogenic hematopiotic stem cell transplants: more common in less HLA matched Tx, umblical cord Tx. 3. Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney. 4. Oncogenic EBV: – expression of its growth inducing proteins. – Induction of the potent oncogenes; LMP1 and LMP2. – EBV variant/HLA types combination permit these proteins to by-pass immune control. – Growth alterations.
Pathogenesis: EBV+ PTLD: Fewer genomic abnormalities, mostly B-cell proliferative lesions, “Non-germinal” center B-cell, more common in the first year of transplant, Almost all cases of HSCT (100%) are EBV positive, EBV- PTLD: Share many genomic/ transcriptmic features with diffuse large B-cell lymphoma in Immunocompetent patients, mostly T-cell proliferative lesions, “Germinal center B-cell type”, less common with peak 10 years after transplantation. Prognosis/response to therapy in adults; a considerable proportion of both EBV+ve and -ve PTLD respond to RI as a sole intervention. Future studies Whole-exome/genome wide sequencing and studies of role of EBV-associated microRNAs, may further define PTLD pathogenesis with more precise molecular-genomic classification of both EBV+ve and EBV-ve PTLD.
Clinical presentation: Constitutional symptoms: fever, wt. loss, neurological deficit. Lymphnode enlargement, GI manifestations, pulmonary symptoms, and fulminant form of infectious mononucleosis. Differential diagnosis: All infections cause lymphadenopathy, pharyngitis, and fever.
Treatment of PTLD: 1. Reduction or discontinuation of immunosuppressive medication. 2. Rituximab. 3. Chemotherapy. 4. Surgical. 5. Adoptive immunotherapy.
Outpatient care: Weekly monitoring of EBV viral titers in higher risk patients, while monthly followed by three monthly monitoring for low risk groups. Viral load monitoring. – Frequent clinical examination, graft function evaluation, and imaging. – Monitoring for rejection while on treatment as the risk of graft loss reaches 40%. – Multidisciplinary team work up, evaluation and followup. – The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality.
Prognosis: The outcome improved as a result of improved lymphoma treatment. 70% of PTLD patients had achieved a complete remission with median survival of approximately 6.6 years.
Re-transplantation: Two years elapsed before re-transplant in PTLD cured patients. Transplant recipient with EBV+ IgG before re-transplantation. Low/ absent viral load before transplantation. Graft PTLD removal curative. Immunosuppression: – Induction with basilixumab not ATG. – Desensitization with rituximab. – Triple therapy (CNI, MMF and steroids) with lowest therapeutic drug levels. – Use of m-TOR inhibitors in maintenance IS Monoclonal gammopathy may indicate incompletely remitted PTLD. Identification of PTLD (donor vs recipient) may help in disease control, type of recurring disease, and future treatment plan.
Conclusion: PTLD are now better understood, new treatment therapeutic option is under investigational studies, and rarely recurs in re-transplantation with proper monitoring. Multidisciplinary team is mandatory in PTLD management and followup. What is the level of evidence provided by this article? Level of evidence V – erratic review
Introduction: After solid organ and allogeneic hematopoietic stem cell transplants, recipients of transplants are more susceptible to developing cancer. Posttransplant lymphoproliferative disorders (PTLD) cover a broad range of illnesses, from benign lymphoid tissue proliferation to overt malignancy with aggressive behavior. The cumulative immunosuppressive load and the Epstein-Barr virus’s carcinogenic potential are the two primary risk factors for PTLD. The latter is a significant pathognomonic force in the progression of PTLD.
The treatment of PTLD includes reduction of immunosuppression, rituximab therapy, either isolated or in combination with other chemotherapeutic agents, adoptive therapy, surgical intervention, antiviral therapy and radiotherapy.
Risk factor includes: Solid organ transplantation, highest in lung and lowest in kidney transplantation also in allogenic HSCT, the incidence is higher in the use of T -cell depleting agents compare to non T cell depleting agent and oncogenic EBV.
Clinical presentations: It can vary from asymptomatic to fulminant disease with multi-organ involvement. It includes pyrexia, weight loss, neurological lesion, nodal involvement, GIT manifestations, pulmonary manifestation, infectious mononucleosis-like symptoms.
Treatment options of PTLD:
Reduction of immunosuppression
Rituximab therapy
Chemotherapy
Adoptive immunotherapy
Future Strategies in treatments:
Bruton thyroxine kinase inhibitor, Ibrutinib
Inhibitor of P13K, Idelalisib and mTOR
Proteosome inhibitor, Bortezomib
Radioimmunotherapy; 90Yibritumomab, tiuxetan
Checkpoint inhibitor; Pembrolizumab, nivolumab
Re-transplantation and PTLD recurrence:
Successful re-transplantation is feasible after a failed allograft due to PTLD by considering the following factors
Time to re-transplantation: 2 years wait is advised
One-year disease free survival is necessary after control of PTLD before re-transplantation
Transplant recipients should experience Epstein–Barr nuclear antigen IgG positivity
Low/absent EBV viral load is recommended at the time of retransplantation.
Close monitoring of TRs with persistently high EBV viral load is advised.
Anti-viral therapy: Long-term prophylactic antiviral therapy with a serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence
Care in the choice of the induction therapy and the magnitude of IM used
Conclusion PTLD is a disease of immunosuppression. Recent progress in our understanding of the underlying pathophysiology of PTLD as well as the role of EBV has led to a better management strategy.
Please summarise this article INTRODUCTION
-Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT).
-PTLD may manifest either as localized lesion or as systemic disease. Epidemiology of PTLD
-There is increased risk which expressed as “standardized incidence ratios” (SIRs) i.e., the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort). Risk factors
Risk factors are, reportedly, varied according to the type of the transplant organ: (1) SOT: The amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors.
(2) Allogenic HSCT: PTLD incidence is primarily related to the degree of HLA
matching with consequent introduction of T-cell depleting agents prior to transplant.The late PTLD is largely determined by cumulative immunosuppressive burden. Compared to EBV seropositive TRs, the seronegative patients in SOT are more vulnerable to develop PTLD with an increased estimated risk of 10-75.
(3) It is noteworthy to mention that the presence of previous exposure to the
immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution.
(4) Oncogenic EBV . Classification
– Depending mainly on histopathological classification, diagnosis of PTLD can be categorized according to WHO 2017 Classification, as follows: (1) Three nondestructive PTLD: plasmacytic hyperplasia,
florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2)Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD. Clinical presentation
Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.An allograft dysfunction may ensue due to graft involvement. Lowering the threshold for PTLD diagnosis is crucial, as TR may
present with nonspecific symptoms (e.g., fever, asthenia). EBV monitoring for preemptive therapy
This higher viral load invites more risk for PTLD evolution. Prophylaxis
Primarily, EBV sero-status of both donor and recipient should be recognized before donor selection. EBV-negative TR is better receiving grafts from EBV-negative donors whenever available. A fine-tuning the immunosuppressive burden to as low as clinically possible. Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression.Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered. TREATMENT OF PTLD
1-Reduction immunosuppression :
2-Rituximab therapy
3-Chemotherapy
4-Adoptive immunotherapy Outpatient care
(1) Weekly monitoring of EBV viral titers[81] in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
(5) Therapeutic options should be tailored as per multidisciplinary team discussion.
(6) The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality. Prognosis
Outcome of PTLD patients has greatly improved owing to the advent of new
lymphoma-specific protocols as well as to the better supportive care. Seventy percent the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years . Re-transplantation and
Feasibility of re-transplantation after successful management of PTLD has been
reported in particular cases; however, one-year disease free survival is necessary after control of PTLD before re-transplantation[ What is the level of evidence provided by this article?
Level 5
PTLD is one of the most important malignancies after SOT & HSCT.
It is due to uncontrolled B cell proliferation as a result of weakenedimmunological surveillance.
Post-transplant viral reactivation and primary EBV infection, through the donor organ or via environmental exposure, are the two ways that B cells might get infected with the virus.
The majority of PTLD cases (> 85%) are usually seen in the 1st post-transplant year. PTLD as a result of T-cell proliferation is seen much less commonly & is mostly EBV-negative.
The level of cumulative immunosuppressive load is very important for the progression of PTLD.
Lymphoma makes up 21% of all cancers in SOT patients, compared to 4% to 5% in immuno-competent people.
PTLD might present as a systemic illness or a localized lesion. It is crucial to lower the clinical threshold for PTLD diagnosis.
Along with proof of EBV DNA, RNA, or protein material, tissue diagnosis is essential for PTLD diagnosis.
The reduction of immunosuppression (RI) is the cornerstone of PTLD primary care. To stop the spread of the disease, IS medication may need to be completely stopped. However, RI is not always practical; in particular, for important organ transplants, a potential danger of allograft loss or graft malfunction must be taken into consideration (e.g., heart transplant).
Surgery, anti-viral drugs, local irradiation, IVIG), chemotherapy, monoclonal antibodies, & cytotoxic T cells are a few of the therapeutic methods with varying degrees of success. Better outcomes can be achieved by combination therapy rather than using them separately.
Epidemiology
The following factors account for the rising awareness of PTLD prevalence:
improved diagnostic technologies
older age of donors and recipients
increased understanding of this condition
the introduction of the haplo-identical HSCT and new IS tactics.
Standardized incidence ratios (SIR) (the incidence in transplant cohort divided by its incidence in general non-transplant cohort):
10 (non-Hodgkin’s lymphoma)
4 (Hodgkin’s lymphoma)
Risk factors for PTLD:
SOT:
the amount of lymphatic tissue in an allograft
the degree of IS are key factors
multi-organ TRs
Intestinal TRs.
HSCT:
the degree of HLA matching
T-cell depleting strategies.
The degree of increased PTLD risk can be categorized as follows:
HSCT (zero in patients who received cyclophosphamide for GVHD & > 20% with selective T-cell depletion)
Umbilical-cord transplantation (4%-5%)
Transplant from unrelated donors (4%-10%)
Transplant from matched, related donors (1%-3%)
The role of IS agents:
Is less clear due to variability in timing, duration, & dosage.
The type of induction therapy has a major role in the early developed PTLD
Late PTLD is largely determined by cumulative IS burden.
The “donor kind” and the “T-cell depleting technique” were the two most important variables in the progression of PTLD. Seronegative patients have a higher estimated risk of 10-75 of developing PTLD compared to EBV seropositive TRs. Previous exposure to IS load (during treatment of the primary renal disease in the native kidney) Oncogenic EBV: EBV may alter cell growth via several mechanisms. Pathogenesis: Role of EBV
EBV infection does not occur in 50% of PTLD cases.
The onset of PTLD in EBV-positive TRs can be linked to an IS-induced decrease in T-cell immune surveillance.
EBV can integrate into healthy B-cells, causing these cells to multiply and change. Normally, these antigens would cause a T-cell response that might kill off the majority of the B cells that were infected with EBV. However, in TRs, this immunological defense system has been weakened, causing unrestricted B cell transformation and the development of lymphoma.
In EBV-negative patients, the pathogenesis is less clear. A number of theories have been suggested:
The hit-&-run hypothesis (EBV starts the pathogenic process & then disappears)
Protracted IS
Allograft-driven chronic antigenic triggering
CMV, or another viral infection.
EBV-positive VS EBV-negative PTLD:
It is difficult to distinguish between the clinical effects of various EBV serotypes and how well they respond to treatment. Molecular-genomic information would help to define best therapeutic strategies for both types
Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
Classic Hodgkin’s lymphoma-like PTLD.
EBV infection is seen in:
all TRs with nondestructive PTLD
> 90% of polymorphic PTLD & Hodgkin’s lymphoma–like PTLD
only 50% of monomorphic PTLD.
Clinical presentation:
Ranges from asymptomatic lesions to multi-organ failure in fulminating disease.
May present as local or disseminated disease.
Clinical manifestations include:
Pyrexia (57%)
Weight loss (9%)
Neurological manifestations (13%)
Nodal lesions (38%)
Gastrointestinal manifestations (27%)
Pulmonary manifestations (15%)
Infectious mononucleosis-like syndrome (19%).
Allograft dysfunction (due to graft involvement).
Lymph nodes, liver, lung, kidney, bone marrow, GIT, spleen, CNS, tonsils, and salivary glands are the areas most frequently affected by PTLD.
Differential diagnosis:
Streptococcal infections or Infectious mononucleosis
Time to PTLD for different transplanted organs:
Shortest for the lung & heart/lung in pediatric TR
Longest for the heart recipients.
Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology; whereas Burkitt’s lymphoma & Hodgkin’s disease are late events.
EBV monitoring for preemptive therapy:
PCR viral load is mandated to monitor preemptive PTLD therapy.
TR with PTLD usually expresses an increased EBV viral load as compared to PTLD free TR.
Pitfalls in preemptive strategy monitoring:
Cut-off values are not clear
Sources of samples are not
Absence of standard points of time to perform the monitoring.
Preemptive strategies to limit the risk of PTLD development include: rituximab therapy, & adoptive transfer of EBV specified T cells.
Prophylaxis:
EBV sero-status of both donor & recipient should be recognized before donor selection.
EBV-negative TR is better receiving grafts from EBV-negative donors.
Keep the IS burden as low as clinically possible.
Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI.
Preemptive antiviral therapy in potentially high-risk groups.
IVIG/ CytoGam to maintenan high titers anti-EBV antibodies.
In those groups that are highly susceptible to developing PTLD, the preemptive therapy should be taken into consideration.
Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers.
Close monitoring of allograft function.
Treatment of PTLD: RI
Partially restore EBV-specific cellular immunity.
RI can reverse 20%-80% of patients with PTLD.
RI plan includes:
50% reduction of CNI & withdrawal of azathioprine or MMF (no evidence of any relation between MMF & PTLD development).
With the exception of glucocorticoids, withdrawal of all IS medications in critically ill cases should be considered.
Monitoring allograft function during the trial of RI to recognize any manifestations of early rejection.
An acute rejection rate of 37% has been observed.
The EBV negative cases respond to RI less than the EBV positive illness does.
Older patients (>50 years), large lesions (>7 cm), and advanced stages of the illness (AnnArbor stage III/IV) have all shown a complete lack of response to RI.
Rituximab therapy
Approved as a standard therapeutic agent in PTLD.
The overall response to Rtx monotherapy in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases.
In the PTLD-1 trial (prospective, multicenter trial including post-SOT PTLD), the complete remission rate approached 25% after standard induction augmented by another 4 doses of 3 weekly Rtx (low-risk patients).
The complete response can be interpreted as three associated benefits:
Better overall survival, extended time to progression, and better progression-free survival.
Chemotherapy
Indications include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, & B-cell PTLD unresponsive to Rtx & RI.
In all CD20+ve subtypes (75% or more), Rtx should be included.
Safety & efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen every 3 wk & G-CSF support have been found in the PTLD-1 trial.
Overall response rate approached 88%.
A reduction of the IS load & risk stratified sequential therapy are widely considered the standardized care of polymorphic & monomorphic diffuse large B-cell lymphoma-like PTLD (regardless to EBV status) after SOT.
Adoptive immunotherapy
It has been demonstrated that administering donor lymphocytes helps HSCT patients with primary donor-cell-derived PTLD. This condition contrasts with PTLD manifesting in SOT TRs.
A robust EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs).
However, the development of GVHD is the main risk associated with this therapeutic approach.
Expanded EBV-specific CTLs have proven to be a potent treatment approach in both donor- & recipient-derived PTLD.
There are now new therapeutic alternatives without the requirement to lower the IS load, including adoptive transfer of “pamidronate-expanded V9V2 T cells” & Tac-resistant, modified CTLs.
Outpatient care
Weekly monitoring of EBV viral titers in higher risk patients.
Monthly monitoring initially followed by three monthly monitoring for low risk groups.
Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
Serial physical examination, radiology testing & monitoring allograft function.
The initial therapeutic step is RI or cessation of IS, after which further therapeutic options is tailored according to the response.
Future strategies (efficacy remains to be validated via RCTs):
Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]; SRL and everolimus
Proteasome inhibition (Bortezomib)
Radioimmunotherapy , (90Yibritumomab, tiuxetan)
Checkpoint inhibitors (Pembrolizumab, nivolumab)
Anti-CD30 therapy (Brentuximab vedotin)
Prognosis
Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care.
Seventy percent of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years.
Re-transplantation & PTLD recurrence
1-year disease free survival is necessary after control of PTLD before re-TX.
An anti-EBV partially acquired immunity is a potential protective mechanism.
There are several ways to reduce the chance of PTLD recurrence:
Waiting 2 years of time after successful PTLD management.
EBV: (a) EBV nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before re-TX. (b) Low/absent viral load at the time of re-TX. (c) Close monitoring of TRs with persistently high EBV viral load. (d) Long-term prophylactic antiviral (Ganciclovir) therapy.
RI/withdrawal of IS
Induction therapy: (a) ATG vs IL-2 receptor antagonists:Exclude T cell-depleting agents from the induction therapy. The top priority appeared to be IL-2 receptor antagonists.(b) Rituximab may be added as an element of de-sensitization regimen in high-risk TR.
Maintenance IS: avoid the intense state of IS so that the recovered immune system can promote the evolution of the anti-EBV cytotoxic T lymphocyte.
(a) Triple therapy (CNI, MMF & steroids): use the lowest safe dosages monitored by target trough levels.
(b) MMF can be included safely in the IS protocols with no more added risk.
(c) The role of mTOR inhibitors in the emergence of PTLD is still debatable.
6. Monoclonal gammopathy: its complete resolution is an obvious indicator of complete remission. 7, Identification of the tumor source (donor vs recipient) is essential for future therapeutic plans. Olagne et al, reported a trend to a better outcome in TRs with “donor” lymphomas. ======================== 2. What is the level of evidence provided by this article? Level V
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
PTLD include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissues to frank malignancy with aggressive behavior.
PTLD; risk factors:
· The cumulative immunosuppressive burden.
· The oncogenic impact of the Epstein-Barr virus, through several mechanisms:
a) With lack of immune recognition, EBV may induce highly regulated growth transformation with expression of all of its growth inducing proteins.
b) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
c) EBV induced proliferating cells as well as EBV variant/HLA types combination may permit these proteins to bypass immune control and go unrecognized.
d) Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA.
PTLD; incidence in transplantation
1. Adults with SOT
· 0.8%- 2.5% in kidney transplant recipients (KTR).
· 0.5%-5.0% in pancreatic TRs.
· 1.0%-5.5% in liver TRs.
· 2.0-8.0% in heart TRs.
· 3.0-10.0% in lung TRs.
· ≤ 20% in multi-organ and intestinal TRs.
2. Allogenic HSCT: PTLD incidence is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant.
· zero in patients who received cyclophosphamide for GVHD.
· > 20% with selective T-cell depletion.
· Umbilical-cord transplantation (4%-5%).
· Transplant from unrelated donors (4%-10%).
· Transplant from matched, related donors (1%-3%).
PTLD;Classification:
1. Early vs late onset PTLD.
2. Histopathological categorization according to WHO 2017 Classification:
a) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
b) Polymorphic PTLD.
c) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
d) classic Hodgkin’s lymphoma-like PTLD.
3. EBV +ve vs EBV-ve PTLD (there is a lack of clear distinction between clinical consequences of different EBV serotypes and their response to therapy);
· An associated EBV infection could be currently seen in almost all TRs with non- destructive PTLD.
· EBV infection is seen in > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD.
· EBV infection is seen in 50% of monomorphic PTLD.
PTLD; diagnostic approach
· Relevant history and clinical examination.EBV serostatus, transplant organ type (SOT vs HSCT) and duration of transplant.
· The EBV-encoded RNA (EBER) in-situ hybridization assessment is mandatory for all the cases.
· Histopathologic configuration.
· Prompt staging for PTLD via application of the currently used staging for lymphoma.
PTLD; Clinical presentation
PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
· Salient features: Pyrexia (57%), weight loss (9%), neurological manifestations (13%), nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant (19%).
· An allograft dysfunction may ensue due to graft involvement.
· The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
PTLD; Differential diagnosis
Any high-risk TR who presents with pyrexia, pharyngitis and cervical lymphadenopathy would make one consider other diagnoses:
· Streptococcal infections.
· Infectious mononucleosis.
PTLD; Management
1. reduction of immunosuppression.
· RI can reverse 20%-80% of patients with PTLD.
· RI plan includes 50% reduction of CNI, in addition to withdrawal of the antimetabolites(azathioprine or MMF).
· With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
· A complete lack of response to RI has been observed in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV).
2. Rituximab therapy, either isolated or in combination with other chemotherapeutic agents.
· RTX has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
· The dose of RTX monotherapy is 375 mg/m2 body-surface area, weekly for 4 weeks.
· Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5%.
3. Chemotherapy:
· indications of Immunochemotherapy include Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to RTX and RI.
· Overall response rate approached 88% when using R-CHOP + G-CSF + anti-PJP prophylaxis.
4. Antiviral therapy; Ganciclovir has been suggested for this purpose.
5. Adoptive therapy.
· Infusion of donor lymphocytes, to achieve adoptive immunotherapy.
· EBV-specific cytotoxic lymphocytes (CTLs) is promising but the risk of GVHD is a major risk.
· Expanded EBV-specific cytotoxic lymphocytes (CTLs)have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD.
· Recent approaches include adoptive transfer of “pamidronate-expanded T cells” and Tac-resistant, engineered CTLs has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load.
· Recognition of EBV serostatus of both donor and recipient.
· A fine-tuning the immunosuppressive burden to as low as clinically possible.
· Preemptive/prophylactic antiviral therapy in potentially high-risk groups.
· Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration.
· Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers.
· Close monitoring of allograft function.
PTLD and re-transplantation
· one-year disease free survival is necessary after control of PTLD before re-transplantation.
· TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before re-transplantation.
· An anti-EBV indicator of robust cytotoxic response) before re-transplantation.
· Low/absent EBV viral load is recommended at the time of re-transplantation.
· Close monitoring of TRs with persistently high EBV viral load is advised.
· Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence.
· Induction therapy: The following agents are considered: (a) ATG vs IL-2 receptor antagonists. (b) Rituximab in induction therapy.
· Maintenance immunosuppression: to avoid the intense state of immunosuppression, therefore, the lowest safe dosages monitored by target trough levels should be considered.
The level of evidence provided by this article
This is a narrative review article with level of evidence grade 5.
Introduction
PTLD is most common post transplant malignancy after skin cancers. It is caused by uncontrolled proliferation of B cells due to weakened immune system. Most of the PTLD is caused by EBV positive B cells in the first year of transplant. PTLD can manifest as a localized lesion or a multisystem disease. Tissue diagnosis is essential for PTLD along with EBV-PCR. The mainstay of treatment of PTLD is reduction in immunosuppression but rejection must be monitored. Epidemiology of PTLD (standardized incidence ratios):
The increased risk of PTLD is expressed as “standardized incidence ratios” (SIRs) i.e., the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort). Risk Factors:
1. The amount of lymphatic tissue in transplanted organ and the degree of immunosuppression are key factors in increasing risk of PTLD. In kidney transplant recipients the risk of PTLD is 0.8-2.5%.
2. Weakened immune system is an instigator for infection related cancers, such as EBV positive PTLD. Pathogenesis: Role of EBV:
Due to weakened immune system, EBV mediated integration and proliferation of B cells goes unchecked leading to PTLD. The pathogenesis of EBV negative PTLD is less evident and may be due to other immunomodulator viruses such as CMV, or due to the type and degree of immunosuppression. WHO 2017 Classification:
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD. Clinical presentation:
It can present as a localized or as a fulminant disseminated multiorgan disease.
1. Pyrexia (57%)
2. weight loss (9%),
3. neurological manifestations (13%),
4. nodal lesions (38%),
5. gastrointestinal manifestations (27%),
6. pulmonary manifestations (15%)
7. infectious mononucleosis-like syndrome that could be fulminant (19%).
An associated high EBV viral load by PCR should make one suspect PTLD. Common sites:
A. Lymph nodes,
B. liver,
C. lung,
D. kidney,
E. bone marrow,
F. gastrointestinal tract (GIT), spleen,
G. central nervous system (CNS),
H. tonsils and salivary glands. Risk of EBV+ve PTLD depends on:
1. Type of transplant organ,
2. Time elapsed until diagnosis of post-transplant PTLD,
3. EBV serological status of both recipient and donor before transplant.
An estimation of the viral load via EBV-PCR is necessary to monitor pre-emptive PTLD therapy. It has been observed that transplant recipients with PTLD usually expresses an increased EBV viral load. Regarding preemptive therapy, cut-off values are not clear, sources of samples are not universal and there is absence of standard points of time to perform the monitoring.
Ideally EBV negative recipient should receive organ from EBV negative donor. Prophylactic anti-viral therapy can be considered in certain high-risk groups. Treatment: Reduction of immunosuppression:
1. 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA).
2. Withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF).
3. Apart from glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
Monitor response for 2-4 weeks. Rituximab therapy:
Rituximab can be used in:
(1) Non-destructive PTLD,
(2) Polymorphic PTLD, and
(3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
Chemotherapy, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone): Indications of Immunochemotherapy include:
1. Burkitt’s lymphoma,
2. Hodgkin’s lymphoma,
3. Peripheral T-cell lymphoma,
4. Primary CNS lymphoma and other uncommon lymphomas.
5. B-cell PTLD unresponsive to Rtx and RI.
Adaptive Immunotherapy in EBV positive PTLD refractory to the above-mentioned treatment modalities. Prognosis Poor prognostic criteria include the following:
1. Monoclonality,
2. Negative EBV serology,
3. Primary CNS involvement,
4. Tumour originated from T-cell,
5. Performance status ≥ 2,
6. Chemotherapy-based therapy (plus RI), and, 7. Multiple involved locations Re-transplantation: Re-transplantation can be considered after successful control of PTLD as the risk of recurrence of PTLD after re-transplantation is low. A minimum of one year may be considered before re-transplantation.
Introduction
Post-transplant lymphoproliferative disorders are among the most common malignancy following solid organ transplantation and hematopoietic stem cell transplantation. EBV, which has been associated with PTLD, infects a B cell either by reactivation of dormant infected B cells as a result of severe immune suppression or from a transplanted organ.
It is of note that most of the PTLD (>85%) either locally or systemically usually present in the first year following organ transplantation
Epidemiology of PTLD
Since 1969 when pen et al first described five cases of PTLD, awareness about the disease has been on the rise due to the following suggested reasons;
better diagnostic tool
older age of the donor and recipient
increase awareness about the disease
new immunosuppressive strategies
introduction of haplo-identica HSCT
Risk factor
Solid organ transplantation, highest in lung and lowest in kidney transplantation
In Allogenic HSCT, the incidence is higher in the use of T -cell depleting agents compare to non T cell depleting agent
Past exposure to immunosuppressive treatment before kidney transplantation
Oncogenic EBV
WHO 2017 Classification of PTLD
Three nondestructive PTLD
Polymorphic PTLD
Monomorphic PTLD
Classic Hodgkin lymphoma PTLD
Clinical presentation
It can vary from symptomless to fulminant disease with multi-organ failure.
Pyrexia
weight loss
Neurological lesion
Nodal lesion
GIT manifestation
Pulmonary manifestation
Infectious mononucleosis-like symptoms
Treatment of PTLD
Reduction of immunosuppression
Rituximab therapy
Chemotherapy
Adoptive immunotherapy
Future Strategies in treatments
Bruton thyroxine kinase inhibitor
Inhibitor of P13K and mTOR
Proteosome inhibitor
Radioimmunotherapy
Checkpoint inhibitor
Re-transplantation and PTLD recurrence
Successful re-transplantation is feasible after a failed allograft due to PTLD by considering the following factors
Time to re-transplantation: 2 years wait is advised
Transplant recipients should experience Epstein–Barr nuclear antigen IgG positivity
Low/absent EBV viral load is recommended at the time of retransplantation.
Close monitoring of TRs with persistently high EBV viral load is advised.
Anti-viral therapy: Long-term prophylactic antiviral therapy with a serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence
Care in the choice of the induction therapy and the magnitude of IM used
Conclusion
PTLD, is largely a disease entity driven mostly by EBV and an increase in the use of immunosuppressive medications and this has helped in the understanding of appropriate prevention and management of the disease.
III.Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Please summarise this article
Abstract
Post-transplant lymphoproliferative disorders (PTLD) include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissues to frank malignancy with aggressive behavior.
Two main risk factors of PTLD are cumulative immunosuppressive burden and impact of Epstein-Barr virus.
Treatment for PTLD includes reduction of immune suppression, rituximab therapy or isolated or in combination with other chemotherapeutic agents
PTLD has been recognized in SOT as well as HSCT since 1969 and this may be due to better diagnostic technology and older age of donors and recipients.
The advent of new immunosuppressive strategies and introduction of the Haplo-identical (HSCT) have also contributed to the increased recognition of PTLD.
SIRs of 10 (non-Hodgkins lymphoma) have been reported among SOT recipients, but not among those who have received HSCT.
In adults, the incidence of PTLD has been reported to range from 0.8%- 2.5% in kidney transplant recipients (KTR) and 0.5%-5.0% in pancreatic TRs.
PTLD incidence is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant.
The risk of PTLD has been relatively lower with the use of non-specific broad lymphocyte depleting agent (T- and B-cells).
The magnitude of increased risk can be graded by whether the patient had a matched donor or not.
PTLDs in allogeneic HSCT are donor-driven (EBV-infected lymphocytes) and are usually observed in 1st post-transplant year, with almost 100% being EBV-positive.
The most crucial contributing factors for PTLD evolution were the “donor type” as well as the “T-cell depleting strategy”.
The lack of long-term follow up of TRs may result in underestimation of actual incidence of PTLD.
By far, the primary EBV infection is considered the most effective factor triggering PTLD development in pediatric age group.
Furthermore, the evolution of the late PTLD has been on rise.
The presence of exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution.
EBV may alter cell growth via several mechanisms, including altering the levels of expression of cell targets and viral and cellular mRNA.
Serology via viral capsid antigens (VCA-IgG) antibody detection is the best solitary test to indicate previous EBV exposure. Healthy donors may carry the high-risk variants of LMP-1 that predispose to malignant evolution.
Understanding EBV molecular epidemiology and recognition of virulent strains can help in institution of preventive strategies.
Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Salient features: PTLD may present as a local or disseminated disease.
In either form, the tumor can behave aggressively in a rapidly progressive manner.
Lowering the threshold for PTLD diagnosis is crucial, as TR may present with nonspecific symptoms (e.g., fever, asthenia).
The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
The time to PTLD is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR.
The risk of EBV+ve PTLD has been postulated to be related to three factors:- A-Type of transplant organ,
B-Time elapsed until diagnosis of post-transplant PTLD C-And EBV serological status of both recipient and donor before transplant.
An estimation of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy
High-risk TR patients who present with pyrexia, pharyngitis and/or lymphadenopathy should consider other diagnoses e.g., Streptococcal infections or Infectious mononucleosis.
Early PTLD is often of diffuse large B-cell or other B- cell lymphoma histology; whereas Burkitt’s lymphoma and Hodgkin’s disease are late events.
“Cell-free plasma” has been reported as a better marker of EBV activity than DNA via peripheral-blood mononuclear cells (PRMC) in patients with polycystic ovary syndrome (PCOS) or post-transplant liver disease (PTLD).
Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be considered.
Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI.
=================================================================== Treatment of PTLD
RI
The treatment of patients with post-traumatic stress disorder (PTLD) is to ameliorate the immunosuppressive burden so that EBV-specific cellular immunity can be partially restored with no additional risk of acute rejection.
RI can reverse 20%-80% of patients’ responses to therapy, but a complete lack of response has been observed in old aged patients and bulky lesions.
Rituximab therapy
Rituximab therapy (Rtx) is a potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen, leading to B cell depletion via several mechanisms e.g., phagocytosis, complement mediated cytotoxicity, and natural killer cells.
Rtx has been approved as a standard therapeutic agent in PTLD for three WHO classification types.
Chemotherapy
Despite unproven efficacy, a reduction of the immunosuppressive burden should be evaluated by transplant physicians.
In all CD20+ve subtypes (75% or more), Rtx should be included.
The poor outcome of chemotherapy-treated PTLD patients between 1980 and 1990 was partially attributed to the high rates of therapy relate mortalities.
Patients with Pneumocystis jirovecii prophylactic therapy (SOT) for diffuse large B-cell lymphoma had poor prognosis before treatment.
However, their outcomes greatly improved after the advent of proper supportive care and administration of granulocyte colony-stimulating factors(G-CSF).
Overall response rate approached 88%, with 70% of cases with any response achieved acomplete response at the end of therapeutic program.
Adoptive immunotherapy has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells.
The major risk of this therapeutic modality, however, is GVHD development.
A variety of recent approaches e.g., adoptive transfer of “pamidronate-expanded Vγ9Vδ2 Tcells” and Tac-resistant, engineered CTLs has been admitted as new therapeutic options.
Patients at risk for EBV infection should be monitored by serial follow-up of their viral load and the response to therapy.
Persistently high or continuous rise in viral load indicates disease development or progression.
Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
Initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonalit.
International prognostic index IPI is a prognostic scoring system that includes the following: age, performance, current stage, lactate dehydrogenase (LDH), and number of extra-nodal locations.
It has been universally applied by most hematologists and oncologists to recognize the prognostic attitude in aggressive lymphoma.
The PTLD-1 trial has settled the prognostic validity of IPI but a second trial is currently in progress to optimize the role of these prognostic factors.
Using univariate analysis, the poor prognostic criteria have been postulated that include Monoclonality, negative EBV serology, primary CNS involvement and chemotherapy-based therapy (plus RI).
Re-transplantation after successful management of PTLD has been reported in only one case.
Retransplantation is possible if PTLD has been successfully managed.
Documented in specific individuals; nonetheless, after one year of disease-free survival PTLD under control before to re-transplantation
An anti-EBV partially acquired immunity has been proposed as a potential protective mechanism.
Close monitoring of TRs with persistently high EBV viral load is advised. Ganciclovir has been recommended for this purpose.
There is a general consensus that PTLD is disease of post-transplant immunosuppression.
Retransplantation after PTLD cure remains controversial due to the re-exposure of immunosutression.
ATG vs IL-2 receptor antagonists may provide two benefits, first, a lower risk of PTLD, and, second, TRs are more amenable to avoid long-term excessive injection facilities.
Potential risk of PTLD development should not interfere with our choice of proper immunosuppressive regimen :. Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy.
Post-transplant immunosuppression can cause major complications including post-transplant lymphoproliferative diseases (PTLD). Epstein-Barr virus (EBV) has a major role in PTLD development, however EBV-negative patients are frequent. Reducing immunosuppression is crucial to treating PTLD. Transplant doctors should be aware of this complication, especially in patients who had immunosuppression for primary renal illness. Early diagnosis requires high suspicion. Rituximab, chemotherapy, antivirals, adoptive therapy, and surgery are treatments.
Risk Factors
A- Solid organ transplantation: lowest in KTR 0.8%-2.5%, maximum in multi-organ and intestinal TRs 20%.
1-HSCT: T cell depletion agent
2-Umbilical-cord transplantation RR 4%-5%
3- Unrelated donor transplant RR 4%-10%
4- Match-related donor transplant RR 1%-3%
C—Immunosuppressive load. Induction therapy affects early-onset PTLD, however, Immunosuppressive load determines late PTLD.
D- Oncogenic EBV may affect cell development in numerous ways:
1- Immune recognition deficiency
2- Environmental conditions induce powerful oncogenes.
3- EBV-induced proliferating cells and variant/HLA types may allow these proteins to bypass immune regulation and go unidentified.
4- Growth changes
Role of EBV: For years, PTLD formation was linked mostly to EBV infection, however, current data reveal that as much as 50% PTLD in SOT are not accompanied by EBV infection. For EBV-positive TRs, the development of PTLD can be linked to immunosuppressive-induced reduction in the T-cell immuno-surveillance.
Classification based on numerous variables:
1- According to the period of onset, PTLD is divided into Early and Late Onset.
2- Based on histopathological classification according to WHO 2017 Classification, as follows:
Plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD are three nondestructive PTLD. EBV infection observed in all TRs.
Polymorphic PTLD. EBV detected in greater than 90% of patients
Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). EBV only observed in 50%.
PTLD resembling classic Hodgkin’s lymphoma.
3- Gene expression profile and immunohistochemistry staining
Clinical picture
Variations in clinical presentation of PTLD range from asymptomatic lesions to fulminant illness with multi-organ failure.
EBV monitoring for preventative therapy:
Viral load by PCR of peripheral blood EBV DNA is required for monitoring preventative PTLD therapy.
Challenges: there are no cutoff values, no universal sources of samples, and there is no standard monitoring time.
Compared to EBV DNA extracted from peripheral blood mononuclear cells, “cell-free plasma EBV DNA” has been described as a more accurate indicator of EBV activity. Treatment
All patients with PTLD should get early therapy that includes immunosuppression reduction unless issues with graft rejection or graft-versus-host disease make this approach impossible.
Rituximab is an effective chimeric anti-CD20 monoclonal antibody that binds to CD-20 antigen and causes B lymphocytes to be eliminated through a variety of processes, including phagocytosis (macrophages), complement-mediated cytotoxicity, and natural killer cells (antibody-dependent cell-mediated toxicity) (antibody-dependent cell-mediated toxicity).
Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and other uncommon lymphomas are among the cancers that can be treated with immunochemotherapy.
PTLD in HSCT patients, which is primarily caused by donor cells, has been reported to be controlled by adoptive immunotherapy using donor lymphocyte infusion. Retransplantation
After 1-2 years without PTLD disease, retransplantation may be an option.
Induction therapy should not have any substances that kill T cells, so IL2 receptor antagonists are the best choice. Rituximab can be used to start treatment in high-risk patients.
The lowest safe doses of triple therapy should be used for maintenance therapy.
There is a place for giving ganciclovir to people with high viral loads as a preventive measure. Should, if possible, have low or no viral loads.
The use of mTORi is debatable.
; Epidemiology of PTLD ; ———————————————————————————-
The increased risk is expressed as “standardized incidence ratios” (SIRs) , the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort). SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients.
Risk factors; ——————————————————————————-
1-The amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors.
2-PTLD incidence is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant.
3-The presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution.
4-Oncogenic EBV: EBV may alter cell growth via several mechanisms .
Pathogenesis; ————————————- The role of EBV :
1-The development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immune-surveillance.
2-EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells.
Classification: ————————————————-
depending mainly on histopathological classification, diagnosis of PTLD can be categorized according to WHO 2017 Classification, as follows:
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD .
Gene-expression profile and immunohistochemical staining have been used to classify the diffuse large B-cell lymphoma in immunocompetent subjects depending on the cell of origin into;
1-“germinal center” B cell .
2-“non–germinal” center B cell.
In PTLD, EBV+ve cases are mostly non-germinal center B-cell type, in contrary to the EBV-ve cases that are more likely to be “germinal center B-cell type”. Clinical presentation: ———————————————————————–
PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure . Clinical manifestations include:
1-Pyrexia (57%) .
2- weight loss (9%) .
3-neurological manifestations (13%)
4-nodal lesions (38%) .
5-gastrointestinal manifestations (27%) .
6-pulmonary manifestations (15%) .
7-infectious mononucleosis-like syndrome that could be fulminant (19%) .
8-An allograft dysfunction may ensue due to graft involvement. Lowering the threshold for PTLD diagnosis is crucial, as TR may present with nonspecific symptoms (e.g., fever, asthenia).
9-An associated high EBVviral load by PCR should make one suspect PTLD.
10-The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands .
Differential diagnosis: ——————————————————
Any high-risk TR who presents with pyrexia, pharyngitis and cervical lymphadenopathy would make one consider other diagnoses e.g., streptococcal infections or Infectious mononucleosis .
Time to PTLD for different transplanted organs: —————————————————————————–
1-The time to PTLD is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR.
2-Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology.
3- Burkitt’s lymphoma and Hodgkin’s disease are late events .
EBV monitoring for preemptive therapy: ——————————————————————– .
1-An estimation of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy.
A- It has been observed that TR with PTLD usually expresses an increased EBV viral load as compared to PTLD free TR.
B- Higher viral load invites more risk for PTLD evolution.
2- Cell-free plasma EBV DNA;
Compared to the reliability of EBV DNA via peripheral-blood mononuclear cells, the “cell-free plasma EBV DNA” has been reported as a better marker of EBV activity .
Considering a suitable preemptive approach should be confined to the high-risk group of PTLD patients, however, the precise definition of the cohort of patients at high risk has not been established yet .
Prophylaxis: ————————————————
1-Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
2-Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
3- Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function have been also recommended .
TREATMENT OF PTLD; —————————————————————————————– 1-RI ;
1-RI can reverse 20%-80% of patients with PTLD.
2-Compared to EBV positive disease, the EBV negative cases are less responsive to RI However, a complete lack of response to RI has been observed in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann
Arbor stage III/IV) .
3-RI plan includes ;
a-50% reduction of calcineurin inhibitors .
b- Withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF) .
c-With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
4-Monitoring allograft function is mandated during the trial of RI to recognize any manifestations of early rejection.
Rituximab therapy ;
1-Rtx has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
2-The overall response to Rtx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases . Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5% .
3- In the PTLD-1 trial the complete remission rate approached 25% after standard induction augmented by another four doses of 3 weekly Rtx (low-risk patients).
4- in comparison with the group of TRs with complete remission with Rtx followed by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), the low-risk group in the cohort receiving risk-stratified sequential expressed longer disease-free survival at 3 year, despite no change in overall survival .
Chemotherapy; ——————————————————-
1-Indications of Immunochemotherapy include:
1- Burkitt’s lymphoma . 2- Hodgkin’s lymphoma . 3- peripheral T-cell lymphoma . 4- primary CNS lymphoma . 5- Other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
2-Safety and efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen every 3 wk and G-CSF support have been elucidated in the PTLD-1 trial .
3- A risk-stratified sequential therapeutic approach has been admitted in the second part of this trial as follows: Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy.
4- Considering an excellent outcome reported of this trial, a
reduction of the immunosuppressive load and risk-stratified sequential therapy are widely considered the standardized care of polymorphic and monomorphic diffuse large B-cell lymphoma-like PTLD (regardless to EBV status) after SOT.
Adoptive immunotherapy; ————————————————————
1-Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD.
2-A variety of recent approaches has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load e.g.,
A-adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells”.
B-Tac-resistant, engineered CTLs .
Outpatient care; ————————————————–
In light of serial follow up of the EBV viral load in identifying the patients at risk and in monitoring the response to therapy, the following steps have been suggested:
(1) Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
(5) Therapeutic options should be tailored as per multidisciplinary team discussion.
(6) The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality . Future strategies; ———————————————-
A list of newer therapeutic medications has been proposed . However, their efficacy remains to be validated via randomized controlled trials:
Re-transplantation and PTLD recurrence; ——————————————————————————-
To limit the possibility of PTLD recurrence the following recommendations are worth noting:
(1) Time to retransplant:
————————————–
Approximately two years of time should elapse after successful PTLD management.
(2) EBV:
—————————-
The following recommendations is currently suggested in the literature:
(a) TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation.
(b) Low/absent EBV viral load is recommended at the time of retransplantation.
(c) Close monitoring of TRs with persistently high EBV viral load is advised.
(d) Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence. Ganciclovir has been
suggested for this purpose.
(3) Induction therapy: The following agents are considered:
—————————————————————————-
(a) ATG vs IL-2 receptor antagonists: The T cell-depleting agents should be excluded from the induction strategies with IL-2 receptor antagonists appeared to have the first priority.
(b) Rituximab in induction therapy: Rt may be introduced as an element of desensitization regimen in high-risk TR. Rtx has been used before in bone marrow or heart TR with seriously high EBV loads in order to inhibit EBV proliferation within lymphocytes, consequently limiting the risk of PTLD development .
(a) Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered.
(b) MMF: Considering the safety of MMF in regard to PTLD evolution, MMF can be included safely in the immunosuppressive protocols with no more added risk.
(c) mTOR inhibitors: Their role in PTLD development remains debatable. These agents may inhibit the development of lymphomas in vitro, but their clinical application in human still warrant the proper evidence.
(d) Graft PTLD: Is very intriguing ( and usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative.
(5) Monoclonal gammopathy:
——————————————–
The presence of monoclonal gammopathy may indicate incompletely remitted PTLD, its complete resolution is an obvious indicator of complete remission.
(6) Origin of PTLD (donor vs recipient):
—————————————————–
Identification of the tumor source is crucial for future therapeutic plans and recognition of the biology of the next PTLD.
. What is the level of evidence provided by this article?
Level V
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches.
1. This is a review article.
2. Summary:
Incidence and Risk factors:
Risk factors are, reportedly, varied according to the type of the transplant organ. For SOT: In adults, the incidence of PTLD has been reported to range from 0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ and intestinal TRs. These figures suggest that the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors.
Compared to EBV seropositive TRs, the seronegative patients in SOT are more vulnerable to develop PTLD with an increased estimated risk of 10-75%.
Two peaks of PTLD incidence have been observed, first peak: In the first post-transplant year (mostly EBV seropositive), and second peak: Usually present 5-15 years after transplant (mostly EBV seronegative). Pathogenesis Role of EBV: For decades, PTLD development was attributed mainly to EBV infection, however, recent reports suggest that as many as 50% PTLD in SOT are not accompanied by EBV infection. Diagnosis of PTLD can be categorized according to WHO 2017 Classification, as follows: (1) Three non-destructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD. (2) Polymorphic PTLD. (3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). And (4) classic Hodgkin’s lymphoma-like PTLD. Clinical presentation: Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure. Differential diagnosis: Any high-risk TR who presents with pyrexia, pharyngitis and cervical lymphadenopathy would make one consider other diagnoses e.g., streptococcal infections or Infectious mononucleosis. TREATMENT OF PTLD
The mainstay of primary PTLD management is to ameliorate the immunosuppressive burden, so that EBV-specific cellular immunity can be partially restored with no additional risk of acute rejection. RI can reverse 20%-80% of patients with PTLD. RI plan includes 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF), despite the lack of evidence demonstrating any relation between MMF and PTLD development . With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered. Considering their early response, TR can be restaged within two to four weeks in contrary to lymphoma staging in immunocompetent patients. Monitoring allograft function is mandated during the trial of RI to recognize any manifestations of early rejection. An acute rejection rate of 37% has been observed in a prospective trial entailed the RI strategy as a sequential plan for post-SOT PTLD therapy .
Compared to EBV positive disease, the EBV negative cases are less responsive to RI. Other therapy includes: Rituximab therapy: However, Rtx has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. The overall response to Rtx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases. Chemotherapy Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and R.
A risk-stratified sequential therapeutic approach has been admitted in the second part of this trial as follows: Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy. Adoptive immunotherapy Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells. The major risk of this therapeutic modality, however, is GVHD development. Outpatient care:
In light of serial follow up of the EBV viral load in identifying the patients at risk and in monitoring the response to therapy, the following steps have been suggested:
(1) Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
(5) Therapeutic options should be tailored as per multidisciplinary team discussion.
(6) The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality. Prognosis
Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care. Seventy percent of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years. Re-transplantation and PTLD recurrence
Feasibility of re-transplantation after successful management of PTLD has been reported in particular cases; however, one-year disease free survival is necessary after control of PTLD before re-transplantation.
PTLD are one of the most important malignancies after solid organ transplantation AND
HBCT.
Usually observed in the first post-transplant year
Due to B cell proliferation
:
B cells may get infected by Epstein-Barr virus (EBV) either by:
(1) Post-transplant viral reactivation.
(2) Primary EBV infection, through the donated organ or via environmental exposure
.
T-cell proliferation is less, most EBV negative.
Epidemiology of PTLD:
Increased awareness of PTLD prevalence:
Better diagnostic technology, older age of donors and recipients, increased awareness
of this disorder, the advent of new immunosuppressive strategies and introduction of the
haplo-identical. Standardized incidence ratios:
SIRs of in SOT, 10 (non.-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma)
PTLD in 3.2% of HSCT. Risk factors:
1- SOT:
0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs,
1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in
multi-organ and intestinal TRs
2-Allogenic HSCT:
Degree of HLA matching with consequent introduction of T-cell depleting agents prior
to transplant.
The type of induction therapy has a fundamental role in the early developed PTLD, the
one that develops late PTLD is largely determined by cumulative immunosuppressive
burden.
(1) HSCT (zero in patients who received cyclophosphamide for GVHD and > 20% with
Introduction: 21% of malignancies post solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) are post transplant lymphoproliferative disorders (PTLD) which occur due to blunted immune surveillance causing uncontrolled B cell proliferation and infection by Epstein-Barr virus (EBV). More than 85% of the cases occur within first year post-transplant. T cell related PTLD is less common, and usually EBV-negative. Tissue histopathology, and evidence of EBV (DNA or protein material) is crucial for diagnosis of PTLD.
Epidemiology: In SOT, the standardized incidence ratio (SIR) of PTLD is high, being 10 for non-Hodgkin’s lymphoma and 4 for Hodgkin’s lymphoma. In HSCT, PTLD incidence is 3.2%. Time to PTLD in children is minimum for lung and lung/heart transplants, while maximum is for heart transplant patients. Diffuse large B-cell PTLD present early while Burkitt’s and Hodgkin’s disease present late.
Risk factors: They include type of SOT (maximum with multiorgan and intestinal transplant, and minimum with renal transplant), donor type and use od T cell depleting strategies in HSCT, history of prior immunosuppressive use, and EBV.
2 peaks of PTLD have been observed – early PTLD (in first year post-transplant, mostly with EBV, and second peak 5-15 years post-transplant, mostly EBV-negative). Early PTLD has been associated with induction immunosuppression, and late PTLD is associated with cumulative immunosuppression dose.
Pathogenesis: In EBV-positive PTLD, immunosuppressive induced reduced T-cell immune-surveillance in presence of integration of EBV in B cell leading to unchecked B cell proliferation causes PTLD. In EBV-negative PTLD, the mechanisms postulated include infections like cytomegalovirus (CMV), prolonged immunosuppression, and allograft-driven persistent antigenic triggering.
Classification: WHO classifies PTLD into 4 different types, namely non-destructive PTLD (100% EBV positive – plasmacytic hyperplasia, follicular hyperplasia, and infectious mononucleosis, IMN like PTLD), polymorphic PTLD (>90% EBV positive), monomorphic PTLD (50 % EBV-positive – B cell type, T cell type, and natural killer cell type), and classic Hodgkin’s lymphoma (>90% EBV positive).
Clinical presentation: Symptoms include fever (57%), lymphadenopathy (38%), gastrointestinal features (27%), IMN like syndrome (19%), pulmonary manifestations (15%), central nervous system (CNS) manifestations (13%), and loss of weight (9%). Graft dysfunction can be seen.
Differential diagnosis: Any patient with fever, weight loss, pharyngitis and cervical lymphadenopathy should be considered for streptococcal infections or IMN.
Prophylaxis: EBV serology of both donor and recipient should be known prior to transplant. EBV-negative recipient should receive organ from EBV-negative donor. Pre-emptive/ prophylactic antiviral therapy in high-risk groups and maintenance of high anti-EBV antibody titres using intravenous immunoglobulin (IVIG) is recommended.
Treatment of PTLD: It includes
a) Reduction of immunosuppression (RIS- reduce calcineurin inhibitors by 50%, stop antimetabolites): Can reverse 20-80% PTLD. EBV-negative, age more than 50, bulky lesions (>7 cm), and Ann Arbor stage III and IV are less responsive. Acute rejection can occur in upto 37%.
b) Rituximab: 4 weekly doses of rituximab are given in nondestructive PTLD, polymorphic PTLD, and monomorphic diffuse large B cell lymphoma like PTLD non-responsive to RIS. It has as response rate of 44-79% with complete remission in 20-55%, which further increases to 34-60% on using 4 more doses.
c) Chemotherapy: It is used for B-cell PTLD non responsive to RIS and rituximab, Burkitt’s’ lymphoma, Hodgkin’s lymphoma, peripheral T cell lymphoma, and primary CNS lymphoma. It includes regimes like Rtx + CHOP (rituximab with doxorubicin, cyclophosphamide, vincristine, and prednisolone) every 3 weeks for 4 cycles. It should be accompanied by GCSF (Granulocyte colony stimulating factor) and pneumocystis jirovecii prophylaxis.
d) Adoptive immunotherapy: It includes using donor lymphocyte infusion and EBV-specific cytotoxic lymphocytes (CTLs) in autologous as well as donor-derived PTLD.
Outpatient care post-transplant includes regular physical examination, radiology, allograft function monitoring, and monitoring of EBV viral titres.
Prognosis: International prognostic index (IPI) is used for prognosis. 70% complete remission with median survival of 6.6 years has been seen with use of newer treatment protocols. Poor prognosis is associated with monoclonality, EBV-negative serology, primary CNS involvement, T-cell origin tumor, performance status ≥2, chemotherapy based therapy, and >site involvement.
Re-transplantation and PTLD recurrence: One year disease free survival is necessary before re-transplant (wait for 2 years), presence of EBV-IgG positive status, low/absent EBV viral load, close monitoring of EBV viral load, long-term prophylactic anti-viral therapy (Ganciclovir), Avoid T-cell depleting agents as induction therapy, avoid intense immunosuppression (MMF safe, mTOR inhibitor use is debatable)
Conclusion: PTLD is due to immunosuppression, hence first step in treatment is reduction of immunosuppression. Multidisciplinary involvement is required for optimal management. It is rare to recur after re-transplant.
2. What is the level of evidence provided by this article?
1- Summary of the study:
A review article sowed the clinical features and management of PTLD.
Epidemiology:
Lymphoma accounts for 21% of all malignancies in SOT recipients as compared to 4% and 5% in immunocompetent individual.
SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients.
Two peaks of PTLD incidence have been observed, first peak: In the first post-transplant year (mostly EBV seropositive), and, second peak: Usually present 5-15 years after transplant (mostly EBV seronegative)
Risk factors:
1- The amount of lymphoid tissue in the graft and degree of IS ( more in intestinal
and muliorgan tx , then lung, then heart, then liver and least incidence in renal
TX)
2-Immunosuppression: induction play a role in early PTLD and cumulative IS
status is responsible for delayed PTLD
3- Previous exposure to IS during CKD
4- EBV:
a- reactivation
b- new infection: more in seronegative recepient and children.
Pathogenesis:
For EBV-positive TRs, the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immunesurveillance. Leading to unlimited Bcell transformation and the evolution of lymphoma.
Pathogenesis of PTLD in EBV-negative patients is less evident. Several hypotheses have been postulated e.g., CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes.
EBV infection could be currently seen in almost all transplant patients with nondestructive PTLD, in > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD, and in only 50% of monomorphic PTLD
Clinical manifestations:
PTLD may present as a local or disseminated disease. Either forms behave aggressively.
Clinical manifestations include: Pyrexia , weight loss, neurological manifestations (13%), nodal lesions (38%), gastrointestinal manifestations, pulmonary manifestations and infectious mononucleosis-like syndrome that could be fulminant
graft involvement
high EBV viral load
The time to PTLD is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR.
Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology; whereas Burkitt’s lymphoma and Hodgkin’s disease are late events.
Treatment:
Reduction of immunosuppression is the cornerstone of PTLD management.
Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and, monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
Chemotherapy (CHOP) is indicated for: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to rituximab and reduction of immunotherapy.
post-R-CHOP supportive G-CSF was mandated in all patients with anti-Pneumocystis jirovecii prophylactic therapy.
Other modalities may include adoptive immunotherapy (EBV-specific cytotoxic lymphocytes (CTLs)). The major risk of this therapeutic modality, however, is GVHD development.
Prognosis:
Seventy percent of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years.
A minimum of one year may be considered before re-transplantation, but a longer period may be needed.
To limit possibilities of recurrence:
1- Time to re-transplant: Approximately two years of time should elapse after successful PTLD management 2- EBV: a- Recipient should experience Epstein–Barr nuclear antigen IgG positivity b- Low/absent EBV viral load is recommended at the time of re-transplantation.
c- Close monitoring of TRs with persistently high EBV viral load is advised
d- Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of
EBV viral load is crucial to limit the incidence of PTLD recurrence. 3- Immunotherapy:
a- ATG vs IL-2 receptor antagonists: The T cell-depleting agents should be
excluded from the induction strategies with IL-2 receptor antagonists
appeared to have the first priority.
b- Rituximab induction may be introduced as an element of desensitization
regimen in high-risk TR.
c- Maintainance triple therapy. Maintain the lowest safe dosages monitored by
target trough levels should be considered
d- MMF is safe
e- mTOR inhibitors: Their role in PTLD development remains debatable
f- Complete resolution of monoclonal gammopathy is an obvious indicator of
complete remission
Post transplantation Lymphoproliferative disorder: Current concepts and future therapeutic approaches. Introduction: PTLD is most common in post-SOT and HSCT, due to B cell uncontrolled proliferation, as a result of immune suppression. Most cases are due to EBV-associated infection, and it can be:
Post-transplant virus re-activation.
Primary EBV infection.
Usually occur within the first year post-transplant and it is a common one, mostly EBV associated, and represents 85% of cases. Rare cases can occur late up to 10% and it can be EBV- negative and it could be T-cell proliferation. It can be:
Localized lesion.
Systemic disease.
Recipients should be aware of this possible complication, and an effort should be done to minimize the incidence and to find a way to a total cure. The cornerstone of treating PTLD is immunosuppressant reduction. Risk factors:
SOT.
HSCT.
Immunosuppressants, and infection-related malignancy.
T cell depleting agents.
Lac of long-term follow-up.
Previous immunosuppressant exposure for the treatment of native kidney primary disease.
Oncogenic EBV.
EBV oncogenicity:
With suppressed immune system, the unrecognized EBV induces a highly regulated transformation and expression of growth-inducing proteins.
Induction of potent oncogenes; LMP1, and LMP2.
EBV-induced cellular proliferation.
Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA.
Pathogenesis:
Many of PTLD is EBV associated.
Immunosuppressant induces reduce T cell surveillance.
B cell proliferation and transformation.
Uncontrolled proliferation led to evolution of lymphoma.
EBV-negative PTLD are attributed to; prolonged immunosuppressant, allograft driven persistent antigenic triggering, and hit- and -run hypothesis.
Classification:
Three non-destructive PTLD: plasmocytic hyperplasia, florid floccular hyperplasia, and infectious mononucleosis-like PTLD.
Polymorphic PTLD.
Monomorphic PTLD; (B-cell, T-cell, or natural killer cell).
Classic Hodgkins lymphoma-like PTLD.
Clinical presentation:
Pyrexia.
Weight loss.
Neurological manifestation.
Nodal lesion.
GIT manifestation.
Pulmonary manifestation.
Infectious mononucleosis like syndrome.
Allograft dysfunction.
Most common sites of involvement of PTLD:
Lymph nodes.
Liver.
Lung.
Kidney.
Bone marrow.
GIT.
Spleen.
CNS.
Tonsils.
Salivary gland.
Differential diagnosis:
Streptococcus infection.
Infectious mononucleosis.
Prophylaxis:
Recipient and donor selection before donation; (EBV serostatus).
A fine tuning of immunosuppressant burden to as low as clinically possible.
Reactivation of other viruses, make over immunosuppressant burden and augment B cell proliferation.
Maintenance of high titer of anti-EBV anti-bodies via IVIG/CytoGam administration.
Monitoring EBV viral load in high- risk case.
Treatment:
reduction of immunosuppressants.
Rituximab therapy.
Chemotherapy.
Adoptive immunotherapy.
Outpatient care.
Serial follow up of viral load.
Weekly monitor of viral titer.
Serial physical examination.
Optimum balance between PTLD management and avoidance of allograft rejection.
Multidisciplinary team management.
Future strategy:
Ibrutinib; Broton’s tyrosine kinase inhibition, effective in allograft rejection, and in B cell activation.
Idelalisib; Inhibitor of PI3K and mTORi.
Bortezomib; proteasome inhibition.
Radioimmunotherapy.
Pembrolizumab, nivolumab; cytotoxic T lymphocyte-associated antigen 4 pathway.
Brentuximab vedotin; anti-CD30.
Prognosis:
Great improved outcome due to new protocol.
70% of PTLD -1 patient achieve a complete remission, with median survival of approximately 6.6 years.
IPI prognostic scoring system, in aggressive lymphoma, which include age, performance attitude, current stage, LDH, extra-nodal location.
Re-transplantation and PTLD recurrence:
1-year free survival before conducting re-transplantation.
Recurrence was low documented in one study involving 55 retransplant patient.
Time to transplant should be 2 years after successful PTLD management.
Role of IS, PTLD is the IS magnitude associated, so IS reduction is the cornerstone of management.
ATG induction should be avoided.
Rituximab as desensitization can be used in high-risk TR.
Maintenance IS should be maintained at dose so as to avoid both risk of PTLD and as well as rejection.
Conclusion: PTLD is the disease of immunosuppression. Identification of risk factor, adjustment of IS dosage, understand the underline pathology, and advances in future treatment, selection of R/D, serial follow up, planning of re transplantation are all vital in dealing with such comorbid condition.
III. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approachesPlease summarise this article
*The objective of this study:
To show the incidence, clinical pointer, prophylactic measures in addition to current and future therapeutic approach of this overwhelming disorder.
Introduction:
* PTLD are frequent malignancies post- sold organ and hematopoietic stem-cell transplantation, due to uncontrolled B cell proliferation as a result of abrupt in immunological surveillance.
* The B cells may get infected by (EBV) in post-transplant viral reactivation; or due to primary infection.
*Great numbers of PTLD cases more than 85% are developed in the first year following transplantation.
*PTLD due to T-cell proliferation was developed in fewer cases and is mostly EBV-negative.
*PTLD may manifest either as localized lesion or as systemic disease.
* Tissue diagnosis is mandatory for PTLD diagnosis, as well as clear identification of EBV DNA, RNA, or protein material.
The risk factors:
According to the type of the transplant organ: (1) SOT:
The amount of lymphatic tissue in an allograft and the degree of immunosuppression are important factors. (2) Allogenic HSCT:
The degree of HLA matching with consequent introduction of T-cell depleting agents before transplantation. (3) The presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution. (4) Oncogenic EBV
EBV may alter cell growth via several mechanisms: growth transformation ,induction of the potent oncogenes, by-pass immune control and go unrecognized. And growth alterations with the right levels of expression of cell targets and viral and cellular mRNA.
The pathogenesis:
*50% PTLD in SOT are not contributed to EBV infection.
*For EBV-positive PTLD, can be attributed to immunosuppressive-induced decline in the T-cell immunesurveillance.
* EBV-negative patients is less evident.CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis.
*EBV-positive vs EBV-negative PTLD: In the light of molecular-genomic data of diffuse large B-cell lymphoma subtype, a range of distinguishing features have been identified to discriminate between EBV+ve and EBV-ve PTLD.
Classification:
Depending on histopathological classification, diagnosis of PTLD can be categorized according to WHO 2017
Classification, as follows: (1) Three nondestructive PTLD: plasmacytic hyperplasia,
florid follicular hyperplasia, and infectious mononucleosis-like PTLD. (2)Polymorphic PTLD. (3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell
types). (4) classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
*It is vary from symptomless lesions to fulminating disease with multi-organ failure.
*Clinical manifestations include: Pyrexia , weight loss, CNS symptoms, nodal lesions, GIT, pulmonary manifestations and infectious mononucleosis-like syndrome.
* An allograft dysfunction may ensue due to graft involvement.
* Lowering the threshold for PTLD diagnosis is crucial, as TR may present with nonspecific symptoms (e.g., fever, asthenia). An associated high EBV viral load by PCR may suspect PTLD.
* The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, (GIT), spleen, (CNS), tonsils and salivary glands.
Differential diagnosis:
Any high-risk TR who presents with pyrexia, pharyngitis and
cervical lymphadenopathy
The treatment of PTLD:
*The important step of management of PTLD reduction of immunosuppression (RI), it can reverse 20%-80% of patients.
*RI plan includes 50% reduction of (CNI), in addition to withdrawal of the antimetabolites.
* With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
* TR can be restaged within two to four weeks in
contrary to lymphoma staging in immunocompetent patients. Monitoring allograft function is mandated during the trial of RI to recognize any manifestations of early rejection.
*Compared to EBV positive disease, the EBV negative cases are less responsive to RI.
*Absent of response to RI occurred in old aged patients (>
50 years), bulky lesions (> 7 cm) and in advanced stages of the disease.
Rituximab therapy:
Rtx has been approved as a standard therapeutic agent in PT: (1) Nondestructive PTLD
(2) Polymorphic PTLD
(3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
The complete response can be interpreted as three associated benefits:
Better overall survival, extended time to progression, and better progression-free survival.
Chemotherapy:
*The indications of Immunochemotherapy:
Burkett’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
* Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with
G-CSF support in cases with no complete response to isolated Rtx therapy.
Adoptive immunotherapy:
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT, with a high risk of GVHD.
Outpatient care:
*Weekly monitoring of EBV viral titers in higher risk patients.
*Monthly monitoring initially followed by three monthly monitoring for low risk groups.
*Persistently high or continuous rise in viral load indicates disease development or progression.
* Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of
comprehensive clinical picture that includes EBV viral load assessment.
* Therapeutic options should be tailored as per multidisciplinary team discussion.
*The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality.
The prognosis:
*Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care.
70% of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years.
CONCLUSION:
*PTLD is a disease of immunosuppression, so understanding it is pathophysiology and the role of EBV has led to a better management.
*PTLD recurrence has been rarely reported after re transplantation that requires careful planning of immunosuppression.
* Improving moleculargenomic technology has had its impact on upgrading our diagnostic and therapeutic strategies that will be reflected in improved recipient’s outcome.
What is the level of evidence provided by this article?
Introduction
Post-transplant lymphoproliferative disorders (PTLD)one the commonest cause of malignancies after solid organ transplantation (SOT) Lymphoma accounts for 21% of all malignancies in SOT recipients as compared to 5% in immunocompetent individuals. most of PTLD cases (> 85%) are usually observed in the first post-transplant year,
commonly, it is associated with B-lymphocyte proliferation and it is associated with EBV infection either pre or posttransplant. less commonly, PTLD is related to T cell proliferation mostly in the absence of EBV infection Epidemiology of PTLD
“Standardized incidence ratios” (SIRs) i.e., the incidence of lymphoma in transplant cohort divided by its incidence in general population used to express the incidence.
SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients in comparison to the HSCT where the incidence is 3.2% of recipients in multicenter studies. Risk factors
A- SOT : amount of lymphatic tissue in different organ
Degree of immunosuppression with the peak incidence in the 1st year post transplantation ((mostly EBV seropositive )owing to the type of induction immunosuppression used and the one that develops late ( mostly EBV negative )PTLD is largely determined by cumulative immunosuppressive burden
B- HSCT: The most crucial contributing factors for PTLD evolution were the “donor type” as well as the “T-cell depleting strategy” Pathogenesis
Role of EBV : EBV is prevalent in adult population by more than 90% infection acquired during childhood where it get attach to B lymphocyte through specific site ( CD21 ) and stimulate the cell protein factory to produce its antigens (3 nuclear antigen and three surface membrane protein) that stimulate Cytotoxic T lymphocyte to control the infection . hence the virus within the infected slave B lymphocyte enter in latent phase inside lymphoid tissue so long the immune system is potent . under any weakness of immune system ( HIV infection or solid organ transplantation SOT) latent antigenic machine inside B lymphocyte will be active and can cause lymphoproliferative disease
An associated EBV infection could be currently seen in almost all TRs with nondestructive PTLD, in > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD, and in only 50% of monomorphic PTLD (Figure 4). Pathologically, monomorphic PTLD cannot be discriminated from lymphomas in immunocompetent patient
Classification : : according to WHO 2017 Classification
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). And
(4) classic Hodgkin’s lymphoma-like PTLD
Clinical presentation: vary from symptomless lesions to fulminating disease with multi-organ failure.
Onset either with local or systemic disease
Course: variable and disease may has a rapidly progressive course Manifestations include
Pyrexia (57%).
weight loss (9%).
neurological manifestations (13%).
nodal lesions (38%).
, gastrointestinal manifestations (27%).
pulmonary manifestations (15%).
and infectious mononucleosis-like syndrome that could be fulminant (19%) Differential diagnosis
Other causes of lymphadenopathy either local or generalized Prophylaxis:
Identification of EBV sero-status of both donor and recipient should be recognized before donor selection.
EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
Adjustment of the immunosuppressive burden to as low as clinically possible.
Ealy detection and treatment of Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression.
Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
Maintenance of high titers anti-EBV antibodies via IVIG/Cyto Gam administration is also recommended Treatment A- Reduction of immunosuppression it can reverse 20%-80% of patients with PTLD Either
– withdrawal of MMF or Azathiopine
– Reduction of CNI by 50%
– Or withdrawal all immunosuppressive leaving steroids in criticall ill patients Note:
– Close monitoring for acute rejection
– a complete lack of response to RI has been observed in :
– old aged patients (> 50 years),
– bulky lesions (> 7 cm),
– in advanced stages of the disease (Ann Arbor stage III/IV) B- Rituximab therapy ( in addition to RI): if PTLD not responding to RI in the 3 class of WHO classification mentioned above
– Complete remission in 20%-55% of cases
– Response is observed in 44%-79% of PTLD cases
– Administration as 4 weekly dosesof 375 mg/m2
– Another 4 weeks doses can improve the response C- Chemotherapy indications are:
– Burkitt’s lymphoma,
– Hodgkin’s lymphoma,
– peripheral T-cell lymphoma,
– primary CNS lymphoma and other uncommon lymphomas,
– and B-cell PTLD unresponsive to Rtx and RI
– Can be used sequentially with rituximab in addition to other supportive treatment like antibiotic ( for associated infection ) and granulocyte colony-stimulating factors (G-CSF) D- adoptive immunotherapy
through Infusion of donor lymphocytes, Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD E- out patient care
Therapeutic options should be tailored as per multidisciplinary team discussion.
(1) monitoring of EBV viral titer
– weekly in in higher risk patients.
– Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) Serial physical examination, radiology testing and monitoring allograft function
(3) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial. New startiges
1. Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib) 2. Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)] 3. Proteasome inhibition (Bortezomib) 4. Radioimmunotherapy (90Yibritumomab, tiuxetan) 5. Checkpoint inhibitors (Pembrolizumab, nivolumab) 6. Anti-CD30 therapy (Brentuximab vedotin) Re-transplantation
Many transplant physicians recommend 12 to 24 mo after complete PTLD remission, before commencing a new kidney transplant The following are of concern: 1- EBV: The following recommendations is currently suggested in the literature:
(a) TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation.
(b) Low/absent EBV viral load is recommended at the time of retransplantation.
(c) Close monitoring of TRs with persistently high EBV viral load is advised.
(d) Anti-viral therapy: Long-term prophylactic antiviral therapy, Ganciclovir has been suggested for this purpose 2- Immunosuppressive Induction therapy: ATG and IL-2 receptor antagonists
– induction with ATG significantly triggers the risk of lymphoma evolution as compared to other agents .
– IL-2 receptor antagonists however, may provide two benefits, first, a lower risk of PTLD development, and, second, TRs are more amenable to avoid long-term excessive immunosuppression after retransplantation. Maintenance immunosupresssion
– The target in regard to maintaining immunosuppression is to avoid the intense state of immunosuppression so that the recovered immune system can promote the evolution of the anti-EBV cytotoxic T lymphocyte, thereby, hampering EBV-triggered B cell proliferation
– Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered
Conclusion
“Risk-stratified sequential” therapeutic approach with monitoring for acute rejection and use of other modalities may include adoptive immunotherapy and outpatient care. Investigational agents that’re currently under trials have been shown above.
PTLD: Current concepts and future therapeutic approaches
Summary
· PTLD is a well-known complication after SOT due to cumulative effect of immunosuppressive and oncogenic properties of EBV infection(either reactivation or 1ry infection) leading to uncontrolled proliferation of infected B cells in 90 % of cases, while in 10 % who are EBV-ve (proliferation of T cells).
· Standardized incidence ratios” (SIRs): the incidence of lymphoma in transplant cohort divided by its incidence in general population and it equals 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) among SOT recipients
· Transplant team should be aware of this complication, particularly in patients who were exposed to large cumulative dose of immunosuppression during treatment of immune mediated original kidney diseases.
· Diagnosis is based on tissue pathology plus evidence of EBV (PCR).
· Available ttt are reduction of immunosuppression, antiviral, rituximab either monotherapy or followed by chemotherapy (CHOP).
· Risk factors:
o Type of organ transplantation (highest risk in intestine then heart and lung (according to the amount of lymphoid tissue in transplanted organ.
o Use of T cell depleting agents as ATG induction therapy, has high risk.
o EBV serostatus prior to transplantation, R-/D+ as in pediatric transplantation.
· Testing for EBV in transplant recipients depends on PCR, not serology, as humoral immune response in such immunocompromised individuals may be affected and antibodies be undetected.
· PCR has 2 limitations: no standard ideal sample (serum, whole blood or peripheral lymphocytes) and no clear cut off level to start ttt.
· Clinical manifestations include generalized constitutional manifestations ads fever, weight loss and may be pure peripheral lymphadenopathy in 10 % of cases, while nodal involvement in 38% of cases, CNS and graft involvement each in 30% of cases.
· Prevention: Use of EBV-ve donor for -ve recipients, chemoprophylaxis against CMV infection which can help or increase risk of PTLD (together with EBV), surveillance of the high-risk group for PTLD.
· Treatment:
o Reduction of immunosuppression (RIS): stop MMF and AZA , decrease CNI by 30-50% with close monitoring of remission of tumor within 2-4 weeks + surveillance of early signs of acute rejection.
o Rituximab:
§ Used if no complete remission is achieved after RIS.
§ old aged patients (>50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (AnnArbor stage III/IV).
§ Effective as monotherapy in nondestructive PTLD, polymorphic PTLD, and, monomorphic diffuse large B-cell lymphoma-like PTLD
o Sequential chemotherapy (CHOP) cycle every 21 days. Indicated in Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI with variable results
o Adoptive immunotherapy as EBVSTs. In recurrent /relapsed cases with EBV+ve.
o Monitoring during therapy:
§ Tumor regression by follow up radiology.
§ Graft function and surveillance for rejection.
§ FU of EBV viral load (Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups). § Although viral titer does not always correlate with PTLD activity, persistent high or rising titer may indicate none responsive or worsening disease. o Future therapy (under trials):
o Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib):
o mTORi SRL and everolimus: robust immunosuppressive impact, introduction in PTLD therapy still controversial.
o Proteasome inhibition (Bortezomib): Particularly efficacious in the early presented PTLD post allogeneic HSCT.
o Radioimmunotherapy
o Yibritumomab, tiuxetan): Apparent efficacy seen only in a small pilot trial.
o Checkpoint inhibitors (Pembrolizumab, nivolumab): Cytotoxic T lymphocyteassociated antigen 4 pathway:
o Anti-CD30 therapy (Brentuximab vedotin): Expression of CD30 in 85% of all PTLD subtypes: only limited to case reports. Level of evidence: narrative review (level V).
PTDs are serious complication following organ transplantation occurring mainly due to cumulative immunosuppression and the impact of oncogenic virus (EBV)
PTLD is characterized by uncontrolled by lymphoid proliferation, mainly EBV infected B cell
The majority of cases of PTLD are EBV positive, and when compared to EBV negative cases, EBV + PTLD occur earlier, is associated with relatively better prognosis than EBV negative cases, and mainly of B cell type (T cell lymphoma is typically EBV negative)
EBV negative PTLD can occur due to CMV or other viral infection like HHV-8, prolonged immunosuppression, lymphoma occurring in non-transplant recipient or disappearance of EBV after development of PTLD ( hit and run).
PTLD accounts for 20% of all cancers occurring after transplantation, around 85% of cases occurring in the first year after transplantation.
Risk factors for post-transplant malignancy
Pre-transplant EBV status, patients with seronegative EBV status are at increasing risk of early PTLD especially if the donor is positive, and this may explain the higher risk of PTLD in children compared to adult
Immunosuppression duration and intensity including the use of ATG and CNI, on the other hand MMF and sirolimus may decrease the risk
Age (pediatric recipients are at greater risk due to seronegative EBV status)
The cause of renal failure, as patients who develop ESRD due to immune disease are a greater risk due to the burden of immunosuppression
Clinical presentation (diagnosis needs high index of suspicion)
Constitutional symptoms (fever, night sweats, weight loss and fatigue)
Lymphadenopathy which is uncommon in PTLD
Extranodal masses ( in 50% of cases)
Compression manifestations (by lymph node or extranodal masses)
Organ dysfunction related to infiltration such as gastrointestinal tract (stomach, intestine), liver, lungs, CNS and skin
Florid follicular hyperplasia; polyclonal or monoclonal polymorphic B cell proliferations with some features of malignant lymphoma
Monoclonal proliferations ( B-cell, T-cell, or natural killer-cell)
Classic Hodgkin’s lymphoma-like PTLD
Prevention of PTLD
EBV negative patients should receive whenever possible EBV negative graft
Screening is indicated only in high risk patients (donor EBV seropositive/ recipient seronegative) using EBV PCR monitoring, although the problem is that there is no clear cut off point to start therapy
Controlled use of immunosuppression, avoid unneeded over immunosuppression
Antiviral prophylaxis should be considered in high risk group
IVIG/CytoGam is recommended to maintain high titers anti-EBV antibodies
Management of PTLD (challenging and needs multidisplinary team)
A- Modulation of immunosuppression
Including either reduction of immunosuppression (stops antimetabolite and reduce CNI by 50%)
Benefit should be weighed against risk of rejection especially in case of vital organs such as the heart
In aggressive PTLD, complete withdrawal of antimetabolite and CNI may be done, keeping high dose steroid to prevent occurrence of symptoms related to acute rejection
Response should be assessed within 2-4 weeks
Older age> 50 years, large lesions > 7 cm and advanced stages of disease (Arbor stage III/IV) predict failure to reduction of immunosuppression.
All patients with PTLD should reduce immunosuppression under the guidance of transplant physician with close follow up of graft function. In patients using reduction of immunosuppression only as a treatment, close follow up within 2-4 weeks is recommended for assessment of response and the need for further therapy. Older patients > 50 years, large lesions > 7 cm and advanced stages of disease (Arbor stage III/IV) predict failure to reduction of immunosuppression alone, so additional therapy may be given from the start
In patients who fail to respond to reduction of immunosuppression, Rituximab induction should be initiated in a dose of 375 mg/m2 per week for four weeks and then the patient response is assessed better using PET-CT scan.
Patients who undergo complete remission after Rituximab induction should receive Rituximab consolidation (4 cycles of Rituximab given every 21 days).
Patients who fail to obtain complete remission or who progress after Rituximab induction should receive 4 cycles of R-CHOP-21 every 21 days.
Patients with clinically aggressive PTLD (severe organ affection) should immediately receive R-CHOP -21 chemotherapy together with reduction of immunosuppression.
Involved-field radiotherapy can be added to the standard protocol in selected patients with certain histological subtypes or can be used as mono-therapy together with reduction of immunosuppression in localized disease.
Adoptive immunotherapy with EBV specific cytotoxic T cells needs further evaluation to asses the safety to use in transplant recipients and may be given for selected EBV + resistant cases.
Resistant and relapsed PTLD patients should be encouraged to participate in clinical trials if available.
What is the level of evidence provided by this article?
● PTLD are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT)
● It is a result of uncontrolled B cell proliferation
● The majority of PTLD (> 85%) are usually observed in the first post-transplant year. ● PTLD as a result of T-cell proliferation is less and is mostly EBV-negative.
● Lymphoma accounts for 21% of all malignancies in SOT recipients as compared to 4% and 5% in immunocompetent individuals respectively in men and women
● SIRs of lymphoma is 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) among SOT recipients.
● The incidence of PTLD is 0.8% – 2.5% in adult kidney transplant recipients and 0.5%-5.0% in pancreatic ,1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ andintestinal TRs
● Risk factors :
☆ The amount of lymphatic tissue in an allograft
☆ The degree of immunosuppression
☆ Use of T-cell depleting strategies
Impaired immune surveillance for EBV , HIV
☆ The “donor” type
☆ The primary EBV infection especially in pediatric age group.
● Two peaks of PTLD incidence have been observed:
◇ first : the first post-transplant year (mostly EBV seropositive)
◇ second : 5-15 years after transplant (mostly EBV seronegative).
☆ Pesence of previous exposure to the immunosuppressive load
(4) Oncogenic EBV:
1- lack of immune recognition
2- Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
3- EBV induced proliferating cells
4- Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA
● Molecular plus serological methods (anti VCA IgG )combination may allow early detection of EBV
● EBV integrate normal B-cell program leading to proliferation and transformation of these cells.
● pathogenesis of PTLD in EBV-negative patients is :
* CMV or another viral infection
* prolonged immunosuppression
* allograft-driven persistent antigenic triggering, hit-and-run hypothesis
● T-cell subtype PTLD (usually EBV-ve)
● Classification of PTLD:
* plasmacytic hyperplasia
* Polymorphic PTLD.
* Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
* classic Hodgkin’s lymphoma-like PTLD.
● > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD associated EBV infection and in only 50% of monomorphic PTLD
● PTLD-EBV+ve are mostly non-germinal center B-cell type, in contrary to EBV-ve that are more likely to be “germinal center B-cell type
● PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
● An allograft dysfunction may due to graft involvement.
● An associated high EBV viral load by PCR should make one suspect PTLD
● The most common locations of PTLD involvement are :
Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands .
● Differential diagnosis:
▪︎Streptococcal infections
▪︎Infectious mononucleosis
● The risk of EBV+ve PTLD is related to three factors:
* Type of transplant organ
* Time until diagnosis of post-transplant PTLD
* EBV serological status of both recipient and donor before transplant
● pitfalls in preemptive strategy monitoring:
☆ Cut-off values are not clear
☆ Sources of samples are not universal
☆ Absence of standard points of time to perform the monitoring.
● preemptive strategies to limit the risk of PTLD development
• RI
• rituximab therapy
• adoptive transfer of EBV-specified T cells. ● Prophylaxis:
☆ EBV sero-status of both donor and recipient should be recognized before donor selection.
☆ EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
☆ A fine-tuning the immunosuppressive burden to as low as clinically possible.
☆ Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
● TREATMENT OF PTLD
● RI :
☆ The mainstay of PTLD management
☆ RI can reverse 20%-80% of patients with PTLD
☆ RI plan includes
▪︎50% reduction of CNI
▪︎withdrawal antimetabolites
▪︎exception of glucocorticoids
▪︎withdrawal of all immunosuppressive medications in critically ill cases should be considered.
☆ Monitoring allograft function during RI to recognize early rejection.
☆ EBV negative are less responsive to RI Compared to EBV positive
☆ lack of response to RI observed in
▪︎Old aged patients (>50 years)
▪︎Bulky lesions (> 7 cm)
▪︎Advanced stages ( stage III/IV)
● Rtx treatment :
☆ A standard therapeutic agent in three of PTLD types :
(1) Nondestructive PTLD
(2) Polymorphic PTLD
(3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
● Chemotherapy Indications include: ▪︎Burkitt’s lymphoma
▪︎Hodgkin’s lymphoma
▪︎Peripheral T-cell lymphoma
▪︎Primary CNS lymphoma
▪︎Uncommon lymphomas
▪︎B-cell PTLD unresponsive to Rtx and RI
☆ Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy.
☆ Overall response rate 88%
● Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown
to manage PTLD in HSCT patients that is primarily originating from donor cells.
● The major risk is GVHD development
● Expanded EBV-specific CTLs have been an effective therapeutic
● Outpatient care
☆ Weekly monitoring of EBV viral titers in higher risk patients.
☆ Monthly monitoring initially followed by three monthly monitoring for low risk groups
☆ load drop denotes a response to therapy
☆ persistently high or continuous rise in viral load indicates disease development or progression
☆ Serial physical examination
☆ keep balance between PTLD management and avoidance of allograft acute rejection
☆ Therapeutic options should be tailored as per multidisciplinary team discussion.
● Future strategies
(1) Bruton’s tyrosine kinase (BTK) inhibition
(Ibrutinib): Virtually active in GVHD and allograft rejection remarkably active in activated B cells (ABC) type diffuse large B cell lymphoma (DLBCL)
(2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)] SRL and everolimus
(3) Proteasome inhibition (Bortezomib)
(4) Radioimmunotherapy
(5) Checkpoint inhibitors
(6) Anti-CD30 therapy (Brentuximab vedotin) Expression of CD30 in 85% of all PTLD subtyps
● Prognosis
☆ 79 % of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years
☆ IPI is a prognostic scoring system that includes the following:
* Patient’s age
* performance attitude
* current stage
* lactate dehydrogenase (LDH)
* number of extra-nodal locations.
☆ poor prognostic
▪︎Monoclonality
▪︎negative EBV serology
▪︎primary CNS involvement
▪︎tumor originated from T-cell, ▪︎performance status ≥ 2
▪︎chemotherapy-based therapy (plus RI)
▪︎multiple involved locations
● Recommendations to limit the PTLD recurrence :
(1) Time to retransplant: two years should elapse after successful PTLD management
(2) positive Epstein–Barr nuclear antigen IgG in TR before retransplantation.
(3) Low/absent EBV viral load at the time of retransplantation.
(4) Close monitoring of TRs with high EBV viral load
(5) Long-term prophylactic antiviral therapy as Ganciclovir
(6) Exposure to immunosuppression in
retransplantation after PTLD cure remains controversial
(7) The T cell-depleting agents should be excluded from the induction strategies with priority to IL-2 receptor antagonists (8) Rituximab in induction therapy
(9) Maintenance immunosuppression: The lowest dosages Of maintenance therapy
(10) mTOR inhibitors: their clinical application in human still warrant the proper evidence
● Graft PTLD usually has good prognostic outcome and graft nephrectomy is almost curative
● Level : 5
Introduction
PTLD are one of the most important malignancies after SOT and HSCT due to uncontrolled B cell proliferation
EBV can infect B cells by either post-transplant viral reactivation or primary EBV infection (donor organ or environmental exposure)
Most cases of PTLD (> 85%) are usually observed in the first post-transplant year
PTLD T-cell is less common and mostly EBV-negative
The magnitude of cumulative immunosuppressive burden has a crucial role in PTLD evolution
PTLD may manifest clinically as localized lesion or as systemic disease
The aim of the study is to discuss the prevalence, clinical clues, prophylactic measures, and the current and future therapeutic strategies of this devastating disorder
Risk factors
According of type of immunosuppression:
1. SOT: the incidence of PTLD is 0.8%2.5% in KTR, ≤ 20% in multi-organ and intestinal TRs. The amount of lymphatic tissue the degree of immunosuppression are the key factors
2. Allogenic HSCT: the incidence of PTLD is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant
3. Previous exposure to the immunosuppressive load during treatment of the primary renal disease
4. Oncogenic EBV
Pathogenesis
Role of EBV:
EBV-positive TRs: immunosuppressive-induced decline in the T-cell immunesurveillance. EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells
PTLD in EBV-negative patients: pathogenesis is not clear (CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes)
EBV-positive vs EBV-negative PTLD:
EBV-positive PTLD (Fewer genomic abnormalities, mostly B-cell proliferative lesions, non-germinal center B-cell, more common (first peak), less risk compared to seronegative TR, and almost all cases of HSCT (100%) are EBV positive)
EBV-negative PTLD (share many genomic/ transcriptmic features with diffuse large B-cell lymphoma in immunocompetent patients, mostly T-cell proliferative lesions, germinal center B-cell type, less common (second peak), seronegative SOT pediatric TR are more vulnerable to develop PTLD with increased estimated risk of 10-75, and in SOT, both EBV positive and negative are present)
Classification
WHO 2017 histopathological classification:
1. Three nondestructive PTLD (plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD). Almost all associated with EBV
2. Polymorphic PTLD. EBV in > 90% of patients.
3. Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). EBV in only 50%
4. Classic Hodgkin’s lymphoma-like PTLD. EBV in > 90% of patients
Clinical presentation
Vary from symptomless lesions to fulminating disease with multi-organ failure. PTLD May present as a local or disseminated disease. Symptoms include: Pyrexia (57%), weight loss (9%), neurological manifestations (13%), nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant (19%)
The most common locations of PTLD involvement are: Lymph nodes, liver, lung, kidney, bone marrow, GIT, spleen, CNS, tonsils and salivary glands
EBV monitoring for preemptive therapy
Should be confined to the high-risk group (viral load via PCR)
Prophylactic antiviral
EBV-negative TR is better receiving grafts from EBV-negative donors (do EBV serology)
Should be considered in potentially high-risk groups (negative recipient, positive donor)
Monitoring of EBV viral load and considering preemptive RI with rising titers, with close monitoring of allograft function
Treatment
RI
The cornerstone of management is to ameliorate the immunosuppressive burden
RI can reverse 20%-80% of patients with PTLD
50% reduction of CNI, in addition to withdrawal of the antimetabolites (azathioprine or MMF)
In critically ill patients, withdrawal of all immunosuppressive medications should be considered with the exception of glucocorticoids
Monitoring allograft function (acute rejection in 37% in a prospective trial)
EBV negative cases are less responsive to RI
No response to RI in old aged patients (> 50 years), bulky lesions (> 7 cm), and advanced stages of the disease (Ann Arbor stage III/IV)[60]
Rituximab (Rtx)
A potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen, leading to B cell depletion
Approved for three types of the WHO classification: nondestructive PTLD, Polymorphic PTLD, and monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI
Response to Rtx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission in 20%-55% of cases. Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5%
Chemotherapy
Indications of Immunochemotherapy include Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
Sequential therapeutic approach: Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy. Overall response rate approached 88%, with 70% of cases with any response achieved a complete response at the end of therapeutic program
Adoptive immunotherapy
Infusion of donor lymphocytes or EBV-specific cytotoxic lymphocytes (CTLs) to abort the EBV-driven proliferation of B cells in EBV-associated PTLD (in HSCT)
The major risk is GVHD
Recent approaches: adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells” and Tac-resistant, engineered CTLs
Outpatient care
To identify patients at risk and monitoring response of therapy:
5. High risk: monitor weekly. Low risk: monthly initially followed by three monthly
6. Viral load drop indicates therapy response; persistent high or increase load denotes disease development or progression
7. Serial physical examination, radiology and monitoring allograft function
8. Optimize balance between PTLD management and avoidance of allograft rejection
9. Therapeutic options through MDT discussion
10. The initial therapeutic step is RI or cessation of immunosuppression and further therapeutic options accordingly
Prognosis
70% of the PTLD-1 patients: complete remission (median survival of 6.6 years) IPI prognostic scoring system includes the following: Patient’s age, performance attitude, current stage, LDH, and number of extra-nodal locations Poor prognostic criteria include: Monoclonality, negative EBV serology, primary CNS involvement, tumor originated from T-cell, performance status ≥ 2, chemotherapy-based therapy (plus RI), and, multiple involved locations
Re-transplantation and PTLD recurrence
Wait for at least one year after complete remission
To reduce PTLD recurrence:
1. Time to retransplant ( 2 years after successful PTLD treatment)
2. EBV: TR should experience Epstein–Barr nuclear antigen IgG positivity before retransplantation. Low/absent EBV viral load is recommended at the time of retransplantation. Close monitoring of TRs with persistently high EBV viral load is advised. Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence (Ganciclovir)
3. Immunosuppression: PTLD is disease of post-transplant immunosuppression. The fundamental trigger for PTLD evolution is the magnitude of immunosuppressive intensity
4. Induction therapy: T cell-depleting agents should be excluded. ATG induction significantly triggers the risk of lymphoma evolution
5. Maintenance immunosuppression: avoid the intense state of immunosuppression. Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered. MMF can be included safely in the immunosuppressive protocols with no more added risk. The role of mTOR inhibitors in PTLD development remains debatable. These agents may inhibit the development of lymphomas in vitro, but their clinical application in human still warrant the proper evidence. Graft PTLD usually has a good prognostic outcome; furthermore, graft nephrectomy is almost curative.
6. Monoclonal gammopathy: complete resolution of monoclonal gammopathy indicates complete remission
7. Origin of PTLD (donor vs recipient): guide using cytotoxic T cell infusions in PTLD management. The outcome is better in TRs with “donor” lymphomas
Conclusion
PTLD is a disease of immunosuppression
Better management relies on understanding the pathophysiology of PTLD and the role of EBV
Although PTLD recurrence is rare, it requires careful plan of strategies
Molecular genomic technology has a great impact on diagnostis and therapeutic strategies with improvement of recipient’s outcome
Close contact with hemato-oncology team is fundamental
What is the level of evidence provided by this article?
Level V (narrative review)
–INTRODUCTION;. Post-transplant lymphoproliferative disorders (PTLD) are lymphoid and/or plasmacytic proliferations that occur as a result of immunosuppression in the setting of solid organ or allogeneic hematopoietic cell transplantation. These conditions lie along a continuum of disease and are categorized by the World Health Organization PTLD classification system . PTLDs are among the most serious complications of transplantation.
-EPIDEMIOLOGY;. -INCIDENCE –PTLD is the most common malignancy complicating solid organ transplantation (excluding nonmelanoma skin cancer and in situ cervical cancer), accounting for approximately 20 percent of all cancers. In contrast, PTLD accounts for a minority of secondary cancers following allogeneic hematopoietic cell transplantation (HCT). -RISK FACTORS -The principal risk factors underlying the development of PTLD are the degree of T cell immunosuppression and the Epstein-Barr virus (EBV) serologic status of the recipient. Additional risk factors include time post-transplant, recipient age, and ethnicity
-PATHOGENESIS EBV-positive disease — In most affected patients, PTLD is an Epstein-Barr virus (EBV)-positive B cell proliferation occurring in the setting of immunosuppression and decreased T cell immune surveillance. –PATHOLOGIC FEATURES The diagnosis of PTLD is based upon the evaluation of histologic, immunophenotypic, and genetic studies. The World Health Organization classification of tumors of the hematopoietic and lymphoid tissues uses morphologic, immunophenotypic, genetic, and clinical features to define four main categories of PTLD: ●Plasmacytic hyperplasia and infectious mononucleosis-like PTLD ●Florid follicular hyperplasia ●Polymorphic PTLD ●Monomorphic PTLD ●Classic Hodgkin lymphoma-like PTLD -DIAGNOSIS An accurate diagnosis of PTLD requires a high index of suspicion. Radiologic evidence of a mass, or elevated serum markers (such as increased lactate dehydrogenase [LDH] levels) are suggestive of PTLD; positive positron emission tomography (PET) scanning also favors the diagnosis. A tissue biopsy, preferably an excisional biopsy, with review by an expert hematopathologist, is required to ensure an accurate diagnosis. Diagnosis of central nervous system or cardiac lymphoma is particularly difficult
TREATMENT
Reduction in immunosuppression RIS should be incorporated into the initial management of all patients with PTLD unless concerns regarding graft rejection or graft-versus-host disease make this approach unfeasible.
Rituximab therapy
Rituximab (Rtx) is a potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen, leading to B cell depletion via several mechanisms e.g., phagocytosis (macrophages), complement mediated cytotoxicity, and through natural killer cells (antibody-dependent cell-mediated toxicity).
Chemotherapy Indications of Immunochemotherapy include:
Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells
PROGNOSIS
Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care.
70% of the PTLD patients had achieved a complete remission with median survival of approximately 6.6 years.
2-What is the level of evidence provided by this article? This article is a narrative review (level of evidence is V).
Introduction
PLTD is a common malignancy post SOT and HSCT,it occurs due to uncontrolled growth of B cell.EBV usually infect B cells either primarily or by reactivation ,it is noticed in the first year post transplant. PTLD of T Cell origin is less common and is EBV negative.
The immunosuppressive load has a direct effect on PLTD occurrence.
In SOT lymphoma accounts for 21% of all malignancies.
PTLD could be localised or systemic disease.
High index of suspicion is needed for the diagnosis ,with histopathology and EBV DNA , RNA or protein material.
The main treatment is RI which carries graft loss risk , surgical clearance, anti-viral agents, local radiotherapy, IVIG, chemotherapeutic agents, monoclonal antibodies and cytotoxic T lymphocytes. PTLD epidemiology
PTLD incidence is 3.2% in HSCT recipients and it’s recognition has increased due to advanced technology, increase of the donor and recipient age and new immunosuppressive regimens as well as haploidentical HSCT. Risk factors
-SOT: Multiorgan and intestinal transplant has the highest incidence while kidney transplant has the lowest.
-Allogenic HSCT: HLA degree of matching and the T cell depleting agents affects the risk, where the more the matching the lower is the risk and the risk was low with broad lymphocyte depleting agents.
EBV negative recipients are more susceptible to develop PTLD, early occurrence is with EBV positive recipients while late occurrence is associated with EBV negative cases.
-Immunosuppressive exposure in primary renal disease therapy before transplantation increase immunosuppression burden.
-Oncogenic EBV causes growth transformation, initiation of oncogenes, bypass immune control, cell targets, viral and cellular mRNA expression.
Molecular and serological methods together early detection of EBV Pathogenesis
50% of PTLD are EBV negative with unclear specific pathogensis.
In EBV positive cases ,defective T cell surveillance through immunosuppressives is implicated. EBV-positive vs EBV-negative PTLD
There is no clear difference but some differences can be noted
EBV negative: has features similar to diffuse large B-cell lymphoma in immunocompetent patients, mostly T cell lesion of germinal B cell center type ,less prevalent , common with seronegative SOT in pediatrics.
EBV positive :is more common , of B cell origin of non germinal center type ,prevalent with HSCT Early versus Late onset PTLD
Early onset represent the majority of PTLD cases ,it is usually associated with EBV positive cases, with graft involvement and is non destructive , donor derived ,less common to be Monomorphic subtypes and bortezomib can be useful after allogeneic HSC also Induction therapy has a role.
Late onset is less prevalent ,mostly EBV negative with extra nodal involvement more than graft affection, with high incidence of late onset Hodgkin’s lymphoma after allogeneic HSCT and cumulative immunosuppressives have an important role. WHO 2017 classified PTLD into 3 non destructive PTLD , Polymorphic ,Monomorphic , classic Hodgkin’s lymphoma-like PTLD.
EBV-encoded RNA (EBER) in-situ hybridization evaluation is mandatory for PTLD diagnosis . Clinical picture varies from being asymptomatic to multiorgan failure
Time to PTLD for different transplanted organs
It is longest for the heart recipients and shortest for the lung and heart/lung transplantation in pediatric . Early PTLD is commonly diffuse large B-cell while late PTLD is usually Burkitt’s
lymphoma and Hodgkin’s disease EBV monitoring for preemptive therapy
It has limitations and suffer lack of standardised recommendations
Type of transplant organ, time elapsed till post-transplant PTLD and EBV serological status before transplant are 3 factors that affect EBV positive PTLD occurrence.
High EBV load increases PTLD risk. Cell-free plasma EBV DNA is a good marker of EBV activity Prophylaxis
Donor and recipient viral status has to be screened before selection where EBV negative donors have to be selected for EBV negative recipients as much as applicable .
Immunosuppression load has to be decreased as much as possible to balance immunosuppression and rejection possibility .
RI is a strategy when ever viral reactivation is recognised along with vaccination for high risk cases with maintenance of high titer of anti-EBV antibodies as well as monitoring viral load level. PTLD treatment -RI
It can be effective in 20-80% of PTLD cases. It includes decrease of 50% of CNI doses and stopping antimetabolites meanwhile for severe cases all immunosuppressives need to be suspended except glucocorticoids.
Tracing allograft function is crucial .EBV negative PTLD is less likely to respond to RI. -Rituximab therapy
It is used as standardised treatment for non destructive PTLD, Polymorphic PTLD and Monomorphic diffuse large B-cell lymphoma-like PTLD unresponsive to RI
Rituximab monotherapy with RI can achieve 44%-79% complete remission detected in 20%-55% of cases also adding 4 doses of Rituximab can increase remission rate.
Comparing those patients with patients receiving RCHOP ,the low risk candidates had nearly the same over all survival but better disease free survival at 3 years . -Chemotherapy
Is used for Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and B-cell PTLD unresponsive to Rituximab and RI.
Chemotherapy treated PTLD cases whom experienced poor outcome was due to therapy related mortality meanwhile mortality was reduced with efficient supportive treatment and GCSF usage .
RCHOP therapy with GCSF had acceptable outcomes in PTLD 1 trial. Adoptive immunotherapy
Managing PTLD of donor’s origin by the donors lymphocytes are applied in HSCT opposite to PTLD occurring in SOT . EBV specific cytotoxic T lymphocytes can be used but GVHD is the main side effect.
Expanded EBV-specific CTLs were used in treatment of recipient-derived PTLD and donor-derived PTLD. Outpatient care
– monitor of EBV viral load for high risk cases weekly and for low risk monthly monitor at first then every 3 months
–monitor response to therapy through viral load tracing
– Serial physical exam, radiological evaluation and monitoring allograft function
-Balancing therapeutic modalities and rejection risk is mandatory
-MDT is crucial to create an individualized therapy
-RI is the first treatment option Future strategies under trial
· Bruton’s tyrosine kinase (BTK) inhibition is estimated to have a therapeutic role in GVHD and allograft rejection,DLBCL.
· Inhibition of PI3K and mTORi in PTLD
· Bortezomib in the early PTLD post allogeneic HSCT.
· Radioimmunotherapy under trial
· Checkpoints inhibitors are adviced only in trials due to the accompanied side effects
· Anti-CD30 therapy was used in case reports Prognosis
Improved due to using lymphoma specific strategies and advanced supportive care. 70% of PTLD cases had complete remission with median survival of 6.6 years.
IPI is the scoring system currently applied. Re-transplantation and PTLD recurrence
1-2 year of disease free survival after PTLD therapy is mandatory before re-transplantation.
Anti-EBV partially acquired immunity was hypothesised as a possible protective
mechanism.
To reduce recurrence risk it is recommended
o 2 years of time interval after PTLD complete remission .
o EBV : Epstein–Barr nuclear antigen IgG positivity indicates immunity before re transplantation, low EBV viral load before pretransplant, monitoring transplant with high viral load and antiviral therapy.
o Immunosuppression burden is a major risk for PTLD .
o Induction therapy; need to include IL2R antagonist instead of ATG, Rituximab can be used as desensitisation protocol
o Maintenance therapy : the lowest targeted trough levels of the triple therapy is recommended; MMF is considered safe while m TORI is controversial, and for graft PTLD , graft nephrectomy is curative.
o Monoclonal gammopathy indicates complete remission if completely resolved .
o Donor PTLD vs recipient PTLD: tumor source detection is essential for therapeutic protocols. Conclusion
Immunosuppression is the main risk for PTLD . Discovering the pathogenesis and EBV role improved the therapeutic options thereby the prognosis.
PTLD is an important post transplant complication which result from uncontrolled B cells proliferation that get infected by EBV through:
post transplant viral reactivation
primary EBV infection.
>85% of PTLD cases occur in first year post transplant.
T cell type of PTLD is less common with late presentation & not associated with EBV infection.
Risk factors:
HLA degree mismatch
use of T-cell depleting agents
EBV infection
prolonged use of immunosuppression before transplantation( for renal disease)
Pathogenesis:
EBV infection is a major cause of PTLD development.
`50% of PTLD in SOT are not associated with EBV infection.
EBV+ve PTLD can be explained by decline in T cell immunosurvillance that caused by immunosuppression
EBV-ve PTLD development hypothesis include CMV or other viral infection, long term use of immunosuppression, allograft-derived persistent antigenic triggering, hit-and- run hypothesis.
EBV+ve PTLD characterized by fewer genomic abnormalities, B cell proliferation, more common type of PTLD, & less risk compared to seronegative TR.
EBV-ve PTLD characterized by many genomic abnormalities, mainly due to T cell proliferation & less common type of PTLD.
Early PTLD characterized by EBV+VE, graft involvement, non destructive subtypes, induction have a role in its development and bortezumib can be useful for HSCT.
Late PTLDcharacterized by EBV-ve, less graft involvement, common extra nodal involvement, less common & cumulative immunosuppression is crucial in pathogenesis.
WHO classification of PTLD:
non destructive PTLD.
polymorphic PTLD.
monomorphic PTLD
classic Hodgkin lymphoma like PTLD.
PTLD can be presented as local or disseminated disease.
Can be presented with fewer, wight loss, neurological, GI or pulmonary manifestation, graft dysfunction& IM-like syndrome
Higher EBV DNA associated with more risk for PTLD development compared to PTLD free TR.
Pre-emptive monitoring of EBV viral load have several pit falls:
unclear cut off value.
non universal sample source.
absence of standard time for viral load monitoring.
Prophylaxis measures to reduce PTLD incidence:
determination of seri-status of both donor & recipients with careful donor selection.
Control of immunosuppression burden
immunosuppression reduction during CMV or BKV infection.
pre-emptive prophylaxis in selected high risk patients.
maintain high EBV antibodies via IVIG/CytoGam.
Treatment of PTLD:
Reduction of immunosuppression
rituximab
chemotherapy
R-CHOP + G-CSF
adoptive immunotherapy.
Follow-up of EBV viral load:
For high risk patients, follow-up done weekly then monthly, for low risk patients every 3 months
persistent high viral load during treatment indicate disease progression.
monitoring of graft function with regular physical & radiological exam.
balance between PTLD treatment & avoidance of acute rejection.
Multidisciplinary team decision about treatment option is essential.
Future treatment strategies:
BTK inhibitors.
inhibition of PI3K & mTOR-i
protease inhibitors.
radiotherapy.
chick point inhibitors.
IPI is a prognostic scoring system include patient age, performance status, current disease stage, LDH, & number of extra nodal involvement.
French registry system is another scoring system. include patient age, serum creatinine, LDH, PTLD localization & histopathological criteria.
1 year of disease free survival is essential before re-transplantation.
Recommendations to reduce risk of PTLD recurrence:
1-2 years after complete remission before considering re-transplantation.
EBV nuclear antigen IgG+ve, low or absent viral load.
Summarise. Introduction
PTLD is a common malignancy following solid organ and hematopoietic stem cell transplantation.
Majority of the cases it is caused by uncontrolled B cell proliferation due to compromised immunosurveillance. However in rare cases it can be caused by T cell proliferation and in this cases it is EBV negative.
In over 80% of the cases it occurs in the first year post-transplantation.
The B cell are infected by EBV either through primary infection from the donated organ or from post-transplant reactivation. Risk factor depends with the organ donated. Solid organ transplant highest risk associated with graft with highest lymphatic tissue and degree of immunosuppression. While hematopoietic stem cell transplant depends with the HLA matching and use of T cell depleting agents prior to transplantation. Pathogenesis:
EBV seropositive disease: the virus integrates itself into the B cell leading to proliferation and transformation. The B cells proliferate due to lack of T cell mediated immune surveillance.
EBV negative disease: pathogenesis less clear but could be due to other viruses like CMV. Classification
WHO classifies PTLD into four categories:
Non destructive
Polymorphic
Monomorphic
Classic Hodgkins lymphoma like PTLD
For non-destructive, polymorphic >90% and classic Hodgkins lymphoma like PTLD are associated with EBV, while monomorphic only 50% are associated. Clinical presentation
Ranges from asymptomatic to constitutional symptoms including weight loss, pyrexia to multi-systemic disease that may involve the cns, git, lungs and spleen. Treatment
First line is reduced immunosuppression which induces remission in 20-80% of cases. The CNIs are reduced by 50% and the antimetabolites are withdrawn.
Steroids should be maintained.
There is a role of withdrawing all immunosuppressive and maintaining only steroids in acute illness.
Should have graft monitoring to detect any early signs of rejection.
EBV negative PTLD is less responsive to reduced immunosuppression.
Rituximab indicated in nondestructive, polymorphic and monomorphic PTLD unresponsive to reduced immunosuppression.
4 weekly doses followed by additional 4 doses have a complete remission rate of 34-60%.
Chemotherapy is indicated in unresponsive to rituximab and reduced immunosuppression.
CD20 positive PTLD should combine rituximab with chemotherapy.
Monitoring to maintain a balance between the reduced immunosuppressive and the cytotoxic and immunosuppressive effect of the chemotherapeutic agents.
Adoptive immunotherapy has a role in hematopoietic stem cell transplantation whereby there is infusion of donor lymphocytes to induce a EBV specific cellular immune response. Prognosis
Improved prognosis with better lymphoma specific protocol and supportive care. Retransplantation
There is a role of retransplantation after 1-2 years free of PTLD disease.
Induction therapy should ideally be free of T cell depleting agents hence IL2 receptor antagonists preferred. Rituximab may be used for induction in patients at high risk.
Maintenance therapy should be triple therapy with the lowest safe doses possible.
There is a role of giving prophylactic antivirals- ganciclovir in patients with high viral loads. Ideally should have low/absent viral loads.
MTOR inhibitors use debatable.
It result from uncontrolled B cell proliferation due to blunted immunological surveillance.
The role of EBV in PTLD evolution is well established, Bcells may get infected by:
Post-transplant viral reactivation
Primary EBV infection; the donated organ or via environmental exposure
Majority of PTLD are B cell origin, EBV positive and observed in the first post-transplant year.
PTLD as a result of T-cell PTLD is less commonly and is mostly EBV-negative.
Epidemiology of PTLD:
It accounts for 21% of all malignancies in SOT recipients
SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients.
Two peaks of incidence; first peak: In the first post-transplant year (mostly EBV+ve), and, second peak: Usually present 5-15 years after transplant (mostly EBV -ve)
Risk factors
A- SOT: the incidence is lowest in KTR 0.8%- 2.5% , and highest among multi-organ and intestinal TRs ≤ 20%.
B- Allogenic HSCT:
1- HSCT : use of T cell depletion agent
2- Umbilical-cord transplantation RR 4%-5%
3- Transplant from unrelated donors RR 4%-10%
4- Transplant from matched related donors RR 1%-3%
C- Immunosuppressive load.
-The type of induction therapy has a role in the early developed PTLD.
-Late PTLD is largely determined by cumulative immunosuppressive burden.
D- Oncogenic EBV: itmay alter cell growth via several mechanisms:
i. Lack of immune recognition
ii. Induction of the potent oncogenes via environmental factors.
iii. EBV induced proliferating cells as well as EBV variant/HLA types may permit these proteins to by-pass immune control and go unrecognized.
iv. Growth alterations.
Pathogenesis Role of EBV:
50% PTLD in SOT are not accompanied by EBV infection.
For EBV-positive TRs, PTLD can be attributed to immunosuppressive-induced decline in the T-cell immune surveillance.
EBV can integrate into normal B-cell leading to proliferation unlimited B cell transformation and the evolution of lymphoma.
Pathogenesis of PTLD in EBV-negative patients is less evident:
· CMV or another viral infection
· Prolonged IS
· Allograft-driven persistent antigenic triggering,
· Hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes.
Distinguishing features have been identified to discriminate between EBV+ve and EBV-ve PTLD by molecular-genomic data. However, the clinical consequences of EBV serotypes and their response to therapy is lacking
Classification:
A- Time of occurrence: Early and late onset PTLD.
B- Histopathological classification according to WHO 2017 Classification, as follows:
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD. EBV infection seen in almost all TRs
(2)Polymorphic PTLD. EBV seen in in > 90% of patients
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). EBV seen in only 50%.
(4) classic Hodgkin’s lymphoma-like PTLD.
C- Gene-expression profile and immunohistochemical staining for DLBCL. Clinical presentation:
– Clinically, can be localized lesion or as systemic disease.
– It manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
– In either form, it can behave aggressively in a rapidly progressive manner.
– Clinical manifestations include:
– Nonspecific symptoms: asthenia Pyrexia, weight loss and infectious mononucleosis-like syndrome.
– Organ involvement : neurological manifestations, nodal lesions, gastrointestinal, pulmonary manifestations.
– Graft involvement: graft dysfunction.
Time to PTLD for different transplanted organs:
-Longest for the heart recipients
-Shortest for the lung and heart/lung in pediatric TR.
-Early PTLD is often of B-cell lymphoma histology; whereas Burkitt’s lymphoma and Hodgkin’s disease are late event.
EBV monitoring for preemptive therapy:
– Viral load via PCR of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy.
-Challenges: no cut-off values, no universal sources of samples, and time to perform the monitoring is not standard.
– Compared to the reliability of EBV DNA via peripheral-blood mononuclear cells, the “cell-free plasma EBV DNA” has been reported as a better marker of EBV activity.
Prophylactic measures: – EBV-negative TR is better receiving grafts from EBV-negative donors whenever possible.
– Fine-tuning the immunosuppressive burden to as low as clinically possible. – RIS when reactivation of other viruses ( CMV, BK) identified.
– High risk group: preemptive/prophylactic antiviral therapy via IVIG/CytoGam.
– Close monitoring of EBV viral load and allograft function.
TREATMENT OF PTLD RI
– It is the mainstay of therapy to restore immune surveillance.
– the EBV negative cases are less responsive to R.
– RI can reverse 20%-80% of patients with PTLD.
– RI includes: CNI reduction by 50% , along with withdrawal of the antimetabolites and maintain glucocorticoids
-In critically ill cases should consider withdrawal of all IS medications except glucocorticoids.
– Monitoring allograft function for rejection.
Rituximab therapy
-It binds CD-20 antigen, leading to B cell depletion via several mechanisms.
-CD20 +ve B-cell PTLD approached 75% of TR.
– Used in addition to RI.
– The overall response to Rtx monotherapy approached 44%-79%.
Chemotherapy
– Indications include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
– Rtx should be included in all CD-20 +ve cells.
– TRM greatly improved after the advent of supportive care G-CSF and PJP prophylactic.
Adoptive immunotherapy
-Robust EBV-specific immune response is induced by EBV-specific cytotoxic lymphocytes(CTLs)
-The major risk is GVHD development.
Investigational agents that are currently under trials.
Outpatient care:
– Weekly monitoring of EBV viral titers in higher risk patients.
– Monthly monitoring initially followed by three monthly monitoring for low risk groups.
– Persistently high or continuous rise in viral load indicates disease development or progression.
– Serial physical examination, radiology testing and monitoring allograft function
Therapeutic options is tailored as per MDT discussion.
Prognosis – 70% of the PTLD-1 patients had achieved a CR with median survival of approximately 6.6 years.
– Multiple prognostic factors present.
Re-transplantation and PTLD recurrence; – PTLD recurrence has been rarely reported after re-transplantation.
– one-year disease free survival is necessary after control of PTLD before re-transplantation
– The following recommendations to limit the possibility of recurrence:
(1) wait time to re-transplant: 12 to 24 months after CR.
(2) EBV: TRs should experience EBV nuclear antigen IgG positivity, Low/absent EBV viral load at the time of re-Tx, Close
monitoring of TRs with persistently high EBV viral load is advised. Long-term prophylactic antiviral therapy Ganciclovir
(3) Role of immunosuppression: the induction with IL-2 receptor antagonists appeared to have the first priority, include RTx in induction, avoid intense state of IS, use the lowest safe dosages
Post-transplantation lymphoproliferative disorders:
Current concepts and future therapeutic approaches
INTRODUCTION ▪︎ Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT), and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance.
▪︎B cells may get infected by Epstein-Barr virus (EBV) either by:
(1) Post-transplant viral reactivation
(2) Primary EBV infection,
▪︎The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year.
▪︎ PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative.
▪︎PTLD may manifest either as localized lesion or as systemic disease.
▪︎Histopathology is crucial for PTLD diagnosis, in addition to a clear evidence of EBV DNA, RNA, or protein material.
◇ Risk factors of PTLD:
(1) In SOT: the amount of lymphatic tissue in the allograft and the degree of immunosuppression.
(2) In allogenic HSCT: the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant.
(3) The presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney
(4) Oncogenic EBV.
EBV may alter cell growth via several mechanisms:
(1) May induce highly regulated growth transformation with expression of all of its growth inducing proteins.
(2) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
(3) EBV induced proliferating cells as well as EBV variant/HLA types combination may permit these proteins to by-pass immune control and go unrecognized.
(4) Growth alterations
◇ Pathogenesis Role of EBV: 50% PTLD in SOT are not accompanied by EBV infection.
For EBV-positive TRs, the development of PTLD can be attributed to IS -induced decline in the T-cell immunesurveillance.
▪︎ EBV can integrate into normal B-cell program leading to proliferation
and transformation of these cells.
▪︎ Pathogenesis of PTLD in EBV-negative patients is less evident.
◇ Classification: A. Early and late onset PTLD
B. Depending mainly on histopathological classification
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD.
C. An associated EBV infection could be currently seen in almost all TRs with nondestructive PTLD.
◇ Clinical presentation 1. Symptomless lesions
2. Fulminating disease with multi-organ failures Salient features: PTLD may present as a local or disseminated disease.
▪︎Clinical manifestations include: Pyrexia, weight loss , neurologica manifestations, nodal lesions, GIT manifestations, pulmonary manifestations and infectious mononucleosis-like syndrome that could be fulminant.
▪︎An allograft dysfunction may.
▪︎An associated high EBV viral load by PCR should make one suspect PTLD.
▪︎The most common locations of
PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone
marrow, GIT, spleen, CNS, tonsils & salivary glands.
◇ Differential diagnosis:
Any high-risk TR who presents with pyrexia, pharyngitis and cervical lymphadenopathy.
◇ TREATMENT OF PTLD ▪︎ Reduction of immunosuppression is the cornerstone of PTLD management.
▪︎ Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and, monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
▪︎ Chemotherapy is indicated for: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI with variable results.
▪︎ However, “risk-stratified sequential” therapeutic approach seems to be promising. Other modalities may include adoptive immunotherapy and outpatient care.
Prognosis ▪︎ Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care.
◇ CONCLUSION ▪︎ PTLD is a disease IS.
▪︎Recent progress in understanding of
the underlying pathophysiology of PTLD as well as the role of EBV has led to a bettermanagement.
▪︎PTLD recurrence has been rarely reported after re-transplantation.
▪︎ Close liaison with hemato-oncology team of key importance since the lessons learnt from lymphoma management in the general population can be applied to the management
of patients who develop PTLD.
Introduction: Post-transplant lymphoproliferative disorders (PTLD) are among the important malignant complications following solid organ (SOT) and hematopoietic stem-cell transplantation (HSCT). There is uncontrolled B proliferation caused by lack of immune-surveillance. Around 85% of cases are seen in the first year and mostly EBV-positive PTLD of B cell origin. T cell PTLD is much less common compared to B cell PLTD.
Epidemiology: Incidence is 0.8 to 2.5% in kidney transplant, 0.5-0.5% pancreatic,1 to 5% liver, 2 t0 8% heart, 3 to 10 % lung and < 20% intestinal TRs
Risk factors:
1.Solid Organ Transplantation (SOT)
2.Allogenic HSCT
3.Previous exposure to immune-suppressive drugs in the native kidney
4.Oncogenic EBV
Pathogenesis:
1.EBV-positive PTLD: EBV infection results in uncontrolled B cell proliferation
-B cell transformation
2.EBV-negative PTLD: may CMV or other viruses, immune-suppression
-chronic antigenic stimulation
3.WHO classification: Early lesions e.g., Infectious mononucleosis, polymorphic, monomorphic, and classical lymphoma PLTD
Clinical features: may be non-specific, mostly extra-nodal disease, and systemic involvements including CNS, lung and the gut. PTLD may present with allograft dysfunction.
Prophylaxis: the best is EBV-negative D t to EBV-negative R, EBV viral load and preemptive/prophylactic antiviral for high-risk groups
Treatment of PLTD:
1.Reduction of immune-suppression; stop or reduce CNIs/anti-metabolites
2.Rituximab: in low-risk group the response rate may be 44 to79%
3.Chemotherapy: indicated for those who fail to respond to RTX or frank lymphoma
-Many regimens e.g., CHOP
4.Adoptive immunotherapy: this is based on removing cytotoxic lymphocytes
-After genetic modification then give them back to the patient for immune-response
-It also uses donor lymphocytes infusion which may result in GVHD
Prognosis: early diagnosis is associated with better outcomes and high index of suspicious is required for getting good prognosis. Prognostic scoring system include age, number of the extra-nodal location, performance attitude, current stage, and LDH.
Re-transplantation: it is advisable to wait for one year after completion of treatment.
-Avoid ATG?
-Keep lowest possible dose of immune-suppression
-Low/absent EBV viral load at the time of transplantation
-Antiviral prophylaxis: Ganciclovir was considered for this aim.
-EBV-PCR serial monitoring
-MMF is safe
-mTORi: may be?
Uncontrolled B cell proliferation owing to weakened immunological monitoring causes post-transplant lymphoproliferative diseases (PTLD), one of the most common malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplantation (HSCT).
Epstein-Barr virus (EBV) could get into B cells through viral reactivation after the transplant or from the donor organ or environment. 85% of PTLD instances occur in the first year post-transplant.
T-cell proliferation-induced PTLD is rare and EBV-negative. PTLD evolution depends on the accumulated immunosuppressive burden. Lymphoma made up 21% of all cancers in SOT patients, but only 4% and 5%, respectively, in immunocompetent men and women. PTLD may be localized or systemic.
Risk factors :
are said to differ depending on the type of transplanted organ:
(1) SOT, (2) Allogenic HSCT, (3) Immunosuppressive load exposure, (4) Oncogenic EBV
Pathogenesis:
EBV: For decades, PTLD formation was predominantly linked to EBV infection, however, current findings reveal that as many as 50% of SOT PTLD are not associated with EBV.
-Immunosuppressive-induced T-cell immune surveillance decrease causes PTLD in EBV-positive TRs. EBV may integrate into the B-cell program and cause proliferation and transformation.
Patients without EBV exhibit reduced PTLD. Several theories have been put forward, such as the “hit-and-run” theory, chronic immunosuppression, allograft-driven persistent antigenic triggering, and CMV or another viral infection.
Classification:
WHO 2017 classifies PTLD as follows:
nondestructive: hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
PTLD polymorphism.
Monomorphic PTLD (B-cell, T-cell, or NK-cell).
classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
Clinical manifestations of PTLD range from symptomless lesions to fulminating illness with multi-organ failure. Pyrexia, weight loss, neurological symptoms, nodal lesions, gastrointestinal and pulmonary symptoms, infectious mononucleosis-like syndrome, and graft involvement may cause allograft dysfunction. Since TR might cause vague symptoms, the PTLD diagnosis must be lowered (e.g., fever, asthenia).
Treatment of PTLD:
RI
Improving the immunosuppressive load is the main goal of primary PTLD therapy. This is done so that EBV-specific cellular immunity can be partially restored without raising the risk of acute rejection. RI may cure 20% to 80% of PTLD patients.
Tacrolimus (Tac) and cyclosporine (CyA) dosages are reduced by 50% as part of the RI plan, and antimetabolites such as azathioprine or mycophenolate mofetil (MMF) are discontinued.
Rituximab therapy
Rituximab (RTX), a powerful chimeric anti-CD20 monoclonal antibody, binds to CD-20 antigen and kills B cells through phagocytosis (macrophages), complement-mediated cytotoxicity, and natural killer cells (antibody-dependent cell-mediated toxicity).
Chemotherapy
Indications of immunochemotherapy include Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
Adoptive immunotherapy:
Adoptive immunotherapy with donor lymphocytes may treat donor-cell-derived PTLD in HSCT patients. The PTLD in SOT TRs is different. EBV-specific CTLs elicit a strong cellular immunological response. This therapy’s main danger is GVHD.
Re-transplantation and PTLD recurrence:
The possibility of re-transplantation after successful management of PTLD has been reported in particular cases; however, one-year disease-free survival is necessary after control of PTLD before re-transplantation.
PTLD recurrence has been rarely reported after re-transplantation, which requires careful planning of immunosuppression.
What is the level of evidence provided by this article?
Narrative review, Level V
– Post-transplant lymphoproliferative disorders (PTLD) is the second most common malignancy in adult recipients post solid organ transplantation.
– Transplant clinicians must have a high index of suspicion of the symptoms and signs of PTLD to allow early detection and appropriate management.
– The cumulative immune suppression state and the Epstein-Barr virus (EBV) infection represents the most critical risk factors for developing PTLD. Therefore, reducing immune suppression represents the first line of management of this condition to allow normal T- cell surveillance.
Pathogenesis:
The exact pathogenesis of PTLD is uncertain. However, several hypotheses were introduced:
· EPV-positive PTLD is thought to be secondary to the incorporation of the DNA of the EPV into the B-cell DNA, producing abnormally proliferating cells resistant to natural apoptosis. A normal T-cell function is essential to eliminate these cells. The marked immune suppression will result in the failure of the immune surveillance function of T-cells and the development of PTLD.
· EPV-negative PTLD is another subgroup of PTLD. Possible pathogenesis includes an old, undocumented EBV infection that is not detectable anymore, another undetermined viral infection, or persistent antigenic stimulation and profound immune suppression.
Classification of PTLD:
There are different classifications of the PTLD, which differ in their morphology, immunophenotypic, and response to treatment. PTLD can be categorized in one of the following categories:
– Plasmacytic hyperplasia and infectious mononucleosis-like PTLD
– Florid follicular hyperplasia
– Polymorphic PTLD
– Monomorphic PTLD
– Classic Hodgkin lymphoma-like PTLD
Clinical presentation:
The clinical picture varies from asymptomatic cases to the aggressive fulminant form with multi-organ affection. Therefore, a high index of suspicion is required during the evaluation of non-specific symptoms such as fever, weight loss, and lymphadenopathy.
Treatment options for PTLD:
o Reduction of immune suppression:
One suggested protocol is to lower the dose of CNI by 50% with the complete withdrawal of anti-metabolites. In severe cases all immune suppressive drugs should be stopped apart from steroids.
o Rituximab:
It is a monoclonal antibody against CD-20, which will cause B-cell depletion. Therefore, it can be used together with the reduction of immune suppression in mild cases and those with polymorphic PTLD that expresses CD20.
o Chemotherapy:
Its indications include Hodgkin’s lymphoma, Burkitt’s lymphoma, primary CNS lymphoma, peripheral T-cell lymphoma and B-cell PTLD unresponsive to Rituximab.
o Adoptive immunotherapy:
This means the use of uses EBV-specific cytotoxic T lymphocytes to attack the EPV-positive PTLD cells or the use of donor lymphocyte infusion in the setting of PTLD post-hematopoietic cell transplantation. The major complication of adoptive immunotherapy is acute and chronic graft-versus-host disease (GVHD).
Follow-up response to treatment:
EPV viral load is usually used for follow-up response to treatment (it is expected to drop significantly in those who respond to treatment and to be rising in the case of non-responders).
Regular physical examination, radiological investigations and monitoring of the allograft function should be planned individually during the treatment course.
Prognosis:
IPI is a prognostic scoring system used by many haematologists and oncologists to recognize the prognostic attitude in aggressive lymphoma. It includes the patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and the number of extra-nodal locations.
The prognosis of PTLD has improved compared to the previous decades due to the implementation of new tumour-specific startigies and better supportive care. Complete remission was achieved in 70% of cases included in the PTLD-1 study, with median survival of about 6.6 years.
Re-transplantation options:
– Patients who were cured of PTLD can be listed for subsequent transplantation after at least one year (and better if two years) of complete cure.
– EPV viral load should be evaluated regularly to detect any significant viral replication early.
– The use of Ganciclovir as an anti-EPV has been suggested.
– The goal will be to balance adequate immune suppression and lowering the risk of PTLD recurrence.
– Lymphocyte-depleting agents should be avoided during the induction phase of immune suppression, and the IL-2 receptor antagonist is the alternative induction agent.
– Rituximab use during the induction was tried in cases of cardiac transplantation for recipients with high EPV viral load.
– Carefully planned maintenance immune suppression in the form of mTOR inhibitor, MMF and steroids may be safe and beneficial.
2. What is the level of evidence provided by this article?
This article is a narrative review article which makes its level of evidence is 5.
Due to blunted immunological Surveillance there is uncontrolled B cell proliferation in PTLD. B cells get infected by EBV during – Viral reactivation post transplant Primary infection via donated organ or by environmental exposure. > 85 % of PTED cases occur in the first year post transplant. PTLD due to Tell proliferation is uncommon and mostly E BV negative. Cumulative immunosuppression burden plays a role in PTLD evolution. PTLD can present as a localised lesion or systemic disease.
Risk factors – Solid organ transplant Allogeneic H SCT Previous exposure to immunosuppression Oncogenic EBV
Pathogenesis – E BV integ rates into normal B cell program. There is immunosuppression induced decline In Tell surveillance. leads to uncontrolled B cell proliferation.
other factors – CMV and other viral infection allograft driven persistent antigenic stimulation prolonged immunosuppression hit and run hypothesis
o EBV positive PTLD Mostly B cell fewer genetic abnormality More common Less risk compared to seronegativeTR All cases post HSCT are EBV positive
o EBV negative PTLD Shares genomic features with diffuse large Bell lymphoma Mostly Tcell Less common Seronegative SOT TR are more vulnerable In SOT both EBV positive and negative are present.
o classification – Non destructive PTLD – plasmacystic hyperplasia, Florid follicular hyperplasia, infectious mononucleosis like PTLD Polymorphic PTLD Monomorphic PTLD ( Bcell, Tcell, NK type ) classic Hodgkin lymphoma like PTLD
o Clinical Presentation Fever Weight loss Neurological manifestation Nodal lesion gastrointestinal manifestation Pulmonary Manifestation
infectious mononucleosis like syndrome Allograft dysfunction Concomitant increased EBV load
o PTLD involvement seen in – lymph rode Liver Lung Kidney bone marrow git spleen CNS tonsils salivary gland
o D/D Streptococcal infection Infectious mononucleosis when pt present with Fever, pharyngitis and cervical lymph node.
Time to PTLD is longest for heart recipient.
Early PTLD is usually diffuse large B cell lymphoma. Burkitts and Hodgkins lymphoma are late events.
o Pre emptive therapy by EBV monitoring
PPV of EBV viral load in SOT is 28%- 100% NPV of EBV viral load in SOT is 75% – 100% cell Free plasma EBV DNA load better than EBV DANA load in peripheral blood mononuclear cells.
o Prophylaxis – Monitoring EBV viral load Recognising Serostatus of donor and recipient pre transplant Missional needed immunosuppression. Iv Ig/ Cytogam can be used.
Treatment –
o Reduction of immunosuppression withdraw anti metabolites Reduce CNI done by 50% In critically ill withdraw all except steroids. Monitor allograft function Acute rejection Rate of 37% EBV negative cases are less responsive to RI Lack of response to RI seen in – old aged > 50years bulky lesions > 7cm Advanced stage of disease Ann Arbor 3/4.
o Rituximab Indicated in – Non destructive PTLD Polymorphic PTLD
Monomorphic DL BCL not responding to RI
375 mg/m2 weeky x 4 doses
o chemotherapy Indications – Burkitts lymphoma Hodgkins lymphoma peripheral T cell lymphoma primary CNS lymphoma other uncommon lymphoma Bcell PTLD unresponsive to Rituximab and RI.
o Adoptive immunotherapy EBV specific cytotoxic lymphocytes. Infusion of donor lymphocyte in HSCT
o Outpatient care In high risk – Monitor EBv titre weekly
In low risk Monitor EBV titre monthly, then 3 monthly Serial physical examination Radiology assessment Allograft function assessment
o Future Strategy Ibrutinib- BTK inhibition
PI3k inhibitor M TORi Bortezomib Checkpoint inhibitor Radio immuno therapy Anti – CD 30 therapy
o Prognosis 70% of patients in PTLD1 achieved CR Median survival of 6.6years
o Retransplantation and PTLD recurrence 12-24 months wait period before retransplant TR should hance EBV Ig G positivity low or absent EBV load ganciclovir lovin therapy long term with EBV load monitoring Induction – IL-2 receptor antagonist prefered. Rituximab can be used as an induction agent. Triple maintenance immuno suppression can be given Role of MTORi Identification of tumour Source is important.
Early PTLD EBV positive graft involvement Rarely extranodal Mostly donor desired Monomorphic type less likely More common
Late PTLD EBV negative graft involvement rare Extra nodal disease common Elevated LDH Less prevalent
Post-transplant lymphoproliferative disorders are one of the critical complications after solid organ transplantation and hematopoietic stem cell transplant. They occurs secondary to uncontrolled B cell proliferation due to EBV infection. B cell gets infection through reactivation or primary infection, the majority of cases are observed in first year after transplantation. On the other hand, PTLD occurs due to T cell proliferation is less commonly and mostly EBV negative.
Epidemiology
Standardized incidence ratio of 10 for non-Hodgkins lymphoma and 4 for Hodgkins lymphoma were reported among SOT. But, incidence of PTLD is 3.2 % in HSCT
Risk factors
1. According to the type of transplant organ.
In solid organ transplant
In kidney transplant, PTLD occurs in 0.8 to 2.5%.
In liver 1 to 5.5 %. In pancreas 0.5 to 5%.
And this variation mainly due to amount of lymphatic tissue in the transplanted organ and the degree of immunosuppression.
2. In hematopoietic stem cell transplant , PTLD incidence is related to the degree of HLA matching and the introduction of T cell depleting agents.
3. Presence of previous exposure to the immunosuppression during treatment of primary renal disease in the native kidney
4. Oncogenic EBV
Pathogenesis
For EBV positive, the development of PTLD can be due to Immunosuppressive decline in the T cell immune surveillance, EBV can integrate into normal B cell program leading to proliferation of these cells , normally, these antigens would trigger a T cell response capable of destruction of most of the EBV infected B cells, however the immune defense mechanism has been compromised in transplant recipients leading to unlimited B cell transformation and the occurrence of lymphoma.
The pathogenesis of PTLD in EBV negative may be due to CMV or another viral infection, prolonged immunosuppression
Classification
Early PTLD is often of diffuse large B cell or other B cell histology
Late PTLD include Burkitt lymphoma and Hodgkins disease
Histological Classification
1. Three non destructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, infectious mononucleosis like PTLD.
2. Polymorphic PTLD
3. Monomorphic PTLD
4. Classic Hodgkins lymphoma like PTLD
Clinical presentation
Non-symptomatic to fulminanting disease with multi-organ failure.
DD
1. Streptococcal infection
2. Infectious mononucleosis
Time to PTLD for different transplant organ
The time to PTLD is longest for the heart recipients and shortest for lung and heart/ lung in pediatric.
Treatment
1.Primary management is reduction of immunosuppression
But in sometimes, it is not feasible due to risk of allograft rejection and loss
2.surgical clearance
3. Antiviral agents
4. Local radiotherapy
5. Intravenous immunoglobulin
6. Chemotherapy
7. Monoclonal antibodies and cytotoxic T cells
Combination of the above modalities lead to better results
Level 5
Level of evidence:5
review article discussed prevalence ,diagnosis and treatment of PTLD
New therapeutics:
Anti CD30
BTK inhibitors
Check point inhibitors
radioimmunotherapy
this review has discussed the prevalence, clinical clues, prophylactic measures as well as the current and future therapeutic strategies of PTLD.
standardized incidence ratios is the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort). SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients. Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Prophylaxis measures include EBV sero-status of both donor and recipient checking before donor selection. EBV-negative TR is better receiving grafts from EBV-negative donors whenever available. Adjusting immunosuppressive drugs and prophylactic antiviral therapy in potentially high-risk groups should be considered. It is advisable to keep high titers anti-EBV antibodies and to provide preemptive therapy to high-risk recipients after monitoring EBV viral load and allograft function.
The mainstay of primary PTLD management is to ameliorate the immunosuppressive burden. Rituximabhas been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to reduction of immunosuppressants.
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to former modalities.
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells.
Newer therapeutic medications are:
(1) Bruton’s tyrosine kinase inhibition
(2) Inhibition of PI3K and mTORi
(3) Proteasome inhibition
(4) Radioimmunotherapy
(5) Checkpoint inhibitors
(6) Anti-CD30 therapy
The level of evidence is 5
Q1: PTLD has been observed among HSCT and SOTs with SIRs of 10 for NHLM and 4 for Hodgkin lymphoma among SOTs.
Risk factors:
1-type of SOT (highest in the lung) multiorgan and intestinal
2-Degree of HLA matching and use of lymphocyte-depleting agents and cumulative IS burden
3-EBV positive donors and seronegative recipients in SOT
4-Pediatric patients with two peaks:
A- First year of TX (mostly EBV seropositive)
B- 5-15 years after TX (mostly EBV seronegative
5-Previous exposure to IS.
6-Oncogenic EBV: (LMP-2) perform VCA-IgG before TX to evaluate EBV exposure.
Pathogenesis: In 50% of SOT patients, PTLD is EBV positive infected B cells in immunosuppressed recipient and can escape from T cell destruction and could transform to lymphoma. For EBV negative PTLD hypotheses are: CMV or other infection, prolonged IS, allograft-driven persistent antigenic triggering and hit-and-run hypotheses. EBV positive PTLD are common and mostly B cell proliferating lesions and more common in the first year of TX. Almost 100% of HSCT are EBV positive with lower risk compared to seronegative ones that are less common and mostly are T cell proliferative lesions and less responsive to IS reduction.
Management:
1-IS reduction
2-Rituximab for non-destructive PTLD and polymorphic PTLD and monomorphic large B cell lymphoma-like PTLD.
3-Chemotherapy for: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T cell lymphoma, primary CNS lymphoma and other uncommon lymphoma and B cell PTLD that is non-responsive to IS reduction and rituximab.
4-Other modalities includes:
-Adoptive immunotherapy
-Out patient care with EBV viral load monitoring and regular physical examination
-Other strategies includes: BTK inhibitors, mTOR inhibitors, bortezomib, radio-immunotherapy, checkpoint inhibitors, anti-CD30 therapy.
*Prognosis:
With new treatments, outlook of PTLD has improved. Scoring systems like IPI is effective to determine prognosis.
*Re-transplantation: One to two years disease free survival is necessary after control of PTLD before re-TX with low rate of recurrence. When EBV viral load become absent with long-term antiviral therapy to avoid recurrence.
In addition, basiliximab is the preferred induction therapy. Donor derived PTLDs have a better outcome.
Q2: The level of evidence is 5. It is a review article.
Level 5 evidence :
-PTLD Risk factors:
-SOT
-Allogenic HSCT
-Previous exposure to the immunosuppression during treatment of the primary renal disease in the native kidney.
-EBV
presentation as :
-Pyrexia , neurological manifestation, nodal lesions , gastrointestinal , pulmonary manifestations.
-Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers.
-Management through :RI ,Rituximab therapy, Chemotherapy. and Adoptive immunotherapy , radiotherapy .
-BTK inhibition, inhibition of PI3K and mTOR , proteasome inhibition , radioimmuno-therapy and checkpoint inhibitors .
Post-transplant lymphoproliferative diseases, often known as PTLD, are serious forms of cancer that can develop in patients who have had solid organ transplantation (SOT) or hematopoietic stem-cell transplantation (HSCT). After an Epstein-Barr virus (EBV) infection, whether due to reactivation of the virus or initial infection, the body’s B cells grow excessively, which results in these conditions. The risk of developing PTLD is not uniform across all types of organ transplants; multiorgan and intestine transplants have the highest risk, while kidney transplants have the lowest risk. In allogeneic stem cell transplantation (HSCT), risk factors include the degree of HLA matching and the use of T-cell depleting drugs.
Pathogenesis:
There are multiple pathways involved in the etiology of PTLD; however, in situations where EBV infection is absent, this process is not well understood. The use of immunosuppressive medication can lead to a decrease in T-cell immunosurveillance, which can lead to the development of EBV-positive PTLD. EBV has the ability to integrate itself into the normal programs of B cells, which can then lead to the proliferation and transformation of these cells. The World Health Organization (WHO) has developed a classification system for PTLD. This approach divides the disease into several subtypes, including non-destructive kinds, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin’s lymphoma-like PTLD.
Clinical Presentation:
The clinical manifestations of PTLD are quite diverse, ranging from asymptomatic lesions to fulminating illnesses characterized by the failure of many organs. Fever, weight loss, nodal lesions, troubles with the gastrointestinal tract and the respiratory system, a state similar to infectious mononucleosis, and neurological sickness are common symptoms. The lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract, spleen, tonsils, central nervous system, and salivary glands are some of the body parts that PTLD may affect. The time it takes to reach PTLD varies from organ to organ, with the least time being required for lung and heart transplant patients, especially in pediatric cases, and the longest time being required for adult heart transplant recipients.
Diagnosis and Monitoring:
Streptococcal infections and infectious mononucleosis are two of the conditions that can be considered alternative diagnoses for PTLD. Monitoring for EBV is absolutely necessary for any preemptive therapeutic techniques that are intended to reduce the likelihood of PTLD development. It is essential to utilize both molecular and serological techniques, in addition to monitoring the EBV virus load, in order to make informed judgments regarding the appropriate course of treatment. Selecting the source of the sample, defining unambiguous cutoff values, and selecting the ideal time to start monitoring are all potential pitfalls that can occur during monitoring.
Treatment
Reducing immunosuppression, employing rituximab therapy, providing chemotherapy in some situations, and researching adoptive immunotherapy are all potential treatment methods for PTLD. Reversing PTLD in a considerable number of patients is possible through the reduction of immunosuppression; however, this approach requires careful monitoring of graft function. Standard treatment for certain kinds of PTLD that do not respond to immunosuppression reduction includes the administration of rituximab, which is a monoclonal antibody against CD20. Chemotherapy is recommended for certain kinds of PTLD as well as for patients who do not respond well to rituximab and have reduced immunosuppression.
Conclusion:
Post-transplant lymphoproliferative disorder (PTLD) is a condition that is linked to immunosuppression after transplantation. After the PTLD has been brought under control, there is a need for careful planning of immunosuppression before considering re-transplantation. It is absolutely necessary for hemato-oncologists to be involved in the treatment of patients suffering from PTLD. One possible way to treat PTLD in the future is to look into several targeted medicines, such as inhibitors of Bruton’s tyrosine kinase, PI3K, and mTOR, as well as radioimmunotherapy and checkpoint inhibitors. For the purpose of directing future therapy approaches and having a better understanding of the biology of PTLD, determining the origin of the tumor (donor versus recipient) is absolutely necessary.
This article level of evidence V.
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important
malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell
transplant (HSCT), and it develops as a result of uncontrolled B cell proliferation
due to blunted immunological surveillance. B cells may get infected by Epstein-Barr
virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV
infection. The PTLD cases (> 85%) usually occurred in the first post-transplant year. PTLD that due to T-cell proliferation is less commonly and is mostly EBV-negative.
Risk factors:
1- Solid Organ Transplantation (SOT):
Estmation in adults from 0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ and intestinal TRs
2- Allogenic HSCT:
High risk mainly with T-cell depleting strategies (relative risk: 8.4-15, and relatively low with the use of non-specific broad lymphocyte depleting agents (T- and B-cells) (relative
risk = 3.1)
3- previous exposure to the immunosuppressive load for treatment of the primary renal disease before transplantation is an unnoticed risk factor for PTLD evolution.
4- Oncogenic EBV: EBV may alter cell growth via several mechanisms:
(1) With lack of immune recognition, EBV may induce highly regulated growth transformation with expression of all of its growth inducing proteins.
(2) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors. (3) EBV induced proliferating cells as well as EBV variant/HLA types combination may permit these proteins to by-pass immune control and go unrecognized.
(4) Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA.
Classification:
1- Early PTLD: in which there is positive EBV infection, graft affection, non destructive , less often to be monomorphic subtype extranodal disease, it comprises the majority of PTLD cases.
2- Late onset PTLD: there is frequent EBV negative tumors, common extranodal involvement with less graft involvement .
Both types have the same risk factors and treatment response.
Clinical presentation:
It could be symptomless of fulminant disease with multi-organ failure.
Symptoms include;
Pyrexia (57%)
weight loss (9%)
neurological manifestations (13%)
nodal lesions (38%)
gastrointestinal manifestations (27%),
pulmonary manifestations (15%)
infectious mononucleosis-like syndrome that
could be fulminant (19%)
Allograft dysfunction may ensue due to graft involvement.
Nonspecific symptoms (e.g., fever, asthenia).
The most common sites of PTLD involvement are : Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
Differential diagnosis: streptococcal infection and infectious mononucleosis
TREATMENT OF PTLD :
1- Reduction of immunosuppression drugs can reverse 20%-80% of patients with PTLD
and this includes 50% reduction of calcineurin inhibitors doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF).
Some times withdrawal of all immunosuppressive medications except steroids should be considered in very ill patients.
2- Rituximab therapy
3- Chemotherapy
Indications include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
3- Adoptive immunotherapy
This is done by infusion of donor lymphocytes, to manage PTLD in HSCT patients that is primarily originating from donor cells.
Prognosis :
Outcome of PTLD patients has greatly improved owing to the advent of new
lymphoma-specific protocols as well as to the better supportive care.
70% of the PTLD-1 patients had achieved a complete remission with median survival of
approximately 6.6 years.
There is a prognostic scoring system that includes the following: Patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and number of extra-nodal locations.
Post-transplant lymphoproliferative disorders (PTLD) are significant malignancies that occur after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT). These disorders arise from uncontrolled B cell proliferation following Epstein-Barr virus (EBV) infection, either through reactivation or primary infection. The incidence of PTLD varies depending on the type of transplant organ, with multiorgan and intestinal transplants having the highest incidence in SOT, while kidney transplants have the lowest. Risk factors include the degree of HLA matching and the use of T-cell depleting agents in allogenic HSCT.
Pathogenesis:
The pathogenesis of PTLD involves various mechanisms, but in cases without EBV infection, it is less understood. EBV-positive PTLD can develop due to a decline in T-cell immunosurveillance induced by immunosuppressive therapy. EBV can integrate into normal B-cell programs, leading to proliferation and transformation of these cells. PTLD is classified according to the World Health Organization (WHO) classification system, which includes non-destructive types, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin’s lymphoma-like PTLD.
Clinical Presentation:
The clinical presentation of PTLD varies widely, ranging from asymptomatic lesions to fulminating disease with multi-organ failure. Common symptoms include fever, weight loss, nodal lesions, gastrointestinal and respiratory issues, infectious mononucleosis-like syndrome, and neurological illness. PTLD can affect various locations in the body, including lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract, spleen, central nervous system, tonsils, and salivary glands. The time to PTLD varies depending on the transplant organ, being shortest for lung and heart recipients, particularly in pediatric cases, and longest for adult heart recipients.
Diagnosis and Monitoring:
Differential diagnoses for PTLD include streptococcal infections and infectious mononucleosis. EBV monitoring is crucial for preemptive therapy strategies aimed at limiting the risk of PTLD development. Monitoring the EBV viral load and using molecular and serological methods for early detection of EBV are important in guiding therapy decisions. Pitfalls in monitoring include determining the source of the sample, establishing clear cutoff values, and determining the optimal time to start monitoring.
Treatment:
Treatment approaches for PTLD involve reducing immunosuppression, using rituximab therapy, administering chemotherapy in specific cases, and exploring adoptive immunotherapy. Reduction of immunosuppression can reverse PTLD in a significant number of patients but requires close monitoring of graft function. Rituximab, an anti-CD20 monoclonal antibody, is a standard therapy for certain types of PTLD that do not respond to immunosuppression reduction. Chemotherapy is indicated for specific PTLD subtypes and cases unresponsive to rituximab and immunosuppression reduction.
Conclusion:
PTLD is a disease associated with immunosuppression following transplantation. Careful planning of immunosuppression is necessary after PTLD control before considering re-transplantation. The involvement of hemato-oncologists in the management of PTLD patients is crucial. Future strategies for PTLD treatment include exploring various targeted therapies, such as inhibitors of Bruton’s tyrosine kinase, PI3K, and mTOR, as well as radioimmunotherapy and checkpoint inhibitors. The identification of the tumor source (donor vs. recipient) is essential for guiding future therapeutic plans and understanding the biology of PTLD. Level of evidence of this article is V.
Please summarize this article
PTLD is the second most common malignancy after SOT and HSCT. The highest incidence is recorded in multi-organ transplant and intestinal recipients and the lowest incidence is among renal Tx Recipients.
Risk factors for PTLD:
1- EBV negative recipients.
2- Early occurrence is seen with EBV +ve recipients with later occurrence in EBV -ve recipients.
3- Prolonged exposure to immune-suppression especially in pre-transplant period for primary native kidney disease.
WHO classification of PTLD:
1- Non-destructive: IMN like, Plasmacytic, follicular, florid.
2- Mono-morphic PTLD: either B-cell, T-cell or natural killer cell type.
3- Poly-morphic PTLD: B-cells and T-cells.
4- Classic Hodgkin’s Lymphoma like PTLD.
PTLD treatment options:
1- Reduction of immune-suppression: stop MMF, and Azathioprine, reduce dose of CNI by 50%, monitor graft function.
2- In critically sick patients: stop all immunosuppression except steroids.
3- Rituximab: approved for type 1-3 PTLD not responding to reduction of immune-suppression.
4- Chemotherapy: for Burkitt’s lymphoma, HL, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD resistant to rituximab.
5- Adoptive immunotherapy: EBV specific CTLs for recipient driven or donor-driven PTLD, carries less risk for rejection because of lack of immunosuppression reduction.
6- Future therapies under trials: Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib), Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)], Proteasome inhibition (Bortezomib), Radioimmunotherapy, (Yibritumomab, tiuxetan), Checkpoint inhibitors (Pembrolizumab, nivolumab), Anti-CD30 therapy (Brentuximab vedotin).
Re-transplantation and PTLD recurrence: at least one-year disease free is required after treatment of PTLD before considering re-transplantation because of low recurrence risk. Consider IL-2 antagonist as induction compared to ATG. graft PTLD requires graft nephrectomy which is very curative
Level of evidence: V
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT) and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells may get infected by Epstein-Barr virus (EBV) either by post-transplant viral reactivation; and Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative.
Risk factors
Risk factors are, reportedly, varied according to the type of the transplant organ:
(1) SOT: In adults, the incidence of PTLD has been reported to range from 0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ and intestinal TRs
EBV-positive vs EBV-negative PTLD:
In the light of molecular-genomic data of diffuse large B-cell lymphoma subtype, a range of distinguishing features have been identified to discriminate between EBV+ve and EBV-ve PTLD However, there is a lack of clear distinction between clinical consequences of different EBV serotypes and their response to therapy. Further studies are warranted to recognize more precise molecular-genomic classification of both types.
Clinical presentation: Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure. Salient features: PTLD may present as a local or disseminated disease. In either form, the tumor can behave aggressively in a rapidly progressive manner. Clinical manifestations include Pyrexia (57%), weight loss (9%) neurological manifestations (13%) nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant.
Time to PTLD for different transplanted organs: The time to PTLD is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR. Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology, whereas Burkitt’s lymphoma and Hodgkin’s disease are late events
EBV monitoring for preemptive therapy: The risk of EBV+ve PTLD has been postulated to be related to three factors: Type of transplant organ, time elapsed until diagnosis of post-transplant PTLD and EBV serological status of both recipient and donor before transplant.
An estimation of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy. It has been observed that TR with PTLD usually expresses an increased EBV viral load as compared to PTLD free TR. This higher viral load invites more risk for PTLD evolution.
The mainstay of primary PTLD management is to ameliorate the immunosuppressive burden, so that EBV-specific cellular immunity can be partially restored with no additional risk of acute rejection. RI can reverse 20%-80% of patients with PTLD.
RI plan includes 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF), despite the lack of evidence demonstrating any relation between MMF and PTLD development
With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
Rituximab therapy
Rituximab (Rtx) is a potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen, leading to B cell depletion via several mechanisms e.g., phagocytosis (macrophages), complement mediated cytotoxicity, and through natural killer cells (antibody-dependent cell-mediated toxicity)
Of note, CD20-positivity in B-cell PTLD approached 75% of TR in the prospective phase 2 trial (largest subgroup)
Chemotherapy Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
Considering the standard-of-care approaches related to specific histologic features in the rare subtype lymphomas, have mostly improved patient’s outcome
Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells. This situation is in contrast to PTLD developing in TRs of SOT. A robust EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs)
Outpatient care
In light of serial follow up of the EBV viral load in identifying the patients at risk and in monitoring the response to therapy, the following steps have been suggested:
(1) Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low-risk groups.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
To summarize
Reduction of immunosuppression is the cornerstone of PTLD management. Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. Chemotherapy is indicated for: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI with variable results. However, “risk-stratified sequential” therapeutic approach seems to be promising. Other modalities may include adoptive immunotherapy and outpatient care. Investigational agents that’re currently under trials have been shown above.
Prognosis Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care. Seventy percent of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years.
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT)[1] , and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells may get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative. The magnitude of cumulative immunosuppressive burden has a crucial role in PTLD evolution[2] . Lymphoma accounts for 21% of all malignancies in SOT recipients as compared to 4% and 5% in immunocompetent individuals, respectively in men and women[3,4] . Clinically, PTLD may manifest either as localized lesion or as systemic disease. Lowering the clinical threshold of PTLD diagnosis is fundamental. Transplant clinicians should be vigilant to this serious disorder. Tissue diagnosis (histopathology) is crucial for PTLD diagnosis, in addition to a clear evidence of EBV DNA, RNA, or protein material[2] . The mainstay of PTLD primary management is reduction of immunosuppression (RI). Complete cessation of the immunosuppressive drugs may be necessary to stop the disease progression. However, RI is not always feasible; a potential risk of allograft loss or graft dysfunction has to be considered particularly for vital organ transplants (e.g., heart transplant). A variety of therapeutic options include surgical clearance, anti-viral agents, local radiotherapy, intravenous immunoglobulin (IVIG), chemotherapeutic agents, monoclonal antibodies and cytotoxic T lymphocytes with variable success[2] . A combination of the above treatment modalities offers better results rather than when used in isolation.
PTLD is a disease of immunosuppression. Recent progress in our understanding of the underlying pathophysiology of PTLD as well as the role of EBV has led to a better management. PTLD recurrence has been rarely reported after re-transplantation that requires careful planning of immunosuppression. An ever-improving moleculargenomic technology has had its impact on upgrading our diagnostic and therapeutic strategies that will be reflected in improved recipient’s outcome. However, close liaison with hemato-oncology team of key importance since the lessons learnt from lymphoma management in the general population can be applied to the management of patients who develop PTLD
What is the level of evidence provided by this article?
Level V
INTRODUCTION:
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT).
Occur due to uncontrolled B cell proliferation when infected by EBV either by reactivation or primary infection.
Epidemiology of PTLD:
Appear in 1969 for the first time. risk is expressed as “standardized incidence ratios” (SIRs) which is of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) in SOT.
Risk factors:
Risk factors vary depending on the type of transplant organ:
SOT: Multiorgan and intestinal transplant has the highest incidence while kidney transplant has the lowest.
Allogenic HSCT: HLA degree of matching and the T cell depleting agents affects the risk, where the more the matching the lower is the risk and the risk was low with broad lymphocyte depleting agents.
EBV negative recipients are more susceptible to develop PTLD, early occurrence is with EBV positive recipients while late occurrence is associated with EBV negative cases.
Immunosuppressive exposure in primary renal disease therapy before transplantation increase immunosuppression burden.
Oncogenic EBV causes growth transformation, initiation of oncogenes, bypass immune control, cell targets, viral and cellular mRNA expression.
Molecular and serological methods together early detection of EBV.
Pathogenesis:
50% PTLD in SOT are without EBV infection and those with EBV-positive TRs, the development of PTLD can be due to immunosuppressive-induced decline in the T-cell immunosurveillance. EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells.
EBV-positive vs EBV-negative PTLD:
Pathogenesis of PTLD is less evident. Several hypotheses have been postulated.
Classification: WHO classification
1) Non-destructive: Plasmocytic; florid Follicular; infectious mononucleosis-like.
2) Polymorphic PTLD: B cells in maturing stages, T cells.
3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell type.
4) classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
Variable presentation – asymptomatic lesions to fulminating disease with multi-organ failure.
Fever (57%), weight loss (9%), nodal lesions (38%), gastrointestinal (27%), respiratory (15%) and infectious mononucleosis-like syndrome (19%), neurological illness (13%).
Common locations: Lymph nodes, liver, lung, kidney, bone marrow, GI Tract, spleen, CNS, tonsils and salivary glands
Time to PTLD: shortest for Lungs and heart + Lung in pediatric recipients; longest for adult heart recipients.
Differential diagnosis:
A. Streptococcal infections
B. Infectious mononucleosis
EBV monitoring for preemptive therapy:
1) strategies to limit the risk of PTLD development:
2) Reduction Immunosuppression, Rituximab, Adoptive T cell (EBVST)
3) viral load correlates with increases risk of PTLD
4) EBV Viral load is mandatory to start and monitoring therapy
5) Cell free plasma EBV-DNA correlates better marker of EBV activity
Pitfalls – source of sample, cut off value, time to start monitoring not clear
Prophylaxis:
Better for EBV-negative people to receiving grafts from EBV-negative donors. Keeping high titres of anti-EBV antibodies (IVIG / Cyto-Gam administration)
High-risk cases – monitoring EBV viral load; rising titres à reduction of immunosuppression with close monitoring of allograft function.
TREATMENT OF PTLD:
Reduction of Immunosuppression (RI):
1) Stop MMF, and AZT and 50% reduction of CNI dose.
2) Reverse PTLD in 20%-80% of patients.
3) Need to monitor graft function – 37% Ac Rejection observed
4) Critically ill patients – withdraw all IS except steroid (low dose Prednisone).
Rituximab (Rtx) therapy:
Chimeric anti-CD20 mab : binds to CD-20 antigen (expressed on 75% B cell) àB cell depletion
Approved standard therapy for WHO- type1-3 of PTLD, not responding to RI.
Retuxi Monotherapy – Overall response rate (ORR) 44%-79%; Complete remission (CR) in 20%-55% cases
With 4 additional doses of 3 weekly-Rtx – CR rises to 34%-60.5%
PTLD-1 trial: CR 25% after standard induction + augmented by 4 doses of 3 weekly Rtx (low-risk group).
Chemotherapy:
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
Adoptive immunotherapy:
A robust EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs) Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD. A variety of recent approaches e.g., adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells” and Tac-resistant, engineered CTLs has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load.
Future strategies:
1) Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib)
2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]
3) Proteasome inhibition (Bortezomib)
4) Radioimmunotherapy, (Yibritumomab, tiuxetan)
5) Checkpoint inhibitors (Pembrolizumab, nivolumab)
6) Anti-CD30 therapy (Brentuximab vedotin)
Their efficacy remains to be validated via randomized controlled trials.
Re-transplantation and PTLD recurrence:
one-year disease free survival is necessary after control of PTLD before re-transplantation.
ATG vs IL-2 receptor antagonists: IL2 first priority
the lowest safe dosages monitored by target trough levels should be considered.
MMF can be included safely in the immunosuppressive protocols with no more added risk.
mTOR inhibitors: Their role in PTLD development remains debatable.
Graft PTLD: Usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative.
Origin of PTLD (donor vs recipient): Identification of the tumor source is crucial for future therapeutic plans and recognition of the biology of the next PTLD.
CONCLUSION:
PTLD is a disease of immunosuppression.
PTLD recurrence is rare after re-transplantation and needs careful planning of immunosuppression.
Hemato-oncologist should be involved in the management of PTLD patients.
INTRODUCTION
Post-transplant lymphoproliferative disorders (PTLD) are a serious malignancy that can occur after solid organ transplantation (SOT) or hematopoietic stem-cell transplantation (HSCT). The disorder develops due to uncontrolled B cell proliferation, often triggered by Epstein-Barr virus (EBV) infection. The incidence of PTLD varies depending on the type of transplant, with the highest incidence observed in lung and intestinal TRs. PTLD can manifest as either localized lesions or systemic disease. Reduction of immunosuppression is the mainstay of PTLD primary management, although this is not always feasible due to the risk of allograft loss or graft dysfunction. Other treatment options include surgical clearance, anti-viral agents, local radiotherapy, intravenous immunoglobulin, chemotherapeutic agents, monoclonal antibodies, and cytotoxic T lymphocytes. PTLD incidence has been increasing in recent years, likely due to improved diagnostic technology, older donors and recipients, and new immunosuppressive strategies. EBV may alter cell growth via several mechanisms, and molecular testing is essential for early detection of infection.
PATHOGENESIS
The pathogenesis of post-transplant lymphoproliferative disorders (PTLD) is attributed mainly to Epstein-Barr virus (EBV) infection, which can integrate into normal B-cell program and lead to B-cell transformation. In EBV-positive transplant recipients, PTLD development is due to a decline in T-cell immune surveillance induced by immunosuppression. However, as many as 50% of PTLD cases in SOT are not accompanied by EBV infection.
The pathogenesis of PTLD in EBV-negative patients is less evident, and several hypotheses have been postulated, including prolonged immunosuppression and allograft-driven persistent antigenic triggering. T-cell subtype PTLD, which is usually EBV-negative, is a rare tumor that presents with dissimilar manifestations to those of T-cell lymphoma in immunocompetent subjects.
Further studies are needed to identify more precise molecular-genomic classification of both types of PTLD.
CLASSIFICATION
It includes nondestructive, polymorphic, monomorphic, and classic Hodgkin’s lymphoma-like types based on histopathological features.
PTLD can manifest as a localized or disseminated disease and present with nonspecific symptoms such as fever, weight loss, neurological and gastrointestinal manifestations, and nodal lesions. An allograft dysfunction may also occur due to graft involvement.
PTLD diagnosis is crucial in transplant recipients, and the threshold for diagnosis should be lowered.
The most common sites of PTLD involvement are lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract, spleen, central nervous system, tonsils, and salivary glands. PTLD can be discriminated from lymphomas in immunocompetent patients based on gene-expression profiles and immunohistochemical staining.
The presence of EBV infection is not necessary for PTLD diagnosis, but it is mandatory to assess the EBV-encoded RNA in-situ hybridization.
DIFFERENTIAL DIAGNOSIS
PTLD can be diagnosed according to WHO 2017 Classification, but there is a lack of consistency due to missing criteria such as EBV sero-status, molecular-genomic data, and transplant organ type.
PTLD may present with a variety of symptoms, and an associated high EBV viral load should raise suspicion.
Differential diagnoses include streptococcal infections and Infectious mononucleosis. Preemptive therapy strategies for PTLD are based on monitoring EBV viral load and recognizing risk factors such as donor and recipient EBV sero-status.
TREATMENT OF PTLD
Post-transplant lymphoproliferative disorder (PTLD) is a rare but serious complication of solid organ transplantation. The main cause of PTLD is Epstein-Barr virus (EBV) infection in immunocompromised transplant recipients. The treatment of PTLD mainly involves ameliorating the immunosuppressive burden and restoring EBV-specific cellular immunity.
Reduction of immunosuppressive burden (RI)
The reduction of immunosuppressive burden involves a 50% reduction in calcineurin inhibitors (CNI) doses and withdrawal of antimetabolites. RI can reverse 20%-80% of patients with PTLD, and acute rejection rates of 37% have been observed in some trials.
Rituximab therapy
Rituximab is a monoclonal antibody that binds to the CD20 antigen, leading to B cell depletion. Rituximab is approved for three types of PTLD and has shown an overall response rate of 44%-79%. Adding 4 doses of rituximab can raise the rate of complete remission to 34%-60.5%.
Chemotherapy
Chemotherapy is indicated for Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to rituximab and RI. The standard-of-care approaches related to specific histologic features in rare subtype lymphomas have mostly improved patient outcomes.
Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients. Expanded EBV-specific CTLs have been an effective therapeutic option in autologous as well as in donor-derived PTLD.
Outpatient care
Outpatient care involves serial follow-up of the EBV viral load in identifying patients at risk and monitoring response to therapy. It also involves a comprehensive clinical picture that includes EBV viral load assessment, physical examination, radiology testing, and monitoring allograft function. The therapeutic options should be tailored as per multidisciplinary team discussion.
Post-transplant lymphoproliferative disorder (PTLD) is a severe complication following organ transplantation, particularly in patients who are receiving long-term immunosuppressive therapy. It is a disease of immunosuppression and can result in malignancy of lymphoid cells. This article provides an overview of the management and prognosis of PTLD.
The reduction of immunosuppression is the primary method for managing PTLD. Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. Chemotherapy is indicated for Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI. Other modalities may include adoptive immunotherapy and outpatient care. Investigational agents that are currently under trials have also been shown to be effective.
PROGNOSIS:
The outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as better supportive care. The IPI is a prognostic scoring system that includes patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and number of extra-nodal locations. A French registry system also relies primarily upon patient’s age, serum creatinine concentration, LDH level, PTLD localization, and histopathologic criteria. However, it is not superior to the IPI. The PTLD-1 trial has settled the prognostic validity of IPI. Hypoalbuminemia is a robust prognostic factor. CD20-positivity in PTLD indicates a poorer outcome.
PTLD RECURRENCE:
Feasibility of re-transplantation after successful management of PTLD has been reported in particular cases; however, one-year disease-free survival is necessary after control of PTLD before re-transplantation. Recommendations to limit the possibility of PTLD recurrence include time to retransplant, EBV, the role of immunosuppression, induction therapy, maintenance immunosuppression, monoclonal gammopathy, and the origin of PTLD.
CONCLUSION:
Recent progress in understanding the underlying pathophysiology of PTLD and the role of EBV has led to better management. PTLD recurrence has been rarely reported after re-transplantation, which requires careful planning of immunosuppression. The ever-improving molecular-genomic technology has had its impact on upgrading diagnostic and therapeutic strategies that will be reflected in improved recipient’s outcome.
Summary of Article
Post-transplant lymphoproliferative disorders (PTLD) are lymphoid and/or plasmacytic proliferations that occur in the setting of solid organ or allogeneic hematopoietic cell transplantation as a result of immunosuppression. They are among the most serious and potentially fatal complications of transplantation. Majority of PTLD cases(≥ 85%) are usually observed in first year post transplant year.
Risk factors-
1)Type of SOT- In adults, the incidence of PTLD has been reported to range from 0.8%2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and 20% in multi-organ and intestinal Transplant.
2)Degree of immunosuppression — The degree of immunosuppression has long been considered a major determinant of the development of PTLD. In particular, the degree of T cell immunosuppression appears to be more important than the degree of immunosuppression overall, due to the impairment of EBV-specific T cell-mediated immunity.
3)EBV serostatus — There is an increased risk of PTLD among EBV-negative recipients of EBV-positive donor organs. the incidence rate of PTLD for EBV-seronegative recipients is around 24 times higher than that for EBV-seropositive recipients. PTLD may be more common in children, because a higher percentage of children is EBV-seronegative prior to transplantation .
4)Time since transplant-The risk of PTLD also varies with time post-transplant.The highest lymphoma rate was observed during the first year post-transplant.
.
5)Other Risks- Some additional risk factors for PTLD include a history of pretransplant malignancy and fewer HLA matches and CMV seromismatch
EBV positive vs EBV negative PTLD- Around 30 % of PTLD are EBV negative.EBV positive PTLD is observed mostly during 1st year post transplant , in comparison EBV negative PTLD observed later.EBV positive PTLD are mostly B cell proliferation and CD20+ whereas EBV negative PTLD are mostly CD20 negative (T cells proliferation). EBV negative PTLD have poor prognosis in comparison to EBV positive PTLD.
Four general types of PTLD have been described in transplant recipients:
●Early lesion (ie, plasmacytic hyperplasia and infectious mononucleosis-like PTLD) – This presents as an infectious mononucleosis-type acute illness characterized by polyclonal B cell proliferation with no evidence to suggest malignant transformation.
●Polymorphic PTLD – Polymorphic PTLD are polyclonal or monoclonal lymphoid infiltrates that demonstrate evidence of malignant transformation but do not meet all of the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients.
.Classic Hodgkin PTLD-Classic Hodgkin lymphoma-like PTLD is the least common form of PTLD. Biopsy of involved tissue should fulfill the criteria required for the diagnosis of classic HL .
Clinical feature-
PTLD may present as a local or disseminated disease. In either form, the tumor can behave aggressively in a rapidly progressive manner. Clinical manifestations include: Pyrexia (57%) weight loss (9%), neurological manifestations (13%) nodal lesions (38%) gastrointestinal manifestations (27%),pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant (19%).An allograft dysfunction may ensue due to graft involvement. Lowering the threshold for PTLD diagnosis is crucial, as TR may present with nonspecific symptoms (e.g., fever, asthenia). An associated high EBV viral load by PCR should make one suspect PTLD. The most common locations of PTLD involvement are as follows-Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
Prophylaxis and Treatment-
Antiviral prophylaxis — Ganciclovir inhibits EBV replication in vitro..Many transplant center uses prophylaxis in High-risk patients (eg, donor EBV-positive, recipient EBV-negative) and uses a minimum of 100 days of intravenous ganciclovir (6 to 10 mg/kg per day).
EBV monitoring for preemptive therapy– While many transplant recipients demonstrate a modestly increased EBV viral load in the peripheral blood post-transplant, the vast majority of patients with EBV-positive PTLD will demonstrate a more marked elevation in the EBV viral load. Many transplant centers incorporate EBV monitoring into the routine evaluation of patients at high risk for PTLD and preemptively treat at the time of viral reactivation.Most centers administer preemptive rituximab therapy for patients at high risk of EBV-associated PTLD if titre of EBV rises significantly.
Initial management is largely dependent upon the type of PTLD:
•Early lesions – For most patients with early lesions, we suggest reduction of immunosuppression alone rather than in combination with other therapies Other agents are generally reserved for those patients with residual disease despite reduced immunosuppression or for those who cannot tolerate reduction of immunosuppression.
•Polymorphic PTLD – For most patients with polymorphic PTLD that expresses CD20 (CD20+ PTLD), we suggest the use of rituximab in addition to reduction of immunosuppression, as tolerated, rather than reduction of immunosuppression alone or this combination with chemotherapy .
•Monomorphic PTLD – For patients with monomorphic CD20+ PTLD, we suggest the use of rituximab, either alone or in combination with chemotherapy in addition to reduction of immunosuppression . Single agent rituximab may be considered for patients who have minimal symptoms and for those who are not candidates for initial chemotherapy. All other patients with CD20+ PTLD are offered rituximab plus combination chemotherapy, administered concurrently or sequentially. Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with combination chemotherapy plus reduction of immunosuppression. Surgery is reserved for patients with complications such as perforation or obstruction.
•Classic Hodgkin lymphoma-like PTLD – Classic Hodgkin lymphoma-like PTLD is the least common form of PTLD and there is a paucity of data regarding management. For most patients with classic Hodgkin lymphoma-like PTLD we suggest management with chemotherapy with or without radiation therapy according to protocols used for classic Hodgkin lymphoma.
●There is a paucity of information concerning mortality of patients with PTLD. Although the prognosis varies with clonality and extent of disease, published series suggest overall survival rates ranging between 25 to 35 percent. Mortality with monomorphic PTLD and T cell PTLD are higher.
Level of Evidence-5
INTRODUCTION:
PTLD remains a considerable concern is post-transplant patients accounting for 1/5th of all post-transplant cancers. Majority are B cell associated secondary to EBV infection. Increased vigilance and early detection is crucial.
First described in 1969, now higher incidence is being noted with better diagnostic technology with a standardized incidence ratio of 10 (non-Hodgkin) and 4 (Hodgkin) PTLD.
Risk factors include transplanted organ, induction and maintenance immunosuppression (T cell depleting agents), EBV status of donor and recipient pre-transplant, age of recipient and EBV infection.
EBV infected B cells remain the cornerstone of pathogenesis combined with immunosuppression related reduction in T cell activity. For EBV negative PTLD many theories are postulated but none proven.
PTLD is a diagnosis requiring tissue confirmation with histopathology and immunophenotyping, as the treatment and outcomes depend on the histopathological subtype. The sub-types include 1. Non-destructive, 2. Polymorphic, 3. Monomorphic, 4. Classical Hodgkin lymphoma. Staging should be done as for normal population.
Variable presentation can be found. B-symptoms are common. Graft dysfunction should be assessed. Differentials include bacterial and other viral infections. EBV monitoring by PCR is not validated as there are no clear cut off values and no standard testing interval is defined. However for high risk cases preemptive strategy should be utilized. Prophylaxis in the form of EBV serology of both recipient and donor at time of donor selection should be routine practice and EBV negative recipient should get graft from EBV negative donor.
Treatment of PTLD includes 1) Reduction in Immunosuppressive therapy 2) Rituximab 3) Chemotherapy and 4) Adoptive Immunotherapy.
1. Reduction in immunosuppression
It remains the cornerstone of PTLD management as reducing the immunosuppression can lead to activation of EBV specific T cells. This is achieved by stopping antimetabolite and reducing CNI by 50%, while monitoring for rejection.
2. Rituximab
B cell PTLD has 75% positivity for CD 20 antigen. Rituximab is a monoclonal antibody against CD-20 positive cells. Rituximab has been approved as standard therapy for 3 subtypes of PTLD (non-destructive, polymorphic and monomorphic DLBCL). Addition of Rituximab to the reduction of immunosuppressive therapy has been shown to achieve complete remission in 1/4th of cases.
3. Chemotherapy
PTLD subtypes unresponsive to RI and Rituximab are indications for chemotherapy including Burkitts, Hodgkin, Peripheral T cell, Primary CNS lymphomas. Standard regime of R-CHOP is widely used and safe provided toxicities are monitored and managed. Up to 88% response rate and 70% complete remission rates have been achieved.
4. Adoptive Immunotherapy
T cells targeting EBV infected B cells by Donor lymphocyte infusion or CTLs are in use for resistant cases.
Regular monitoring during treatment for both toxicities and response should be done. This includes 1) Viral load monitoring 2) Screening for toxicities of therapy 3) Monitoring for rejection 4) MDT involvement.
A few experimental therapies have been suggested but no robust evidence is available for their use.
The prognosis of PTLD has improved markedly with 70% complete remission rates achieved. This is in large part due to better supportive acre and better management of treatment related toxicities. The use of prognostic scoring systems is also helping improve outcomes by identifying high risk cases.
Re-transplantation after successful remission and disease free interval of 1-2 years, however certain modification in induction and maintenance immunosuppression needs to be kept in mind.
What is the level of evidence provided by this article?
Level V
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Introduction
This article discusses the clinical evidence, measures, and strategies for treating Post-Transplantation Lymphoproliferative Disorders (PTLD). PTLD are the disorders that occur due to immunosuppression after Solid Organ Transplantation.
Discussion
The primary management of PTLD includes reduction of immunosuppression (RI). A combination of methods is considered to treat PTLD instead of an isolated method because administration of immunosuppressants cannot be completely ceased. These methods are discussed in this article.
Only 50% of PTLD is not caused by EBV infections. However the clinical consequences of different EBV serotypes require further studies to recognize molecular genome classification of both types. According to WHO PTLD can be categorized as non-destructive PTLD, polymorphic PTLD, monomorphic PTLD and Hodgkin’s lymphoma-like PTLD.
The manifestation of PTLD clinically varies widely from symptomless lesions to fulminating disease with multi-organ failure.
Heart transplant recipients take the longest to develop PTLD while the shortest is lung and lung/heart in paediatric recipients.
To monitor pre-emptive PTLD therapy, an estimation of viral load through PCR amplification of peripheral blood EBV DNA is mandatory. PTLD patients express increased EBV viral load.
EBV sero-status of donor and recipient is to be recognized before donor selection.
Immunosuppressive burden reduction is the primary objective of PTLD treatment. RI involves reducing calcineurin inhibitors by 50%. Allograft function should be monitored during RI trial for early rejection manifestations.
Rituximab (Rtx) binds to CD-20 antigen leading to B-cell depletion.
Uncommon lymphomas and B-cell PTLD lymphomas which are unresponsive to RI and Rtx are considered for immunochemotherapy.
EBV-specific cytotoxic lymphocytes (CTLs) induce a EBV-specific cellular immune response.
Outpatient care included weekly monitoring for high-risk TRs and monthly followed by three-monthly monitoring for low-risk TRs. Increase in viral load indicates progression. EBV viral load assessment includes comprehensive clinical picture like radiology and physical examination. Balance in PTLD management and allograft rejection avoidance is crucial. Multidisciplinary teams (MDTs) should discuss therapeutic options.
Lymphoma-specific protocols with the support of better supportive care has greatly improved PTLD patients’ outcomes.
Recommendations for reducing PTLD recurrences include 12 -24 months from remission should be given for new transplant, monitoring of EBV, immunosuppression monitoring, induction therapy, monoclonal gammopathy and origin of PTLD.
Conclusion
PTLD management has significantly improved since the understanding of pathophysiology and the role of EBV. Molecular genomic technology has aided in building management strategies. A close liaison of MDT with haemato-oncology team plays a vital role in successfully management of PTLD and recurrence.
INTRODUCTION:
· Post transplant lymphoproliferative disorder is a malignancy caused by uncontrolled B cell proliferation due to blunted immunological surveillance.
· B cells can be infected by EBV through post-transplant reactivation, primary EBV infection, or environmental exposure.
· PTLD is most common in the first post-transplant year, while T-cell proliferation is less common.
· PTLD is a serious disorder requiring tissue diagnosis and evidence of EBV DNA, RNA, or protein material.
Epidemiology of PTLD:
PTLD has been recognized in both SOT and HSCT since 1969. PTLD prevalence has increased due to better diagnostic technology, older donors, increased awareness, new immunosuppressive strategies, and HSCT.
Risk factors:
Risk factors vary depending on the type of transplant organ.
1- SOT: In adults, 0.8%-2.5% in kidney transplant recipients (KTR),
• 0.5%-5.0% in pancreatic TRs,
• 1.0%-5.5% in liver TRs,
• 2.0-8.0% in heart TRs,
• 3.0-10.0% in lung TRs,
• ≤ 20% in multi-organ and intestinal TRs
2- Allogenic HSCT: PTLD incidence is related to HLA matching and T-cell depletion.
3- Immunosuppressive load exposure during primary renal illness is a risk factor for the development of PTLD.
4- Oncogenic EBV: EBV may alter cell growth via:
• Lack of immune recognition,
• Induction of the potent oncogenes
• EBV-induced proliferating cells as well as EBV variant/HLA types.
• Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA
Pathogenesis:
Role of EBV:
Recent reports suggest that as many as 50% of PTLD in SOT are not accompanied by EBV infection
• For EBV-positive TRs, EBV can integrate into normal B-cell programs, Defences by compromised T-cells in TRs lead to uncontrolled transformation and lymphoma.
• EBV-negative patients Pathogenesis of PTLD is less evident. Several hypotheses have been postulated like
• CMV
• Another viral infection,
• Prolonged
• Immunosuppression,
• Allograft-driven persistent antigenic triggering,
• Hit-and-run hypothesis
Classification:
WHO 2017 Classification,
• Non-destructive PTLDs: plasmocytic hyperplasia, florid follicular hyperplasia and infectious mononucleosis-like PTLD.
• Polymorphic PTLD.
• Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
• Classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure. It may present as a local or disseminated disease.
It includes :
• Pyrexia (57%)
• Weight loss (9%)
• Neurological manifestations (13%)
• Nodal lesions (38%)
• Gastrointestinal manifestations (27%)
• Pulmonary manifestations (15%).
• Infectious mononucleosis-like syndrome that could be fulminant (19%)
Differential diagnosis:
In TRs with pyrexia, pharyngitis, and cervical lymphadenopathy, should be taken into consideration.
Prophylaxis:
• In some populations that are very susceptible to developing PTLD, preemptive treatment should be taken into consideration.
• Donor and recipient EBV serostatus should be known before choosing a donor, and EBV-negative donors ideally better to be used for EBV-negative TR
• Achieving the lowest immunosuppressive load clinically feasible.
• IVIG/CytoGam injection to maintain high titers of anti-EBV antibodies is also advised.
TREATMENT OF PTLD
Reduce Immunosuppression:
The reduction of the immunosuppressive load is the cornerstone of basic PTLD therapy,
Rituximab therapy
Rituximab is an effective chimeric anti-CD20 monoclonal antibody that binds to CD-antigen and causes B cell depletion through a variety of mechanisms.
Chemotherapy
Indications:
• Burkitt’s lymphoma,
• Hodgkin’s lymphoma,
• Peripheral T-cell lymphoma,
• Primary CNS lymphoma and other uncommon lymphomas,
• B-cell PTLD unresponsive to Rtx and RI
Adoptive immunotherapy
EBV-specific CTLs are a potent treatment in both donor- and recipient-derived PTLD, but GVHD is the main danger.
Future strategies
• Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib).
• Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)
• Proteasome inhibition[83] (Bortezomib).
• Radioimmunotherapy. (90Yibritumomab, tiuxetan).
• Checkpoint inhibitors (Pembrolizumab, nivolumab).
• Anti-CD30 therapy (Brentuximab vedotin).
Prognosis:
IPI is a prognostic scoring system that includes the following:
• Patient’s age,
• Performance attitude,
• Current stage,
• Lactate dehydrogenase (LDH),
• Number of extra-nodal locations.
Using univariate analysis, poor prognostic criteria have been postulated that include the following:
• Monoclonality,
• Negative EBV serology,
• Primary CNS involvement,
• Tumour originated from T-cell, performance status ≥ 2,
• Chemotherapy-based therapy (plus RI),
• Multiple involved locations
Re-transplantation and PTLD recurrence:
• The feasibility of re-transplantation after successful management of PTLD has been reported, but one-year disease-free survival is necessary.
• Retransplantation after the PTLD cure remains controversial due to the re-exposure of immunosuppression.
• To limit the possibility of PTLD recurrence, the following recommendations are worth noting:
Time to retransplant:
· EBV positivity,
· Low/absent EBV viral load,
· Close monitoring,
· Anti-viral therapy,
· Role of immunosuppression.
Conclusion:
• PTLD is a disease of immunosuppression, with improved understanding and management.
• Moleculargenomic technology has improved diagnostic and therapeutic strategies to reduce PTLD recurrence.
• Rare reports of PTLD recurrence following re-transplantation necessitate cautious immunosuppressive planning.
INTRODUCTION;.
Post-transplant lymphoproliferative disorders (PTLD) are lymphoid and/or plasmacytic proliferations that occur as a result of immunosuppression in the setting of solid organ or allogeneic hematopoietic cell transplantation.
These conditions lie along a continuum of disease and are categorized by the World Health Organization PTLD classification system .
PTLDs are among the most serious complications of transplantation.
PTLD epidemiology
PTLD incidence is 3.2% in HSCT recipients and it’s recognition has increased due to advanced technology, increase of the donor and recipient age and new immunosuppressive regimens as well as haploidentical HSCT.
Risk factors
-SOT: Multiorgan and intestinal transplant has the highest incidence while kidney transplant has the lowest.
-Allogenic HSCT: HLA degree of matching and the T cell depleting agents affects the risk, where the more the matching the lower is the risk and the risk was low with broad lymphocyte depleting agents.
EBV negative recipients are more susceptible to develop PTLD, early occurrence is with EBV positive recipients while late occurrence is associated with EBV negative cases.
-Immunosuppressive exposure in primary renal disease therapy before transplantation increase immunosuppression burden.
-Oncogenic EBV causes growth transformation, initiation of oncogenes, bypass immune control, cell targets, viral and cellular mRNA expression.
Molecular and serological methods together early detection of EBV
Pathogenesis
50% of PTLD are EBV negative with unclear specific pathogensis.
In EBV positive cases ,defective T cell surveillance through immunosuppressives is implicated.
EBV-positive vs EBV-negative PTLD
There is no clear difference but some differences can be noted
EBV negative: has features similar to diffuse large B-cell lymphoma in immunocompetent patients, mostly T cell lesion of germinal B cell center type ,less prevalent , common with seronegative SOT in pediatrics.
EBV positive :is more common , of B cell origin of non germinal center type ,prevalent with HSCT
Early versus Late onset PTLD
Early onset represent the majority of PTLD cases ,it is usually associated with EBV positive cases, with graft involvement and is non destructive , donor derived ,less common to be Monomorphic subtypes and bortezomib can be useful after allogeneic HSC also Induction therapy has a role.
Late onset is less prevalent ,mostly EBV negative with extra nodal involvement more than graft affection, with high incidence of late onset Hodgkin’s lymphoma after allogeneic HSCT and cumulative immunosuppressives have an important role.
Clinical presentation: variable presentation – asymptomatic lesions to fulminating disease with multi-organ failure.
Fever (57%), weight loss (9%), nodal lesions (38%), gastrointestinal (27%), respiratory (15%) and infectious mononucleosis-like syndrome (19%), neurological illness (13%).
Common locations: Lymph nodes, liver, lung, kidney, bone marrow, GI Tract, spleen, CNS, tonsils and salivary glands
Time to PTLD: shortest for Lungs and heart + Lung in paediatric recipients; longest for adult heart recipients
Prophylactic measures:
better for EBV-negative people to receiving grafts from EBV-negative donors. Keeping high titres of anti-EBV antibodies (IVIG / Cyto-Gam administration)
High-risk cases – monitoring EBV viral load; rising titres à reduction of immunosuppression with close monitoring of allograft function
Pre-emptive strategies to limit the risk of PTLD development:
– Reduction Immunosuppression, Rituximab, Adoptive T cell (EBVST)
– viral load correlates with increases risk of PTLD
– EBV Viral load is mandatory to start and monitoring therapy
– Cell free plasma EBV-DNA correlates better marker of EBV activity
Pitfalls – source of sample, cut off value, time to start monitoring not clear
TREATMENT OF PTLD
1. Reduction of Immunosuppression (RI)
– Stopping antimetabolites (MMF, AZT); 50% reduction of CNI dose
– reverse PTLD in 20%-80% of patients
– Need to monitor graft function – 37% Ac Rejection observed
– Critically ill patients – withdraw all IS except steroid (low dose Prednisone)
EBV positive disease responds better than EBV negative cases
No response to RI observed in – old age (>50years), bulky disease (>7cm); advanced stage (Ann-Arbor III/IV)
2- Rituximab (Rtx) therapy:
Chimeric anti-CD20 mab : binds to CD-20 antigen (expressed on 75% B cell) àB cell depletion
Approved standard therapy for WHO- type1-3 of PTLD, not responding to RI.
Retuxi Monotherapy – Overall response rate (ORR) 44%-79%; Complete remission (CR) in 20%-55% cases
With 4 additional doses of 3 weekly-Rtx – CR rises to 34%-60.5%
PTLD-1 trial: CR 25% after standard induction + augmented by 4 doses of 3 weekly Rtx (low-risk group).
3- Chemotherapy
Indications: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma; Lymphoma & B-cell PTLD unresponsive to Retuxi + RI
Incomplete / no response to Retuxi monotherapy –> 4 cycles of R-CHOP-21 given every 3 wks, with G-CSF support; ORR 88%; CR of 70% at end of therapy.
Risk-stratified sequential therapeutic approach
Rtx weekly x 4cycles –> response assessment at 2-4 weeks
good response –> 4 more doses of Rtx at 3wks interval
poor response –> R-CHOP-21 with supportive care and G-CSF
Reduced Immunosuppression + Stratified Sequential Chemo-therapy is considered the standard of care for Polymorphic and Monomorphic DLBL-like PTLD (regardless to EBV status) after SOT.
Selection in to poor risk group depending on presence of risk factors (type of allograft type, response to Rtx and performance status) formed the basis of PTLD-2 trial.
4- Adoptive immunotherapy
Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD.
GVHD can be the complication
5- Outpatient care
Serial monitoring of viral load, allograft function, physical examination and imaging – to optimize balance between PTLD management and avoidance of allograft acute rejection is crucial.
6. Future strategies:
newer therapeutic medications – their efficacy remains to be validated via RCT.
(1) Bruton’s TKI – (Ibrutinib) – used in GVHD and allograft rejection; in DLBCL
2. A Inhibition of PI3K – Idelalisib
2. B mTORi – SRL and Everolimus – role in PTLD controversial
(3) Proteasome inhibition (Bortezomib) – in early presented PTLD post allogeneic HSCT
(4) Radioimmunotherapy, (90Yibritumomab, Tiuxetan) – small pilot trial
(5) Checkpoint inhibitors (Pembrolizumab, nivolumab): Cytotoxic T lymphocyte associated antigen 4 pathway: recommended in clinical trials,
(6) Anti-CD30 therapy (Brentuximab Vedotin) – CD30 expressed in 85% PTLD; limited clinical experience (only case reports).
Re-transplantation and PTLD recurrence
· 12 to 24 mo after complete PTLD remission
· Epstein–Barr nuclear antigen IgG positivity
· Low/absent EBV viral load is recommended at the time of re-transplantation
· persistently high EBV viral load – Anti-viral therapy: Gancyclovir long-term prophylaxis
· T cell-depleting agents should be excluded from induction strategies (IL-2R blocker first choice)
· Triple therapy (CNI, MMF and steroids) in lowest safe dosage
Level V
1. Please summarise this article
SUMMARY:
This is a systematic review, discussed prevalence, clinical clues, prophylactic measures as well as the current and future therapeutic strategies.
Introduction:
PTLD is a disease of over-immunosuppression
Lack of T-cell led immune surveillance results in uncontrolled B cell proliferation
EBV-infection is triggering factor – primary infection (EBV-positive donor to EBV-negative recipient), or late reactivation due to cumulative immunosuppression
Lymphoma account for 21% of all malignancies in SOT recipients
Epidemiology:
SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients. Reported incidence of PTLD in 3.2% of HSCT, 1-2% of SOT
85% PTLD occurs within 1 yr post-transplant; Second peak at 5-15 yrs
Risk factors:
(1) SOT: lymphatic tissue in allograft (highest in small intestine 20%, Lungs 3-10%, heart 2-8%, lowest in kidney 0.8-2.5%) and the degree of immunosuppression (cumulative immunosuppression level)
(2) Allogenic HSCT: HLA matching à consequent T-cell depleting Induction used
(3) Prior immunosuppression treatment of primary disease in native kidney
(4) Oncogenic EBV – induction of LMP1, LMP2 oncogene
Pathogenesis:
EBV+ : immunosuppression-induced decline in the T-cell mediated immune surveillance
EBV negative (50% PTLD in SOT) – CMV & other Viral infections, prolonged immunosuppression, allograft-driven persistent antigenic trigger, hit & run hypothesis
Histopathological (WHO) classification of PTLD:
(1) Non-destructive: Plasmacytic; florid Follicular; infectious mononucleosis-like
(2) Polymorphic PTLD: B cells in maturing stages, T cells,
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell type
(4) classic Hodgkin’s lymphoma-like PTLD
EBV infection could be currently seen in almost all non-destructive PTLD, in > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD, and in only 50% of monomorphic PTLD.
Cell of origin: (Gene-expression profile and IHC) – EBV+ve cases are mostly non-germinal center B-cell type; EBV-ve cases are more of “germinal center B-cell type
EBV-encoded RNA (EBER) in-situ hybridization assessment is mandatory for all the cases, although presence of EBV infection is not necessary for PTLD diagnosis.
Clinical presentation: variable presentation – asymptomatic lesions to fulminating disease with multi-organ failure.
Fever (57%), weight loss (9%), nodal lesions (38%), gastrointestinal (27%), respiratory (15%) and infectious mononucleosis-like syndrome (19%), neurological illness (13%).
Common locations: Lymph nodes, liver, lung, kidney, bone marrow, GI Tract, spleen, CNS, tonsils and salivary glands
Time to PTLD: shortest for Lungs and heart + Lung in paediatric recipients; longest for adult heart recipients
Prophylactic measures:
better for EBV-negative people to receiving grafts from EBV-negative donors. Keeping high titres of anti-EBV antibodies (IVIG / Cyto-Gam administration)
High-risk cases – monitoring EBV viral load; rising titres à reduction of immunosuppression with close monitoring of allograft function
Pre-emptive strategies to limit the risk of PTLD development:
– Reduction Immunosuppression, Rituximab, Adoptive T cell (EBVST)
– viral load correlates with increases risk of PTLD
– EBV Viral load is mandatory to start and monitoring therapy
– Cell free plasma EBV-DNA correlates better marker of EBV activity
Pitfalls – source of sample, cut off value, time to start monitoring not clear
TREATMENT OF PTLD
1. Reduction of Immunosuppression (RI)
– Stopping antimetabolites (MMF, AZT); 50% reduction of CNI dose
– reverse PTLD in 20%-80% of patients
– Need to monitor graft function – 37% Ac Rejection observed
– Critically ill patients – withdraw all IS except steroid (low dose Prednisone)
EBV positive disease responds better than EBV negative cases
No response to RI observed in – old age (>50years), bulky disease (>7cm); advanced stage (Ann-Arbor III/IV)
2- Rituximab (Rtx) therapy:
Chimeric anti-CD20 mab : binds to CD-20 antigen (expressed on 75% B cell) àB cell depletion
Approved standard therapy for WHO- type1-3 of PTLD, not responding to RI.
Retuxi Monotherapy – Overall response rate (ORR) 44%-79%; Complete remission (CR) in 20%-55% cases
With 4 additional doses of 3 weekly-Rtx – CR rises to 34%-60.5%
PTLD-1 trial: CR 25% after standard induction + augmented by 4 doses of 3 weekly Rtx (low-risk group).
3- Chemotherapy
Indications: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma; Lymphoma & B-cell PTLD unresponsive to Retuxi + RI
Incomplete / no response to Retuxi monotherapy –> 4 cycles of R-CHOP-21 given every 3 wks, with G-CSF support; ORR 88%; CR of 70% at end of therapy.
Risk-stratified sequential therapeutic approach
Rtx weekly x 4cycles –> response assessment at 2-4 weeks
good response –> 4 more doses of Rtx at 3wks interval
poor response –> R-CHOP-21 with supportive care and G-CSF
Reduced Immunosuppression + Stratified Sequential Chemo-therapy is considered the standard of care for Polymorphic and Monomorphic DLBL-like PTLD (regardless to EBV status) after SOT.
Selection in to poor risk group depending on presence of risk factors (type of allograft type, response to Rtx and performance status) formed the basis of PTLD-2 trial.
4- Adoptive immunotherapy
Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD.
GVHD can be the complication
5- Outpatient care
Serial monitoring of viral load, allograft function, physical examination and imaging – to optimize balance between PTLD management and avoidance of allograft acute rejection is crucial.
6. Future strategies:
newer therapeutic medications – their efficacy remains to be validated via RCT.
(1) Bruton’s TKI – (Ibrutinib) – used in GVHD and allograft rejection; in DLBCL
2. A Inhibition of PI3K – Idelalisib
2. B mTORi – SRL and Everolimus – role in PTLD controversial
(3) Proteasome inhibition (Bortezomib) – in early presented PTLD post allogeneic HSCT
(4) Radioimmunotherapy, (90Yibritumomab, Tiuxetan) – small pilot trial
(5) Checkpoint inhibitors (Pembrolizumab, nivolumab): Cytotoxic T lymphocyte associated antigen 4 pathway: recommended in clinical trials,
(6) Anti-CD30 therapy (Brentuximab Vedotin) – CD30 expressed in 85% PTLD; limited clinical experience (only case reports).
Re-transplantation and PTLD recurrence
· 12 to 24 mo after complete PTLD remission
· Epstein–Barr nuclear antigen IgG positivity
· Low/absent EBV viral load is recommended at the time of re-transplantation
· persistently high EBV viral load – Anti-viral therapy: Gancyclovir long-term prophylaxis
· T cell-depleting agents should be excluded from induction strategies (IL-2R blocker first choice)
· Triple therapy (CNI, MMF and steroids) in lowest safe dosage
2. What is the level of evidence provided by this article?
– Not levelled
PTLD AFTER TRANSPLANT
incidence
SIR is 10 for non hdgkins and 4 for hodgkins lymphoma
two peaks – FIRST aroun 1 yr and SECOND at 10-15 yrs
risk factors
organ depending on amount of lymphatic tissue in it so small intestine is highes and kidney is lowest
cummulative immunosuppression(IS) level – hish risk with more IS
more with T cell depletion
pathology
EBV positice case – non germinal type B cell lymphoma
EBV neg cases of PTLD- germinal type B cell lymphoma
symptoms
asyptomatic
LN enalrgement
systemic symptoms like weight loss or fever
organ specific symptoms
mutiorgan failure
EBV monitering in transplant recipient as preemptive therapy for PTLD
more viral load increases the risk of PTLD
cell free plasma DNA EBV is best
souce of sample and cut off is not clear
prevention of PTLD
always accept EBV negative graft for EBV negative recipient
IS to be kept at lower level
CMV reactivation should also lead to reduction of IS
TREATMENT
reduction of IS – stop antimetabolites, 50% reductioon or more in CNI
reverese 20-80% of PTLD cases
assess the response in 2-4 week
EBV positive cases show more response to reduction in IS
RETUXIMAB(Rtx) BINDS TO cd20 AND LEAD TO DEPLETION OF B cell
recommanded for all three types of PTLD except hodgkin lymphoma type
25% COMPLETE RESPONSE afetr Rtx weekly 4 doses followed by 3weekly 4 doses- LOW RISK GROUP (ptld1 TRIAL)
ABOVE GROUP HAS BETTER SURVIVAL CHANCES COMAPRED TO complete remission with
Rtx followed by CHOP
CHEMOTHARPAAY
for burkits lymphoma, hodgkins lymphoma, CNS lesion , uncommon lymphoma , cases not responding to Rtx
chemo to be used with supportive care and G-CSF to prevent complications
Risk-stratified sequential therapeutic approach
Post Rtx – assess the respone
good response – 4 more doses of Rtx
poor response – RCHOP with supportive care and G-CSF
this also for the basis for PTLD-2 trial where two groups are radamised based on type of allograft , response to Rtx and performance status – level 1 eveidence
Adaptive immunotherapy
in PTLD after stem cell transplant – EBV specific cytotoxic T cell can give traansfused to generate T cell response
GVHD can be the complication
Summary
Post-transplant lymphoproliferative disorders (PTLD) develop as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells may get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The mainstay of PTLD primary management is reduction of immunosuppression (RI). A potential risk of allograft loss or graft dysfunction has to be considered particularly for vital organ transplants (e.g., heart transplant).
In adults, the incidence of PTLD has been reported to range from 0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ and intestinal TRs[9,10] (Figure 1). These figures suggest that the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors
The magnitude of increased risk of PTLD can be graded as follows: (1) HSCT (zero in patients who received cyclophosphamide for GVHD and > 20% with selective T-cell depletion); (2) Umbilical-cord transplantation (4%-5%); (3) Transplant from unrelated donors (4%-10%); and (4) Transplant from matched, related donors (1%-3%)
Considering the improving patient and allograft survival, two peaks of PTLD incidence have been observed, first peak: In the first post-transplant year (mostly EBV seropositive), and, second peak: Usually present 5-15 years after transplant (mostly EBV seronegative)
50% PTLD in SOT are not accompanied by EBV infection.
Pathogenesis
For EBV-positive TRs, the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immunosurveillance. EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells. Normally, these antigens would trigger a T-cell response capable of destruction of most of the EBV-infected B cells. This immune defense mechanism has been compromised in TRs leading to unlimited Bcell transformation and the evolution of lymphoma. In PTLD in EBV-negative patients several hypotheses have been postulated e.g., CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes.
EBV-positive vs EBV-negative PTLD
Further studies are warranted to recognize more precise molecular-genomic classification of both types and would help to define best therapeutic strategies,
Classification
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD.
Gene-expression profile and immunohistochemical
1-germinal center” B cell (EBV-ve)
2-Non–germinal” center B cell (EBV+ve cases )
Despite wide-spread application of preemptive monitoring of peripheral-blood EBV viral load, it seems to be devoid of any diagnostic benefit
Clinical feature
Pyrexia (57%)
nodal lesions (38%)
gastrointestinal manifestations (27%)
infectious mononucleosis-like syndrome (19%)
pulmonary manifestations (15%)
neurological manifestations (13%)
weight loss (9%)
allograft dysfunction
Management
MDT approach
Prevention
Primarily, EBV sero-status of both donor and recipient should be recognized before donor selection.
EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
A fine-tuning the immunosuppressive burden to as low as clinically possible.
Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression.
Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function
RI
Compared to EBV positive disease, the EBV negative cases are less responsive to RI
However, a complete lack of response to RI has been observed in old, aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV)
Rituximab
It has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI
Chemotherapy
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
Adoptive immunotherapy
A robust EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs) Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD. A variety of recent approaches e.g., adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells” and Tac-resistant, engineered CTLs has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load.
Future strategies
(1) Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib)
(2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]
(3) Proteasome inhibition (Bortezomib)
(4) Radioimmunotherapy, (Yibritumomab, tiuxetan)
(5) Checkpoint inhibitors (Pembrolizumab, nivolumab)
(6) Anti-CD30 therapy (Brentuximab vedotin)
Their efficacy remains to be validated via randomized controlled trials.
Re-transplantation and PTLD recurrence
one-year disease free survival is necessary after control of PTLD before re-transplantation.
ATG vs IL-2 receptor antagonists: IL2 first priority
the lowest safe dosages monitored by target trough levels should be considered.
MMF can be included safely in the immunosuppressive protocols with no more added risk.
mTOR inhibitors: Their role in PTLD development remains debatable.
Graft PTLD: Usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative.
Origin of PTLD (donor vs recipient): Identification of the tumor source is crucial for future therapeutic plans and recognition of the biology of the next PTLD.
Level of evidence- non leveled.
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
INTRODUCTION
· Post-transplant lymphoproliferative disorders (PTLD) develop as a result of uncontrolled B cell proliferation due to blunted immunological surveillance.
· B cells may get infected by EBV either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure
· Lymphoma accounts for 21% of all malignancies in SOT recipients
· Clinically, PTLD may manifest either as localized lesion or as systemic disease
· The mainstay of PTLD primary management is reduction of immunosuppression (RI).
· A variety of therapeutic options include surgical clearance, anti-viral agents, local radiotherapy, intravenous immunoglobulin (IVIG), chemotherapeutic agents, monoclonal antibodies and cytotoxic T lymphocytes with variable success
Risk factors
(1) SOT: the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors
(2) Allogenic HSCT: incidence is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant
(3) Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney
(4) Oncogenic EBV
Pathogenesis
· PTLD development was attributed mainly to EBV infection, however, recent reports suggest that as many as 50% PTLD in SOT are not accompanied by EBV infection
· For EBV-positive TRs, the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immunesurveillance.
Classification: depending mainly on histopathological classification:
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD. (2) Polymorphic PTLD. (3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). And (4) classic Hodgkin’s lymphoma-like PTLD
Clinical presentation: Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Salient features: Pyrexia (57%), weight loss (9%), neurological manifestations (13%), nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant (19%)
The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands
Time to PTLD for different transplanted organs: is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR
EBV monitoring for preemptive therapy: preemptive strategies to limit the risk of PTLD development:
RI, rituximab therapy, and adoptive transfer of EBV-specified T cells.
Prophylaxis:
· EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
· Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
· monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function have been also recommended
TREATMENT OF PTLD
1-RI
· RI can reverse 20%-80% of patients with PTLD
· RI includes 50% reduction of calcineurin inhibitors doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil.
· With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered
· EBV negative cases are less responsive to RI than EBV positive disease
· A complete lack of response to RI has been observed in patients > 50 years, bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV)
2- Rituximab (Rtx) therapy
· Rtx indicated in: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
· The overall response to Rtx monotherapy in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases
3- Chemotherapy
· Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
· Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy, with overall response rate approached 88%
4- Adoptive immunotherapy
Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD
5- Outpatient care
(1) Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial. (5) Therapeutic options should be tailored as per multidisciplinary team discussion.
(6) The initial therapeutic step is RI or cessation of immunosuppression
6- Future strategies: (1) Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib) (2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]; SRL and everolimus (3) Proteasome inhibition (Bortezomib) (4) Radioimmunotherapy, (90Yibritumomab, tiuxetan) (5) Checkpoint inhibitors (Pembrolizumab, nivolumab): Cytotoxic T lymphocyteassociated antigen 4 pathway: recommended only in clinical trials. And (6) Anti-CD30 therapy (Brentuximab vedotin)
Re-transplantation and PTLD recurrence
Recommendations to limit the possibility of PTLD recurrence:
(5) Time to retransplant: Approximately two years of time should elapse after successful PTLD management
(6) EBV: The following recommendations is currently suggested in the literature: (a) TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation. (b) Low/absent EBV viral load is recommended at the time of retransplantation. (c) Close monitoring of TRs with persistently high EBV viral load is advised. (d) Anti-viral therapy
(7) Role of immunosuppression: Retransplantation after PTLD cure remains controversial due to the re-exposure of immunosuppression
(8) (4) Induction therapy: The following agents are considered:
(a) ATG vs IL-2 receptor antagonists: ATG induction significantly triggers the risk of lymphoma evolution as compared to other agents
(b) Rituximab in induction therapy: inhibit EBV proliferation within lymphocytes, consequently limiting the risk of PTLD development
(9) Maintenance immunosuppression:
(a) Triple therapy (CNI, MMF and steroids): consider lowest safe dose
(b) MMF can be included safely in the immunosuppressive protocols with no more added risk
(c) mTOR inhibitors: Their role in PTLD development remains debatable.
(d) Graft PTLD usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative
(10)Monoclonal gammopathy complete resolution is an obvious indicator of complete remission of PTLD
(11)Origin of PTLD: a better outcome in TRs with “donor” lymphomas.
CONCLUSION
· PTLD is a disease of immunosuppression
· PTLD recurrence is rare after re-transplantation and needs careful planning of immunosuppression
· Hemato-oncologist should be involved in the management of PTLD patients
Please summaries this article
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation and hematopoietic stem-cell transplant and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance.
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT. Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.
Role of EBV 50% of PTLD in post kidney transplant are EBV +ve. EBV cause abnormal b cell proliferation because of the inability of t cell to destruct the infected EBV -B cells because of the immunosuppression the EBV -ve PTLD may be explained by another viral infection like CMV or prolonged immunosuppression.
PTLD is a disease of immunosuppression, with improved understanding and management.
• Moleculargenomic technology has improved diagnostic and therapeutic strategies to reduce PTLD recurrence.
• Rare reports of PTLD recurrence following re-transplantation necessitate cautious immunosuppressive planning.
What is the level of evidence provided by this article?
level 3
INTRODUCTION
· PTLD is a malignancy caused by uncontrolled B cell proliferation due to blunted immunological surveillance.
· B cells can be infected by EBV through post-transplant reactivation, primary EBV infection, or environmental exposure.
· PTLD is most common in the first post-transplant year, while T-cell proliferation is less common.
· PTLD is a serious disorder requiring tissue diagnosis and evidence of EBV DNA, RNA, or protein material.
Epidemiology of PTLD
PTLD has been recognized in both SOT and HSCT since 1969. PTLD prevalence has increased due to better diagnostic technology, older donors, increased awareness, new immunosuppressive strategies, and HSCT.
Risk factors
Risk factors vary depending on the type of transplant organ.
1- SOT: In adults, 0.8%-2.5% in kidney transplant recipients (KTR),
• 0.5%-5.0% in pancreatic TRs,
• 1.0%-5.5% in liver TRs,
• 2.0-8.0% in heart TRs,
• 3.0-10.0% in lung TRs,
• ≤ 20% in multi-organ and intestinal TRs
2- Allogenic HSCT: PTLD incidence is related to HLA matching and T-cell depletion.
3- Immunosuppressive load exposure during primary renal illness is a risk factor for the development of PTLD.
4- Oncogenic EBV: EBV may alter cell growth via:
• Lack of immune recognition,
• Induction of the potent oncogenes
• EBV-induced proliferating cells as well as EBV variant/HLA types.
• Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA
Pathogenesis
Role of EBV:
Recent reports suggest that as many as 50% of PTLD in SOT are not accompanied by EBV infection
• For EBV-positive TRs, EBV can integrate into normal B-cell programs, Defenses by compromised T-cells in TRs lead to uncontrolled transformation and lymphoma.
• EBV-negative patients Pathogenesis of PTLD is less evident. Several hypotheses have been postulated like
• CMV
• Another viral infection,
• Prolonged
• Immunosuppression,
• Allograft-driven persistent antigenic triggering,
• Hit-and-run hypothesis
Classification:
WHO 2017 Classification,
• Three nondestructive PTLDs: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
• Polymorphic PTLD.
• Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
• Classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure. It may present as a local or disseminated disease.
It includes :
• Pyrexia (57%)
• Weight loss (9%)
• Neurological manifestations (13%)
• Nodal lesions (38%)
• Gastrointestinal manifestations (27%)
• Pulmonary manifestations (15%).
• Infectious mononucleosis-like syndrome that could be fulminant (19%)
Differential diagnosis:
In TRs with pyrexia, pharyngitis, and cervical lymphadenopathy, should be taken into consideration.
Prophylaxis:
• In some populations that are very susceptible to developing PTLD, preemptive treatment should be taken into consideration.
• Donor and recipient EBV serostatus should be known before choosing a donor, and EBV-negative donors ideally better to be used for EBV-negative TR
• Achieving the lowest immunosuppressive load clinically feasible.
• IVIG/CytoGam injection to maintain high titers of anti-EBV antibodies is also advised.
TREATMENT OF PTLD
Reduced Immunosuppression:
The reduction of the immunosuppressive load is the cornerstone of basic PTLD therapy,
Rituximab therapy
Rituximab is an effective chimeric anti-CD20 monoclonal antibody that binds to CD-antigen and causes B cell depletion through a variety of mechanisms.
Chemotherapy
Indications:
• Burkitt’s lymphoma,
• Hodgkin’s lymphoma,
• Peripheral T-cell lymphoma,
• Primary CNS lymphoma and other uncommon lymphomas,
• B-cell PTLD unresponsive to Rtx and RI
Adoptive immunotherapy
EBV-specific CTLs are a potent treatment in both donor- and recipient-derived PTLD, but GVHD is the main danger.
Future strategies
• Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib).
• Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)
• Proteasome inhibition[83] (Bortezomib).
• Radioimmunotherapy. (90Yibritumomab, tiuxetan).
• Checkpoint inhibitors (Pembrolizumab, nivolumab).
• Anti-CD30 therapy (Brentuximab vedotin).
Prognosis:
IPI is a prognostic scoring system that includes the following:
• Patient’s age,
• Performance attitude,
• Current stage,
• Lactate dehydrogenase (LDH),
• Number of extra-nodal locations.
Using univariate analysis, poor prognostic criteria have been postulated that include the following:
• Monoclonality,
• Negative EBV serology,
• Primary CNS involvement,
• Tumor originated from T-cell, performance status ≥ 2,
• Chemotherapy-based therapy (plus RI),
• Multiple involved locations
Re-transplantation and PTLD recurrence
• The feasibility of re-transplantation after successful management of PTLD has been reported, but one-year disease-free survival is necessary.
• Retransplantation after the PTLD cure remains controversial due to the re-exposure of immunosuppression.
• To limit the possibility of PTLD recurrence, the following recommendations are worth noting:
Time to retransplant,
· EBV positivity,
· Low/absent EBV viral load,
· Close monitoring,
· Anti-viral therapy,
· Role of immunosuppression.
Conclusion:
• PTLD is a disease of immunosuppression, with improved understanding and management.
• Moleculargenomic technology has improved diagnostic and therapeutic strategies to reduce PTLD recurrence.
• Rare reports of PTLD recurrence following re-transplantation necessitate cautious immunosuppressive planning.
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Introduction:
PTLD are one of the most common malignancy post SOT& HSC. Immunosuppression & EBV infection are the main factors by controlled proliferation of B cells EBV infection be by reactivation of the virus post-transplant or primary via the infected graft or environmental exposure majority of PTLD(85%) developed in the 1st year. PTLD can be due to T cell proliferation this is less common & EBV negative. diagnosis based on a high level of suspicion presence of tissue histopathology & evidence of EBV DNA, RNA or protein material positivity.
The incidence of lymphoma post-transplantation 21% of all malignancies in post-SOT compared to 4-5 % in immunocompetent individuals.
Options of management are reduction or cessation of immunosupressions surgical intervention , antivirals IV IG, local radiotherapy monoclonal AB & cytotoxic T lymphocytes graft dysfunction has to be considered.
Risk factors :
– Incidnence of PTLDs is lower in PKT in comparison to others with highest for HSCT & intestine ( dgteee of immunosuppressions & amount of lymphatic tissue are key factors)
– Previous exposure of immunosuppression before transplantation is a risk factor
– Oncogenic effect of EBV
Pathogenesis:
– Role of EBV 50% of PTLD in PKT are EBV +ve. EBV cause abnormal b cell proliferation because of the inability of t cell to destruct the infected EBV -B cells because of the immunosuppression the EBV -ve PTLD may be explained by another viral infection like CMV or prolonged immunosuppression hit & run hypothesis.
c/p :
– Ranging from asymptomatic to fulminant multiorgan failure & may be localized or disseminated.
– High level of suspicion is very important for diagnosis.
– Pyrexia ,weight ,loss GIT involvement graft dysfunction & neurological manifestations, and IMN picture especially in the presence of high titre of EBV PCR is the most salient features.
Prophylaxis :
– EBV -ve recipients are better to receive a graft from EBV -ve donors whenever available.
– Reactivation of other viruses like CMV or BK should trigger initiation of reduction of immunosuppression as viral replication might indicate overimmunosuppression .
– Maintenance of high titer of anti-EBV AB by IV IG /cytoGam also is recommended.
– Monitoring of viral load in a high-risk case & considering pre impetive RI with rising titer & close monitoring of graft function is also recommended.
Treatment :
1- RI :
– Reduction of immunosuppression by 50% reduction of CNI dose & withdrawal of antimetabolites is the mainstay of primary management. It can revere 20-80% of PTLD. Holding all immunosuppression apart from glucocorticoid should be considered in critically ill patients.
– Re-evaluating of the lymphoma staging after 2-4 weeks along with graft function.
– EBV +ve are more responders.
– Poor response is shown in old age >50 ys, bulky lesion >7 cm & advanced stages of the disease (Ann-Arbor stage III /IV)
2-rituximab:
– Monoclonal chimeric antibody against CD20, which is positive in 75% of PTLD patients.
– 375 mg/m2 body surface area weekly for 4 doses + RI.
3-chemotherapy:
– CHOP regimen every 3 weeks for 4 cycles. The overall response to R-CHOP reached 88%.
– Indications:
Burkitt’s lymphoma, Hodgkin’s
lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and other
uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
4- adoptive immunotherapy:
Infusion of donor cytotoxic t-lymphocytes. the major risk is GVHD.
5- future strategies:
Bortezomib & radioimmunotherapy.
>>poor prognostic criteria are EBV negativity, primary CNS involvement, monoclonality, T-cell origin, multiple organ involvement & chemotherapy-based therapy +RI.
Retransplantaion:
– Re transplantation after successful management of PTLD can be done with some precautions :
1- 1-2 year disease free survival before retransplantation
2- TR should experience EBV IgG before retransplantation
3- Low or absent EBV load
4- Long term Anti-Viral therapy by ganciclovir is recommended.
5- Exclude T-cell depleting agents from induction immunosuppression, IL-2 receptor antagonists are the 1st priority.
6- Rituximab may be used as an element of desensitization regimen
7- Lowest safest doses of maintaince immunosuppresice medications with MMF can be used safely
1- One of the commonest malignancies post SOT , it happens because of uncontrolled proliferation of B-cell in reaction to poor immune response, two key factors are present; immunosuppression medications burden and infection with EBV which infect B-cells, this infection could be reactivation from or primary infection of the patient or from the donor himself, so reduction of immunosuppression is a key for management and to hold immunosuppression in some cases to save the life of the patient.
2- SIR standardized incidence ratio is the incidence of the disease in specific population (like transplant population) divided on the incidence of disease in general population.
3- Risk factors:
a- Amount of lymphatic tissue in an allograft and the degree of immunosuppression; the lowest incidence in the kidney 0.8-2.5%, and the highest in multi-organ and intestine transplantation reaches 20%.
b- Degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant; type of induction therapy is a key in the early developed PTLD, the one that develops late PTLD is determined by cumulative immunosuppressive burden, and EBV is responsible for early PTLD in the 1st year post-transplant, as well as the incidence of PTLD in pediatrics is higher because of increased risk of primary EBV infection.
c- Previous exposure to the immunosuppressive medication as a treatment of the primary renal disease in the native kidney may be not a risk factor for PTLD.
d- EBV it infects B-cells and integrate into it leads to proliferation, this may be due to blunted T-cell response, this leads to development of lymphoma, sometimes there PTLD with negative EBV , and this may be due to the degree of immunosuppression and other viruses like CMV, HHV-8, EBV positive PTLD happens in the first year post-transplant and negative EBV happens in the late post-transplant after 1 year and may be at 10 years post-transplant.
4- Classification of PTLD:
a- Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
b- Polymorphic PTLD.
c- Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
d- classic Hodgkin’s lymphoma-like PTLD
5- clinical manifestations:
a- localized or disseminated
b- rapid progressive disease
c- Pyrexia, weight loss, neurological manifestations, nodal lesions, gastrointestinal manifestations, pulmonary manifestations, and infectious mononucleosis-like syndrome that could be fulminant.
d- allograft dysfunction
e- Most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
f- High clinical suspicion with positive EBV PCR can confirm the diagnosis of PTLD.
g- Can be differentiated from other conditions based on clinical symptoms like infectious mononucleosis and streptococcal infection.
h- Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology; whereas Burkitt’s lymphoma and Hodgkin’s disease are late.
i- EBV+ve PTLD is related to three factors: Type of transplant organ, time elapsed until diagnosis of post-transplant PTLD and EBV serological status of both recipient and donor before transplant.
j- The preemptive therapy by IVIG should be considered in high-risk groups for developing PTLD. Furthermore, monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function have been also recommended.
6- Treatment of PTLD:
a- RI reduction of immunosuppression can reverse 20-80% of PTLD and the plan is reduction of CNI by 50% and holding of azathioprine/MMF and continue steroid, and of course, in life threating condition holding of all immunosuppression is highly recommended, EBV negative cases are less responsive to RI than EBV positive cases, there is a complete lack of response to RI in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease.
b- Rituximab therapy Rtx it is anti-CD20 monoclonal antibody leads to B-cell depletion, it is considered as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
c- Chemotherapy: it is recommended in Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI. It is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).
d- Adoptive immunotherapy; infusion of donor cells.
7- Prognosis; prognostic scoring system that includes the following: Patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and number of extra-nodal locations. Another scoring system has been also given in a French registry system that relies primarily upon patient’s age, serum creatinine concentration, LDH level, PTLD localization, and histopathologic criteria.
8- Re-transplantation and PTLD recurrence:
a- To limit the possibility of PTLD recurrence: 1- Time to retransplant: Approximately two years of time should elapse after successful PTLD management.
b- EBV: The following recommendations is currently suggested:
1- transplant recipient TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation.
2- Low/absent EBV viral load is recommended at the time of retransplantation.
3- Close monitoring of TRs with persistently high EBV viral load is advised.
4- Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence. Ganciclovir has been suggested for this purpose.
c- Role of immunosuppression: Retransplantation after PTLD cure remains controversial due to the re-exposure of immunosuppression.
d- Induction therapy:
1- ATG (antibody depleting agents) should be avoided, and basiliximab is recommended.
2- Rituximab as induction therapy may be used as desensitization agent in high risk patient.
e- Maintenance immunosuppression:
1- Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered.
2- mTOR inhibitors: Their role in PTLD development remains debatable.
3- graft nephrectomy is curative in graft PTLD.
f- Monoclonal gammopathy: monoclonal gammopathy may indicate incompletely remitted PTLD, its complete resolution is an obvious indicator of complete remission.
g- Origin of PTLD (donor vs recipient):
level 3
Please summarize this article
Post-transplantation Lyphoproliferative disorder is complication of uncontrolled B cell proliferation due to irregularities in immune system secondary to immunosuppression drugs and post- transplant viral reactivation. Usually those secondary to EBV infection related PTLD, they present in first year after transplantation.
According to this article post SOT this accounts around 21% all cancers, with significant cancer related mortality. However, it has association with age, type of immunosuppression, dose, and duration. Although, the renal transplant having the lowest incident, while the intestinal transplant has highest incidence up-to 20%.
Epidemiology of PTLD;
PTLD was described initially in 1969 by Penn et al.
Since then it was observed in both SOT and HSCT both. The good thing is better diagnostic technology, newer approaches in treatment and awareness of this disorder.
The reported incidence of PTLD in HSCT recipient is around 3.2% in multicenter studies.
Risk factors;
The key factors are lymphatic tissue in allograft,
EBV infection and reactivation, positive donor and negative recipient,
Burden and duration of immunosuppression,
And also type of graft, the most common association with intestinal transplantation and very rarely with renal transplantation that is 0.8% to 2.5%.
Impaired immune surveillance would be a explanation for infection associated malignancy, while role of immunosuppression, its duration, dosages, varies with different immunosuppression.
The data shows the seronegative recipient for EBV associated PTLD are more vulnerable to develop PTLD 10-75%.
Prevalence of PTLD is more in children population.
Pathogenesis;
EBV infects the B-cells and become dormant form, when there is depressed immune system there is reactivation and leading abnormal proliferation and transformation of B-cell and different type’s malignancies.
There are other associated viral infection can cause proliferation of clones of B-cells like EBV infection.
Other hypothesis like hit and run hypothesis, graft driven persistent antigenic triggering, prolonged immunosuppression.
Classification;
Classification depends on early and late onset PTLD.
WHO 2017 classification is categories mainly based on histopathological classification that is gene- expression profile and immunohistochemical staining.
1. Nondestructive PTLD,
2. Polymorphic PTLD,
3. Monomorphic PTLD, and
4. Classic Hodgkin lymphoma like PTLD.
Treatment;
Reduction of immunosuppression, cyclosporine up-to 50%, stop antimetabolites.
If no response switch to rituximab ( a monoclonal antibody CD20 inhibitors,
Second line chemotherapy not responding to rituximab like CHOP.
For refractory disease Adaptive immunotherapy,
Radiotherapy,
Antiviral treatment,
Supportive care.
Future strategies;
. Protease inhibitor,
. Inhibition of PI3K and mTORi,
. Radio immunotherapy,
. Checkpoint inhibitors,
. Anti-CD30 inhibitors.
Prognosis;
The current advances in awareness in treatment has improved the survival disease free and has decreased mortality. The patients who has achieved remission the median survival is approximately 6.6 years.
CD20 positive PTLD has poor prognosis.
Using different scoring system like IPI, PTLD-I, II and others postulated the poor prognostic factors like native for EBV-associated PTLD, monoclonality, primary CNS involvement, T-cell associated origin, performance status >2, extended disease, need of second line chemotherapy.
Retransplantation;
Re-transplantation with all consideration carries a good response and low risk of PTLD recurrence if EBV IgG positive and prophylactic antiviral therapy.
Can be considered if in remission and no disease after two years of treatment.
EBV virus load should be monitored, and prophylactic antiviral should be started.
Induction in second transplantation should not be done with ATG.
Immunosuppression should be with lowest dosages.
Level of evidence V
Two main risk factors of PTLD are: Firstly, the cumulative immunosuppressive burden, and secondly, the oncogenic impact of the Epstein-Barr virus. The latter is a key pathognomonic driver of PTLD evolution.
The treatment of PTLD includes reduction of immunosuppression, rituximab therapy, either isolated or in combination with other chemotherapeutic agents, adoptive therapy, surgical intervention, antiviral therapy and radiotherapy.
The key step in the management of PTLD is to reduce the immunosuppressive load.
B cells may get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year.
Clinically, PTLD may manifest either as localized lesion or as systemic disease.
Tissue diagnosis (histopathology) is crucial for PTLD diagnosis, in addition to a clear evidence of EBV DNA, RNA, or protein material.
The mainstay of PTLD primary management is reduction of immunosuppression (RI). Complete cessation of the immunosuppressive drugs may be necessary to stop the disease progression.
The increased risk is expressed as “standardized incidence ratios” (SIRs) i.e., the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort).
a reported incidence of PTLD in 3.2% of HSCT recipients has been observed in multicenter studies.
(1) SOT: In adults, the incidence of PTLD has been reported to range from 0.8%-2.5% in kidney transplant recipients (KTR)
(2) Allogenic HSCT: PTLD incidence is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant.
The role of immunosuppressive agents is less clear due to variability in timing, duration, and dosage in different immunosuppressive strategies.
A number of PTLDs in allogeneic HSCT are donor-driven (EBV-infected lymphocytes) and are usually observed in 1 st post-transplant year, with almost 100% being EBV positive.
Compared to EBV seropositive TRs, the seronegative patients in SOT are more vulnerable to develop PTLD with an increased estimated risk of 10-75
Considering the improving patient and allograft survival, two peaks of PTLD incidence have been observed, first peak: In the first post-transplant year (mostly EBV seropositive), and, second peak: Usually present 5-15 years after transplant (mostly EBV seronegative).
previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution.
Oncogenic EBV: EBV may alter cell growth via several mechanisms: (1) With lack of immune recognition, EBV may induce highly regulated growth transformation with expression of all of its growth inducing proteins. (2) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors. (3) EBV induced proliferating cells as well as EBV variant/HLA types combination may permit these proteins to by-pass immune control and go unrecognized. And (4) Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA
Pathogenesis
Role of EBV: For decades, PTLD development was attributed mainly to EBV infection, however, recent reports suggest that as many as 50% PTLD in SOT are not accompanied by EBV infection
EBV monitoring for preemptive therapy: The risk of EBV+ve PTLD has been postulated to be related to three factors: Type of transplant organ, time elapsed until diagnosis of post-transplant PTLD and EBV serological status of both recipient and donor before transplant
Compared to the reliability of EBV DNA via peripheral-blood mononuclear cells, the “cell-free plasma EBV DNA” has been reported as a better marker of EBV activity
Primarily, EBV sero-status of both donor and recipient should be recognized before donor selection
Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered. Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
RI can reverse 20%-80% of patients with PTLD.
RI plan includes 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF), despite the lack of evidence demonstrating any relation between MMF and PTLD development . With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
Compared to EBV positive disease, the EBV negative cases are less responsive to RI
However, a complete lack of response to RI has been observed in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV
However, Rtx has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. The overall response to Rtx monotherapy (375 mg/m 2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases.
. Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5%. In the PTLD-1 trial (prospective, multicenter trial including post-SOT PTLD), the complete remission rate approached 25% after standard induction augmented by another four doses of 3 weekly Rtx (low-risk patients).
The complete response can be interpreted as three associated benefits: Better overall survival, extended time to progression, and better progression-free survival.
Furthermore, in comparison with the group of TRs with complete remission with Rtx followed by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), the low-risk group in the cohort receiving risk-stratified sequential expressed longer disease-free survival at 3 year, despite no change in overall survival.
More recent prospective trial PTLD-2 is registering TRs with the “risk stratification” based on the following parameters: Type of the allograft, response to Rtx therapy, and international prognostic index (IPI) scoring
Chemotherapy
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
In all CD20+ve subtypes (75% or more), Rtx should be included.
Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells. This situation is in contrast to PTLD developing in TRs of SOT
summarize
Reduction of immunosuppression is the cornerstone of PTLD management. Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and, monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. Chemotherapy is indicated for: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI with variable results. However, “risk-stratified sequential” therapeutic approach seems to be promising. Other modalities may include adoptive immunotherapy and outpatient care. Investigational agents that’re currently under trials have been shown above.
level of evidence 5
III. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Please summarise this article
INTRODUCTION
Post-transplant lymphoproliferative disorders (PTLD), are malignancies occurring post solid organ transplantation (SOT) or hematopoietic stem cell transplant (HSCT). Lymphomas account for 20% of all cancers in SOT patients as compared to 4-5% among immunocompetent individuals.
PTLD develops as a consequence of blunted immunological surveillance resulting in uncontrolled B cell proliferation. The B cells get infected by EBV either by post-transplant viral reactivation or primary EBV infection through the donated organ or through environmental exposure. Most cases occur within the first-year post-transplant. PTLD due to abnormal T cell proliferation is less common and is mostly EBV-negative. PTLD can present as either a localized lesion or as a systemic disease. In addition to EBV DNA, RNA and protein material, tissue diagnosis is key in the diagnosis of PTLD.
The cumulative immunosuppressive burden plays a key role in PTLD. The mainstay of treatment is reduction in immunosuppression (RIS) although this comes with a potential risk graft or dysfunction or loss. Complete cessation of immunosuppressive medication can be attempted with an aim to stop disease progression.
Other treatment modalities include: – surgical intervention, local radiotherapy, antiviral therapy, chemotherapeutic agents, intravenous immunoglobulin (IVIG), monoclonal antibodies, cytotoxic T lymphocytes (CTLs). Combined therapies offer better outcomes compared to monotherapy.
Epidemiology of PTLD
There has been an increase in the incidence of PTLD in both SOT and HSCT patients since 1969 when the first 5 cases of PTLD were reported.
Risk factors
– type of organ transplanted – incidence of PTLD is lowest among kidney transplant recipients and highest in multi-organ and intestinal transplant recipients
– degree of HLA matching
– use of T-cell depleting induction strategies
– cumulative immunosuppressive burden
– donor type i.e., donor-driven EBV-infected lymphocytes
– EBV seronegative transplant recipients
– prior exposure to immunosuppression in the management of the primary kidney disease
– oncogenic EBV
Pathogenesis
Immunosuppressive-induced decline in T-cell immune-surveillance results in development of PTLD among EBV-positive transplant recipients. EBV infects the B cells leading to abnormal proliferation and transformation of the B cells and evolution into a lymphoma.
Several hypotheses have been suggested among EBV-negative transplant recipients i.e., CMV or other viral infections, prolonged immunosuppression, hit-and-run hypothesis, graft-driven persistent antigenic triggering. T-cell subtype PTLD is usually EBV-negative whereas B-cell subtype is EBV-positive.
Classification
– Early and late onset PTLD
· Early PTLD is often associated with EBV positivity, graft involvement, less often extra-nodal disease, non-destructive PTLD, less often monomorphic subtype, higher prevalence
· Late onset PTLD is associated with EBV negative tumors, less graft involvement, extra-nodal disease, high incidence of late onset Hodgkin’s after allogeneic HSCT, elevated LDH levels, lower prevalence
– Histopathological classification
· Non-destructive PTLD i.e., plasmacytic hyperplasia, florid follicular hyperplasia, infectious mononucleosis-like PTLD
· Polymorhphic PTLD
· Monomorphic PTLD i.e., B-cell, T-cell or Natural killer-cell types
· Classical Hodgkin’s lymphoma-like PTLD
Clinical presentation
The patients can be asymptomatic or have non-specific symptoms but can also present with sudden, severe symptoms with multi-organ failure.
Salient features
– PTLD can present as a local or disseminated disease, which can be aggressive and rapidly progressive
– Pyrexia, nodal lesions, gastrointestinal symptoms, fulminant infectious mononucleosis-like syndrome, pulmonary manifestations, neurological symptoms, weight loss
– Graft dysfunction
– Common locations of PTLD involvement include: – lymph nodes, GIT, liver, lung, CNS, bone marrow, kidney, spleen, tonsils, salivary glands
Differential diagnosis
– Streptococcal infections
– Infectious mononucleosis
Time to PTLD for different transplanted organs
Longest in heart transplant recipients and shortest among lung and heart/ lung paediatric transplant recipients.
Early PTLD is of diffuse large B-cell or other B-cell lymphomas histology, on the other hand, Burkitt’s lymphoma and Hodgkin’s disease are associated with late PTLD.
EBV monitoring for preemptive therapy
Factors associated with the risk of EBV-positive PTLD: –
– Type of organ transplanted
– Time elapsed until diagnosis of post-transplant PTLD
– Donor and recipient pre-transplant EBV serological status
Estimation EBV viral load via PCR amplification of peripheral blood EBV DNA is essential in monitoring preemptive PTLD therapy. High viral loads are associated with increased risk for PTLD evolution.
Drawbacks in this preemptive monitoring strategies: –
– Unclear cut-off values
– Sources of samples are not universal
– Absence of set standard points of time to perform the monitoring
Preemptive strategies put into place to limit the risk of development of PTLD in SOT and HSCT recipients include: –
– Reduction in immunosuppression
– Rituximab therapy
– Adoptive immunotherapy i.e., adoptive transfer of EBV-specific T cells
Prophylaxis
Determine the pre-transplant EBV status of the donor and recipient. An EBV-negative transplant recipient should receive a graft from EBV-negative donors.
Adjust the immunosuppressive burden to the lowest possible and safe level
Reactivation of other viruses e.g., CMV, BKV indicates over-immunosuppression and should prompt a reduction in the immunosuppression dose
Preemptive/ prophylactic antiviral therapy should be offered to high-risk patients
Maintain high titers of anti-EBV antibodies via administration of IVIG/ CytoGam
Monitor EBV viral load in high-risk patients, if rising titers are noted then consider preemptive reduction in immunosuppression and close monitoring of the graft function
TREATMENT OF PTLD
· Reduction of immunosuppression (RI)
RI helps restore EBV-specific cellular immunity without any additional risk of acute rejection
RI strategies involve 50% reduction in CNI doses in addition to withdrawal of antimetabolites.
In critically ill cases, withdrawal of all immunosuppressive drugs except corticosteroids can be considered.
Due to the early response to RI, PTLD patients should be reassessed within 2-4 weeks.
Graft function should be monitored so as to recognize any signs of early rejection.
EBV-negative cases are less responsive to RI when compared to EBV-positive disease.
Risk factors associated with complete lack of response to RI: –
o Old age (>50 years)
o Bulky lesions (>7cm)
o Advanced disease (Ann Arbor stage III/ IV)
· Rituximab therapy
Rituximab is indicated as a standard therapeutic agent in the following types of PTLD: –
o Non-destructive PTLD
o Polymorphic PTLD
o Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI
Rituximab is given weekly for 4 weeks in addition to RI. An additional four does of 3 weekly rituximab can be given to patients who fail to achieve complete remission.
· Chemotherapy
Indications for immunochemotherapy include: –
o Burkitt’s lymphoma
o Hodgkin’s lymphoma
o Peripheral T-cell lymphoma
o Primary CNS lymphoma
o Other uncommon lymphomas
o B-cell PTLD unresponsive to rituximab and RI
RI should be considered in view of the immunosuppressive effect of chemotherapeutic agents and their toxicity.
Ritxumab should be included in all CD20+ subtypes.
Proper supportive care and G-CSF administration has improved the outcomes in chemotherapy treated patients.
Chemotherapy treatment options include: –
o Weekly rituximab for 4 weeks followed by CHOP every 3 weeks and G-CSF support
o Four cycles of R-CHOP given every 3 weeks with G-CSF support for patients who do not respond to rituximab monotherapy i.e., risk-stratified sequential therapeutic approach
RI and risk-stratified sequential therapy are considered as the standard of care for polymorphic and monomorphic diffuse large B-cell lymphoma-like PTLD post-SOT regardless of EBV status.
· Adoptive immunotherapy
This therapy involves infusion of donor lymphocytes to manage PTLD that is primarily originating from donor cells post-HSCT. On the other hand, in SOT recipients, the EBV-specific immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs). Expanded EBV-specific CTLs can be used in both autologous (recipient-derived PTLD) and donor-derived PTLD. Engineered CTLs can be used with no need to reduce the immunosuppressive burden. GVHD is the major risk associated with adoptive immunotherapy.
Outpatient care
– Weekly monitoring of EBV viral titers should be done in high-risk cases.
– Initial monthly monitoring then 3-monthly monitoring for low-risk patients.
– A viral drop indicates response to therapy while persistently high or continuous rise in viral load denotes disease development or progression.
– Serial physical examination, radiological assessment and graft function monitoring should also be carried out.
– Aim at a favorable balance between avoidance of rejection and management of PTLD.
– Multidisciplinary team should be engaged to tailor a regimen for the patients
Future strategies
The efficacy of these strategies is yet to be validated via RCTs.
o Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib)
o Inhibition of PI3K (Idelalisib) and mTORi (sirolimus, everolimus)
o Proteosome inhibition (Bortezomib)
o Radioimmunotherapy (90Yibritumomab, tiuxetan)
o Checkpoint inhibitors (Pembrolizumab, nivolumab)
o Anti-CD30 therapy (Brentuximab vedotin)
Summary
Reduction of immunosuppression is the mainstay of treatment in PTLD
Indications for rituximab: –
· Non-destructive PTLD, Polymorphic PTLD and Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI
Indications for chemotherapy: –
· Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and B-cell PTLD not responding to Rituximab/ RI
Risk-stratified sequential therapeutic approach seems to be gaining favor.
Other therapeutic options include adoptive immunotherapy.
Prognosis
Better supportive care and presence of new lymphoma-specific protocols has greatly improved the outcomes among PTLD patients.
Various prognostic scoring systems have been used to assess patient’s prognostic attitude in aggressive lymphoma.
Indicators of poor prognosis include: –
Re-transplantation and PTLD recurrence
A period of one-year disease free survival is necessary after control of PTLD before considering re-transplantation.
Measures to reduce the possibility of PTLD recurrence – the following should be considered: –
– Allow 2 years to elapse after successful PTLD management before re-transplanting.
– Aim for a low/ absent EBV viral load at the time of re-transplantation.
– The transplant recipient should have EBV nuclear antigen IgG positivity – an anti-EBV marker of robust cytotoxic response.
– Close monitoring of transplant recipients with high EBV viral load
– Offer long-term prophylactic antiviral therapy (e.g., Ganciclovir) and serial EBV viral load checks to reduce incidence of PTLD recurrence.
– RI/ withdrawal has been the standard in management of PTLD.
– Avoid ATG-based induction regimens since ATG has been shown to trigger the risk of lymphoma evolution.
– Rituximab can be used to inhibit EBV proliferation within the lymphocytes hence limiting development of PTLD.
– Avoid intense maintenance immunosuppression to allow recovery of the immune system and promote evolution of the anti-EBV cytotoxic lymphocyte which will in turn impair EBV-triggered B-cell proliferation. Use the lowest safe dosages and monitor the trough levels. MMF does not seem to have any added risk in regard to PTLD evolution. Role of mTORi in PTLD remains debatable.
What is the level of evidence provided by this article?
Level V – narrative article
SUMMARY.
PTLD;CURRENT CONCEPTS AND FUTURE THERAPEUTIC STRATEGIES
INTRODUCTION;
PTLD is common post transplant and results from uncontrolled B cell proliferation from low immunity post transplant.B Cell +VE PTLD occurs in 1st year post transplant while B Cell -VE later.
PTLD has varied presentations either locally or systemically.
Mainstay tx is RI which has to be balanced to avert graft dysfunction.Other treatment options include ; SX,antiviral medications,DXT,IVIG,Chemo & Monoclonal abs
EPIDEMIOLOGY.
SIRS of 10 (NHL) and 4 % among SOT compared to 3.2% in HSCT recipients have been reported.
RISK FACTORS.
1.SOT
-Amount of lymphatic tissue in allograft (0.8-2.5% in KTR and less than 20% in multiorgan and intestinal TR)
-Degree of immunosuppression.
2.Allogeneic HSCT.
-Level of HLA matching with addition of T cell depleting agents before transplant e.g In HSCT – 0 in those who had CYC for GVHD and more than 20% with T cell depletion.
-Seronegative patients in SOT > seropositive pts in SOT in getting PTLD,this explains why more paediatrics than adults get PTLD.
-1ST peak -1 yr post transplant ; EBV +VE.
-2ND pEAK- 5-15 yrs post transplant ; EBV -VE.
3.Previous exposure to immunosuppressive meds for primary underlying kidney diseas is a risk factor for dev of PTLD.
4.Oncogenic EBV.
-EBV that’s oncogenic is not recognized by the immune system and thus leads to unregulated proliferation of growth inducing proteins.
-This also stimulates potent oncogenes;LMP1& LMP2.
-They also induce proliferation of cell + EBV +VE variant/HLA types that will stimulate malignant transformation.
PATHOGENESIS.
-In EBV +VE TR,PTLD is secondary to immunosuppressive meds that impair T cell immune syaytem allowing the EBV infected B cells to proliferate unchecked and be malignant.
-For EBV -VE TR,pathogenesis is unclear but other factors e.g CMV,prolonged immunosuppressive meds may lead to PTLD development.
EBV +VE vs EBV -VE PTLD.
-EBV +VE PTLD is mostly B cell,more common in 1st 1 yr post transplant and has less risk of PTLD while EBV -VE PTLD is mostly common in the 2nd peak,5-15 yrs post transplant,is mostly T cell and has more risk of developing PTLD
-The clinical consequences of this distinction is not clear.
CLASSIFICATION;WHO 2017
-Non destructive PTLD-Plasmacytic hyperplasia,follicular hyperplasia and infectious mononucleosis like PTLD.
-Polymorphic PTLD.
-Monomorphic PTLD.
-Classic HL like PTLD.
-EBV +VE cases are mostly non germinal centre B cell types while EBV -VE cases are mostly germinal centre B cell types.
CLINICAL PRESENTATION.
-Local or disseminated.
-Pyrexia,wt loss,CNS symptoms,nodal lesions,GI manifestations,Pulmonary manifestations and infectious mononucleosis like syndrome.
-Common location ; LN,liver,pulmonary,renal,bone marrow,GI tract,spleen,CNS & Salivary glands.
DDX
-Strep infection.
-Infectious mononucleosis.
Time to PTLD for transplanted organs.
-Longest in cardiac recipients.
-Shortest;Pulmonary and cardiac in paediatric TR.
-Early PTLD ; DLBC or other B cell lymphoma.
-Late PTLD;Burkitts,HL.
EBV Monitoring for preemptive therapy;
-VL monitoring via PCR – TR with PTLD has increased EBV VL compared to PTLD free TR.The downside of VL monitoring is lack of clear cut off values,lack of universal source of samples and finally lack of standard points of time to monitor.
-Cell free plasma EBV DNA is a better marker of EBV activity.
Prophylaxis;
-EBV -VE TR should, when possible get donations from EBV -VE donor.
-Immunosuppressive meds should be kept at the lowest possible dose to maintain graft function.
-RI should be done once CMV and BK have been detected.
-Prophylactic meds should be administered to those at highest risk of PTLD.
-Monitor viral loads in those at highest risk of PTLD.
-Pre-emptive RI should be done with increasing titres and graft function monitored.
TREATMENT.
1.RI
-This is the mainstay treatment aimed at restoring immunity against EBV.It involves;
> 50% CNI reduction + withdrawal of anti metabolites.In critically ill,all immunosuppressive medication with exception of steroids are withdrawn.
-With RI graft function is monitored and pt restaged every 2-4 weeks.
-Pts predisposed to no response to RI ; >50 yrs,bulky lesions > 7cm and those with Ann Arbor stage ¾
2.RITUXIMAB.
-This is a CD 20 Monoclonal antibody that acts by depleting B cells in treating PTLD.
-Used in;
>Non destructive PTLD.
>Polymorphic PTLD.
>Monomorphic PTLD.
-Given as 375 mg/m2 weekly for 4 weeks with upto 20-55% CR being recorded.When combined with RI,It gives better results – 34-60.5% CR
-Addition of another 4 doses of RTX increases CR by upto 25%
-R – CHOP is associated with a longer disease free survival at 3 yrs.
3.CHEMOTHERAPY.
INDICATIONS;
a.Burkitts lymphoma.
b.HL.
c.Peripheral T cell lymphoma.
d.Primary CNS lymphoma.
e.B Cell PTLD not responsive to RTX + RI.
f.Rare lymphoma.
-In all CD 20+VE subtypes RTX should be added on treatment.
-Addition of G CSF decreases infection rate and mortality in those on chemotherapy.Anti PCP therapy should be considered on those on chemo.
4.ADOPTIVE IMMUNOTHERAPY.
-Despite GVHD ,donor lymphocyte infusion has shown good results in PTLD in HSCT pts and not PTLD in TRs of SOT.
-Expanded EBV specific CTL have shown good results in autologous (Recipient + donor derived)PTLD.
5.OUTPATIENT CARE.
-Weekly monitoring of EBV VL in at high risk patients,monthly and later 3 monthly in at low risk pts.
-Persistent high titres or rising VL indicate aggressive or progressive dx.
-Serial PE,Imaging and monitoring of graft function.
-Balance PTLD tx and graft function to avoid rejection.
-MDT directed therapeutic options.
-Stepwise approach;RI/cessation of immunosuppressive meds and then individual pt directed therapeutic options.
6.FUTURE STRATEGIES
-BTK inhibitors.
-P13K and MTOR inhibitors.
-Proteasome inhibitors.
-Radioimmunotherapy.
-Anti CD30 therapy.
PROGNOSIS.
-Poor prognostic factors ; Hypoalbuminemia,monoclonality,EBV -VE,primary CNS Involvement,T cell tumor, ECOG>2, and more than x1 involved location.
RETRANSPLANT AFTER PTLD RECURRENCE.
-1yr needed of disease free state before it is considered.
-Atleast 2 yrs should lapse before transplant after successful PTLD tx.
-Prolonged antiviral prophylaxis with serial EBV viral markers needed to reduce incidence of recurrence.
-RTX and IL2R antagonists can be considered as part of retransplant induction meds to decrease PTLD development.
-Lowest safest doses of immunosuppressive meds should be given to decrease risk of PTLD.
LEVEL OF EVIDENCE ; NARRATION,LEVEL 5
1. Please summarise this article
This narrative review published in the World Journal of Transplantation in 2020 provides a broad overview of our current understanding of post-transplantation lymphoproliferative disorders (PTLD). The key messages are outlined below:
When do transplant recipients develop PTLD?
Solid organ transplant recipients, or patients who have undergone hematopoietic stem-cell transplant are at significantly increased risk of developing a lymphoproliferative disorder compared to the general population. The authors highlight the majority of PTLD cases are linked to abnormal B cell proliferation, with Epstein-Barr virus (EBV) infection playing a key role in the aetiology. The source of EBV infection may come from either post-transplant viral reactivation or primary infection (donor organ or environmental exposure). There is a spike in the incidence of such cases in the first year after transplantation, when exposure to potent immunosuppression (with its impact on immunological surveillance) is at its peak. Meanwhile, cases of PTLD driven by T cell proliferation rather than abnormal B cell proliferation tend to be associated with the absence of detectable EBV infection but are a much rarer phenomenon and more likely to occur later in the post-transplantation course.
Peaks in incidence of PTLD
1. First 1 year after transplantation
EBV infection plays a key role in aetiology of many of these cases
2. 5-15 years after transplantation
Patients may be EBV seronegative in such cases
3. Late PTLD >20 years after transplantation
Increasing number of cases- possibly relating to increased recipient age/survival +/- cumulative immunosuppression burden
What are the risk factors for developing PTLD?
Analysis of standardised incidence ratios (SIRS) reveals that transplant recipients have a 10 and 4 times greater risk of developing Non-Hodgkin’s lymphoma and Hodgkin’s lymphoma respectively, compared to the general population.
The authors summarise the main risk factors which can predispose organ transplant recipients to PTLD:
· Type of organ (with possible link to lymphatic tissue burden from donor organ and intensity of immunosuppression protocol required). Multi-organ and intestinal transplants infer a significantly higher risk than pancreas and kidney transplants
· Impaired immune surveillance as a direct consequence of potent immunosuppression places patients at higher risk of infection-related malignancies. This is particularly relevant to patients who may be EBV seronegative at the time of transplantation, such as paediatric recipients
· Previous exposure to immunosuppressive treatments e.g. renal transplant recipients who previously received potent immunosuppression to treat the primary disease affecting their native kidneys
· Epstein-Barr virus (EBV) infection plays a key role in the aetiology of many cases of PTLD including via the induction of potent oncogenes such as LMP1 and LMP2 which may be present in the donor organ alongside other pathways for triggering abnormal cell proliferation. It is imperative to ascertain donor and recipient EBV sero-status prior to transplantation
The authors acknowledge the 2017 World Health Organisation (WHO) classification according to histopathology, and describe the trends in EBV infection in such cases
Non-destructive PTLD
– Plasmacytic hyperplasia
– Florid follicular hyperplasia
– Infectious-mononucleosis-like
Almost 100% of cases associated with detectable current EBV infection
Polymorphic PTLD
>90% cases associated with detectable current EBV infection
Monomorphic PTLD
– B cell type
– T cell type
– Natural Killer cell type
50% cases associated with detectable current EBV infection
Hodgkin’s lymphoma-like PTLD
>90% cases associated with detectable current EBV infection
How might a patient with PTLD present clinically?
The key message here is that, in the context of increased risk in this specific population, clinicians should remain vigilant and have a low threshold for investigating for potential PTLD. PTLD may affect one or multiple organs, and may or may not be associated with impaired allograft function depending on the particular organ involvement. The disease may be localised or disseminated but local disease does not infer more benign disease and either form may be rapidly progressive.
Key symptoms may include:
· Fever (commonest)
· Loss of energy
· Weight loss
· Lymphadenopathy
· Change in bowel habit
· Neurological symptoms including change in behaviour or seizures
What are the current treatment strategies for PTLD?
The authors summarise the current treatment approaches for PTLD.
1. Reduction in immunosuppression (RI)
This is the first and most important step.
Usually includes 50% reduction of calcineurin inhibitor and withdrawal of antimetabolite (azathioprine, MMF)
This approach is likely to produce the best results in EBV-positive disease
Careful monitoring for any signs of acute rejection is warranted
In some cases, RI alone may be an effective treatment
2. Rituximab
Rituximab is an anti-CD20 monoclonal antibody leading to B cell depletion
Can be used for:
1. non-destructive PTLD
2. polymorphic PTLD
3. monomorphic diffuse large B-cell lymphoma-like PTLD with incomplete response to RI
Often given as an infusion on a weekly basis for 4 weeks (induction) +/- further less frequent doses
3. Chemotherapy
Can be used for:
1. Burkitt’s lymphoma
2. Hodgkin’s lymphoma
3. Peripheral T cell lymphoma
4. Primary CNS lymphoma
5. B-cell PTLD not responding to above steps
Outcomes have improved following recognition of the need for GCSF administration and PJP prophylaxis
4. Adoptive immunotherapy
Has been shown to be of benefit in hematopoietic stem-cell transplant recipients where donor lymphocytes are infused which are programmed to facilitate an adequate response to EBV
What might be the future treatment options for PTLD?
At the conclusion to this review paper the authors briefly touch upon emerging treatments which are yet to undergo robust randomised controlled trials but which may form part of our future treatments
1. Bruton’s tyrosine kinase inhibition
2. Inhibition of PI3K and mTORi
3. Proteasome inhibitors
4. Radioimmunotherapy
5. checkpoint inhibitors
6. Anti-CD30 therapy
Can patients be re-transplanted after PTLD
The authors discuss the important question regarding whether a patient may be re-transplanted following PTLD. They highlight that this is possible but must be given very careful consideration, especially in light of the re-exposure to immunosuppression which will be required. The timing of any potential further transplant is crucial: it is imperative the patient has at least 1 year disease-free survival following successful treatment of their PTLD, although many clinicians will advise waiting 2 years before the patient receives another transplant. The recipient should also have: EBV IgG antigen positivity beforehand, a low/absent EBV viral load at the time of re-transplantation, close monitoring of those with higher EBV viral load and long-term prophylaxis (Ganciclovir).
2. What is the level of evidence provided by this article?
This article is a narrative review rather than systematic review. It provides a good summary of the topic but is a lower level of evidence than a systematic review as the search methods/decisions to include/exclude papers are not explicit and therefore may be more prone to bias. The review in itself is detailed with 104 references but one cannot ascertain how comprehensive this is. In addition, the topic is broad rather than specific- this has the advantage of providing the reader with a good opportunity to understand key concepts for this large topic but is likely to be at the expense of finer details (e.g. specific exploration of trials within areas of this topic).
Introduction:
PTLD is common and account 21% from cancer post transplant and main cause are immunosuppressive therapy and reactivation of infection mainly EBV and treatment by reducing immunosuppressive therapy or stop immunosuppressive drug ti prevent progression of cancer.
Epidemiology of PTLD:
Prevalence of PTLD disease increase because increase awareness to PTLD disorders especially in increase new advent of immunosuppressive therapy and old age of donor and recipient and new diagnostic modalities to detect PTLD.
Risk factors:
Solid organ transplant
HSCT
Oncogenic of EBV
Previous exposure to immunosuppressive agents in treatment of primary kidney disease.
Clinical picture:
It’s varying from symptomless to fulminating multi organ damage
Main features is low grade fever, weight loss, neurological manifestations and nodal lesions gastrointestinal manifestations, pulmonary manifestations, and infectious mononucleosis-like syndrome and allograft dysfunction may ensue due to graft involvement. PTLD is associated high EBV viral load by PCR.
The most common locations of PTLD involvement are Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract, spleen, central nervous system, tonsils and salivary glands.
Differential diagnosis:
Presence of fever/ pharyngitis and lymphadenopathy should be role out PTLD
IMM
Streptococcal infection.
Time of PTLD in transplant patients :
Early PTLD is always B cell lymphoma
Late is associated with Burkitt’s lymphoma and Hodgkin’s disease.
Treatment of PTLD:
Reduce calcinurine inhibitors to half and stop azathioprine and MMF
Continuous steroid dose
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen against B cell.
Chemotherapy
Indication of chemotherapy is Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and B-cell PTLD unresponsive to Rituximab.
Adaptive immunotherapy:
Infusion of donor lymphocytes is mainly to manage PTLD in HSCT patients which primarily originating from donor cells. However there is risk of GVHD.
Prognosis:
Outcome of PTLD patients has been improved due to advent of new lymphoma-specific protocols and better supportive care.
Compete remission reach to 70%. with average survival rate is 6.6 years.
Level 5
Introduction:
PTLD develops as a result of uncontrolled B cell proliferation due to a blunted immunologic surveillance. B cells may get infected by EBV by post viral reactivation or through the donated organ or via environmental exposure. It is most commonly observed during the first year after transplantation. It accounts for 21% of all malignancies in SOT recipients, and 4% in immunocompetent patients. The mainstay of management is RIS, and there are various other treatment modalities including surgical clearance, anti-viral agents, local radiotherapy, IVIG, chemotherapy, monoclonal antibodies and cytotoxic T lymphocytes. These have shown varying amounts of success, and usually work better when in combination.
Epidemiology and Risk Factors
In SOT recipients, the incidence of PTLD ranges from 0.8 to 10% depending on the organ transplanted. The risk is highest in multi organ transplant and intestinal transplant and lowest for kidney transplant
The risk factors of PTLD in allogenic HSCT included a higher risk in umbilical-cord transplantation and transplant from unrelated donors compared to transplant from related donors.
Recent reports suggest that approximately 50% of PTLD may be accompanied by EBV infection. This may be due to immunosuppressive-induced decline in the T-cell immune surveillance.
The other risk factors include:
Classification
The classification of PTLD can be categorized according to the WHO 2017 classification, as follows:
Plasmacytic hyperplasia
Florid follicular hyperplasia
Infectious mononucleosis-like PTLD
Clinical Presentation
PTLD presents in many forms. It may present as lesions with no symptoms to fulminating disease with multi-organ failure. It may present as a local or disseminated disease. Patients may present with pyrexia, weight loss, neurological manifestations, nodal lesions, gastrointestinal manifestations, pulmonary manifestations and infectious mononucleosis-like syndrome.
Treatment
Reducing the immunosuppression in the mainstay of PTLD management. It involves reducing CNIs by 50% and withdrawal of antimetabolites (e.g. azathioprine and MMF). The patients need to be restaged in 2-4 weeks and the allograft function needs to be monitored. Lack of response to immune suppression reduction has been noted in older patients, patients with bulky lesions and advanced stages of the disease.
Rituximab is a monoclonal antibody that binds to CD 20 antigen leading to B cell depletion. Rituximab has been approved as a standard therapeutic agent, for PTLD, for three types as per the WHO classification mentioned previously:
Non-destructive PTLD
Polymorphic PTLD
Monomorphic diffuse large B-cell lymphoma-like PTLD, not responding to decreased immune suppression.
It has been shown that rituximab, followed by chemotherapy (CHOP) has a longer disease-free survival at 3 years.
Infusion of donor lymphocytes, to achieve adoptive immunity, has been shown to manage PTLD in NSCT patients that is originally from donor cells. However, this treatment modality has a risk of GVHD development.
Summary
The main management involves the reduction of immune suppression. Rituximab treatment is indicated in non-destructive PTLD, polymorphic PTLD and monomorphic diffuse large B-cell lymphoma-like PTLD, not responding to decreased immune suppression. Chemotherapy is indicated for Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and B-cell PTLD that is not responsive to immune suppression reduction.
Retransplant
Patients can undergo re-transplantation after successful PTLD treatment, to limit the possibility of PTLD recurrence, some recommendations should be considered:
Time to re-transplant
Awaiting approximately 2 years after successful PTLD management
EBV
Low/absent EBV viral load is recommended at time of re-transplantation, with continuous monitoring and antiviral treatment
Role of immune suppression
It has been noted that PTLD is a disease of post-transplant immune suppression, hence reduction of immune suppression is the cornerstone of management. MMF is safe to be used in re transplant regimen. The role of mTOR inhibitors in PTLD is debatable
Induction therapy
IL2 receptor agonists, rituximab
Maintenance immune suppression
Its important to maintain the lowest safe doses of CNIs. MMF can be included in the maintenance ISS protocol
Monoclonal gammopathy
Its important to confirm clearance of monoclonal gammopathy to reduce the risk of recurrence
Origin of PTLD
Identifying the tumor source is crucial for determining future therapeutic plans
Level of Evidence
This is a narrative review: Level V
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation. It develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative.
Important Risk factors:
-In Solid Organ Transplant : the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors therefore it is highest in intestinal, ht, lung transplant compared with kidneys.
-Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney.
-Oncogenic EBV: EBV may alter cell growth via several mechanisms:
-EBV may induce highly regulated growth transformation.
Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
-EBV induced proliferating cells may permit these proteins to by-pass immune control
-Growth alterations with the right levels of expression of cell targets
Treatment of PTLD :
1- Reduction of immunosuppression: the cornerstone of management.
2- Rituximab :
it is indicated in the following types:
a- Non-destructive PTLD.
b- Polymorphic PTLD.
c- Monomorphic diffuse large B-cell lymphoma -like PTLD that is not responsive to reduction of immunosuppression.
3- Chemotherapy:
it is indicated in the following types :
a- Burkitt’s lymphoma.
b- Hodgkin’s lymphoma.
c- peripheral T- cell lymphoma.
d- 1ry CNS lymphoma.
e- B-cell PTLD that is not responding to either reduction of immunosuppression or Rituximab.
4- Other modalities:
a- adaptive immunotherapy.
b- outpatient care.
c- risk-stratified sequential therapeutic approach.
d- anti-viral therapy.
e- Radiotherapy.
Re-transplantation and PTLD recurrence:
To limit the possibility of PTLD recurrence:
Time to re-transplant: Approximately two years of time should elapse after successful PTLD management.
Level of study evidence: V
( Narrative review article)
sorry, I replied twice i forget to headline the topic of Treatment
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation. It develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative.
Important Risk factors:
-In Solid Organ Transplant : the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors therefore it is highest in intestinal, ht, lung transplant compared with kidneys.
-Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney.
-Oncogenic EBV: EBV may alter cell growth via several mechanisms:
-EBV may induce highly regulated growth transformation.
Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
-EBV induced proliferating cells may permit these proteins to by-pass immune control
-Growth alterations with the right levels of expression of cell targets
1- Reduction of immunosuppression: the cornerstone of management.
2- Rituximab :
it is indicated in the following types:
a- Non-destructive PTLD.
b- Polymorphic PTLD.
c- Monomorphic diffuse large B-cell lymphoma -like PTLD that is not responsive to reduction of immunosuppression.
3- Chemotherapy:
it is indicated in the following types :
a- Burkitt’s lymphoma.
b- Hodgkin’s lymphoma.
c- peripheral T- cell lymphoma.
d- 1ry CNS lymphoma.
e- B-cell PTLD that is not responding to either reduction of immunosuppression or Rituximab.
4- Other modalities:
a- adaptive immunotherapy.
b- outpatient care.
c- risk-stratified sequential therapeutic approach.
d- anti-viral therapy.
e- Radiotherapy.
Re-transplantation and PTLD recurrence:
To limit the possibility of PTLD recurrence:
Time to re-transplant: Approximately two years of time should elapse after successful PTLD management.
Level of study evidence: V
( Narrative review article)
Please summarise this article
Transplant recipients are at high risk of developing malignancy especially, after solid organ transplant. Skin malignancy are the most common followed by PTLD. PTLD spectrum include benign proliferation of lymphoid tissues to frank malignancy.
The main risk factors of PTLD include, cumulative immunosuppressive burden, and secondly, the oncogenic impact of the Epstein-Barr virus. The main treatment option of PTLD include, reduction of immunosuppression, rituximab therapy, either isolated or in combination with other chemotherapeutic agents, adoptive therapy, surgical intervention, antiviral therapy and radiotherapy.
Pathogenesis
EBV positive PTLD
It can be due to immunosuppressive-induced decline in the T-cell immune surveillance. EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells. The immune defence mechanism has been compromised in TRs leading to unlimited B cell transformation and the evolution of lymphoma.
EBV negative PTLD
It can be due to CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis
Categories of PTLD
These include-
plasmacytic hyperplasia
Mono Morphic
Polymorphic
Classical Hodgkin lymphoma
Clinical Presentations.
These include , Pyrexia , weight loss, neurological manifestations , nodal lesions, gastrointestinal manifestations , pulmonary manifestations and infectious mononucleosis-like syndrome that could be fulminant. An allograft dysfunction may ensue due to graft involvement.
Treatment
The options include-
Reduction of immune suppression
For early stage , low risk cases antimetabolites can be stopped. CNI can be reduced by 30-50%. Patient should be monitored until complete remission is achieved.
Rituximab
Rituximab is a monoclonal anti-CD20 antibody that has become a standard of care in patients with polymorphic PTLD, or monomorphic DLBCL-like PTLD, who are unresponsive to initial RIS. Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) (with Deauville ≤ 3) after four cycles of weekly standard-dose Rituximab.
Chemotherapy
If remission is not achieved with Rituximab alone or with disease progression R -CHOP every three weeks should be given with total of 4 cycles. In addition GCSF and Prophylaxis for P Jerovecii should be given.
Adoptive immunotherapy
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD. If available, autologous or allogeneic EBV-directed CTLs should be considered in patients with R/R EBV-positive PTLD
Retransplantation
It can be considered 2 years post treatment and remission.
EPV viral load should be assessed and use of Gancylovir and anti EPV agent
ATG should be avoided in induction phase
Rituximab can be used during induction
Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered
What is the level of evidence provided by this article?
Narrative article
Level of Evidence V
· Response to therapy Patient survival 65% and 46%, (In adult heart/lung tx)[1,45] 53% and 41% (In adult heart/lung tx)[1,45].
Role of immun-osuppression Induction therapy has a role Cumulative immunosuppression is crucial
· Prevalence Majority of PTLD cases Less prevalentSafety and efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen every 3 wk and G-CSF support have been elucidated in the PTLD-1 trial.
A risk-stratified sequential therapeutic approach has been admitted in the second part of this trial as follows: Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with.
G-CSF support in cases with no complete response to isolated Rtx therapy.
Overall response rate approached 88%, with 70% of cases with any response achieved a complete response at the end of therapeutic program.
Considering an excellent outcome reported of this trial, a reduction of the immunosuppressive load and risk-stratified sequential therapy are widely considered the standardized care of polymorphic and monomorphic diffuse large B-cell lymphoma-like PTLD after SOT
· Adoptive immunotherapyTo achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells.
This situation is in contrast to PTLD developing in TRs of SOT.
A robust EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes (CTLs).
The major risk of this therapeutic modality, is GVHD development.
Expanded EBV-specific CTLs have been an effective therapeutic option in autologous as well as in donor-derived PTLD.
A variety of recent approaches e.g., adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells” and Tac-resistant, engineered CTLs has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load.
· Outpatient careIn light of serial follow up of the EBV viral load in identifying the patients at risk and in monitoring the response to therapy, the following steps have been suggested.
Monitoring of EBV viral titers in higher risk patients.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
The latter does not necessarily correlate with PTLD status.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
· Early PTLD Late PTLDGeneral criteria Diffuse large B-cell or other B-cell lymphoma Burkitt’s lymphoma and Hodgkin’s disease are late events.
Specific tumorigenic events e.g., C-myc translocations are restricted to late PTLDs. Time to PTLD Shortest for lung, heart/lung TR.
PTLD is quite frequent in liver TR (Late PTLD beyond 5 yr is rare, immunosuppression can be tapered/hold due to tolerance).
Longest for the heart TR and at risk for late PTLD even > 10 yr after trans-plantation.
Distinct criteria B-cell origin, almost exclusively EBV+ve, reflecting reduced immunosurv-eillance as major pathogenetic factor.
Resembles tumors with distinct pathogenetic alterations and nodal appearance.
Role of immunos-uppression Induction therapy has a role.
More likely to develop graft rejection and switch to Tac before
· Cumulative immunosuppression is crucialTx: Transplantation; TR: Transplant recipient; PTLD: Post-transplant lymphoproliferative disorders; EBV: Epstein-Barr virus; HSCT: Haplo-identical allogeneic hematopoietic stem-cell transplant; LDH: Lactate dehydrogenase.
Initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality
· Future strategiesA list of newer therapeutic medications has been proposed.
Their efficacy remains to be validated via randomized controlled trials. Bruton’s tyrosine kinase (BTK) inhibition. Virtually active in GVHD and allograft rejection; remarkably active in activated B cells (ABC) type diffuse large B cell lymphoma (DLBCL).
(2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]; SRL and everolimus: Evident – in vitro evidence – of involved pathways; mTORi have robust immunosuppressive impact, introduction in PTLD therapy still controversial.
(6) Anti-CD30 therapy (Brentuximab vedotin): Expression of CD30 in 85% of all PTLD subtypes; the given effects is only limited to case reports
· To summarizeReduction of immunosuppression is the cornerstone of PTLD management. Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and, monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
IPI is a prognostic scoring system that includes the following: Patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and number of extra-nodal locations.
Another scoring system has been given in a French registry system that relies primarily upon patient’s age, serum creatinine concentration, LDH level, PTLD localization, and histopathologic criteria.ATG induction significantly triggers the risk of lymphoma evolution as compared to other agents The latter agents, may provide two benefits, first, a lower risk of PTLD development, and, second, TRs are more amenable to avoid long-term excessive immunosuppression after retransplantation.
Clinical clues about the origin of lymphoma cell line is an important therapeutic guide in using cytotoxic Tcell infusions in PTLD management
· FindingsOverall response rate approached 88%, with 70% of cases with any response achieved a complete response at the end of therapeutic program
· CONCLUSIONRecent progress in our understanding of the underlying pathophysiology of PTLD as well as the role of EBV has led to a better management.
PTLD recurrence has been rarely reported after re-transplantation that requires careful planning of immunosuppression.
An ever-improving moleculargenomic technology has had its impact on upgrading our diagnostic and therapeutic strategies that will be reflected in improved recipient’s outcome.
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT)
Risk factor
1-Type of solid organ transplant
· In adults, the incidence of PTLD is 0.8%- 2.5% in kidney transplant recipients And 1.0%-5.5% in liver TRs,
2- Allogenic HSCT
· T-cell depleting agents prior to transplant. Higher risk,
With lower risk with the use of non-specific broad lymphocyte depleting agents (T- and B-cells)
· the type of induction therapy has a role in development early PTLD, and late PTLD is largely determined by cumulative immunosuppressive burden.
(3) the presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease
(4) Oncogenic EBV: EBV may alter cell growth via several mechanisms:
Pathogenesis
Role of EBV:
· 50% PTLD in SOT are not accompanied by EBV infection
· For EBV-positive TRs, the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immune- surveillance.
· EBV can integrate into normal B-cell program leading to proliferation and transformation which should be destructed by T-cell response
EBV POSITIVE VS NEGATIVE
Not prognostic/predictive of response to therapy
EBV positive PTLD
Fewer genomic abnormalities
Mostly B-cell proliferative lesions
More common (first peak)
EBV NEGATIVE
hare many genomic/ transcriptmic features
Mostly T-cell proliferative
Less common
Early PTLD.
EBV positivity
Graft involvement
Less often: Extranodal disease Nondestructive
Induction therapy has a role
Majority of PTLD cases
Late onset PTLD
Frequent EBV negative
Less graft involvement
Extra-nodal disease: more common
Cumulative immunosuppression is crucial Less prevale
Classification
1. plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
2. Polymorphic PTLD.
3. Monomorphic PTLD
4. classic Hodgkin’s lymphoma-like PTLD
Clinical presentation:
PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Prophylaxis:
EBV sero-status of both donor and recipient before donor selection.
EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
A fine-tuning the immunosuppressive burden to as low as clinically possible.
TREATMENT OF PTLD
1-Reduction of immunosuppression
· The mainstay of primary PTLD management is to ameliorate the immunosuppressive
· 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate
Rituximab
· Rtx is a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
· The overall response to Rtx monotherapy in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases[
Chemotherapy
Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells.
Outpatient care
1. Weekly monitoring of EBV viral titers in higher risk patients.
2. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
3. viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
4. Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment.
5. Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
6. Therapeutic options should be tailored as per multidisciplinary team discussion.
7. An the initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality
Re-transplantation and PTLD recurrence
· To limit the possibility of PTLD recurrence the following is recommended
(1) Time to retransplant: Approximately two years of time after successful PTLD management.
(2) .. EBV.
(a) TR should experience Epstein–Barr nuclear antigen IgG positivity before retransplantation.
(b) Low/absent EBV viral load is recommended at the time of retransplantation.
(c) Close monitoring of TRs with persistently high EBV viral load is advised.
(d) Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load
(3) Role of immunosuppression:
· it is the magnitude of immunosuppressive intensity that is the fundamental trigger for PTLD evolution.
· Retransplantation after PTLD cure remains controversial due to the re-exposure of immunosuppression.
(4) Induction therapy:
· The T cell-depleting agents should be excluded from the induction strategies
(5) Maintenance immunosuppression:
· the potential risk of PTLD development should not interfere with our choice of proper immunosuppressive regimen
· Triple therapy (CNI, MMF and steroids), the lowest safe dosages monitored by target trough levels should be considered.
· MMF can be included safely in the immunosuppressive protocols with no more added risk
6) Monoclonal gammopathy:
complete resolution is an obvious indicator of complete remission.
(7) Origin of PTLD
(donor vs recipient): Identification of the tumor source is crucial for future therapeutic plans and recognition of the biology of the next PTLD,
Post-transplant lymphoproliferative disease PTLD:
The most common malignancy in solid organ transplantation SOT with incidence of 25% in comparison to non-transplant population of 2-4 %.
Two major related factors are intertwined in provoking malignant transformation, immunosuppression and EBV.
its peak incidence is in the first-year post-transplant, around 85%, 15% is encountered after that.
Its predominantly B-lymphocyte mediated in the majority of cases, almost all of the first post operative year cases are EBV positive, B-lymphocytes PTLD. T-lymphocyte PTLD is non EBV related.
PTLD spectrum : might be simple lymphoid proliferation to lymphoma.
Clinical presentation is either localized or systemic with protean features entailing extra vigilance and low threshold for diagnosis of PTLD by treating physician.
Risk factors:
Several risk factors were observed in context of PTLD, including.
1} SOL. it was noted that, higher incidence was related to certain organs, such as multiple organs transplantation and Intestinal transplantation as the most common relevant context. As a role of thumb, the bigger and multiple organs transplanted, the vastest lymphatic tissues would be transferred. Hence, PTLD was more prevalent in Intestine, liver and lung transplant than kidney s, which is the least reported to be associated with PTLD.
2} Induction with lymphocyte depleting agent:
In situation when T lymphocytes depleted with ATG during induction, or as part of treatment of ACMR, B lymphocytes are imbalanced to T lymphocytes which keep it in check and inhibit its over-proliferation. When, the patient receives antilymphocyte medications that deplete both of the lineage B and T lymphocytes, less risk would be reported.
3} Previous transplant or glomerular disease treated with immunosuppression.
4}EBV:
Sero-negative recipient with positive donor is link to higher risk of PTLD. As the acute infective status is a major trigger for robust lymphocytic spread .
The other way of infection is reactivation.
Treatment:
Minimization of immunosuppression RIS, is the cardinal policy of therapy with withdrawal of MMF and AZA and reducing the dose of CNi,
Rituximab and chemotherapy might be implemented.
Post-transplantation lymphoproliferative disorders: Current
concepts and future therapeutic approaches.
INTRODUCTION.
PTLD is one of the most common malignancy post solid organ transplant which is mainly due to multi-factorial causes such as long term immunosuppressive therapy, viral infection such as EBV which lead to uncontrolled B cell proliferation, tissue biopsy is considered the gold standard of diagnosis and the corner stone of treatment is to reduce the immunosuppression with Rituximab and other chemotherapy but still no definitive therapy that carries the best prognosis.
Epidemiology of PTLD.
It is accounts about 10% of all solid organ transplantation, 1-2% of kidney transplantation and considered the most common malignancy in children with SOT.
There are many risk factors for PTLD such as EBV infection, immunosuppressive drugs, Age, length of time post-transplant, ethnic origin, CMV and other viral infections and recipient or donor origin-PTLD.
Pathogenesis.
EBV play a role in developing PTLD as it leads to proliferation and transformation of B cell with loss of apoptosis, especially with decline in the T-cell immune surveillance due to immunosuppressive state.
Pathogenesis of PTLD in EBV-negative patients is less evident and have many theories such as CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run theory as EBV commences the pathogenic process leading to the development of PTLD and then disappeared.
Classification.
WHO 2017 Classification
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular
hyperplasia, and infectious mononucleosis-like PTLD. (100%associated with EBV).
(2)Polymorphic PTLD. (90% associated with EBV).
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). (50% associated with EBV).
(4) classic Hodgkin’s lymphoma-like PTLD.( (90% associated with EBV).
Clinical presentation.
No specific symptoms for PTLD, the classic symptoms of weight loss, sweats and fever can still occur often with symptoms of the related organ involved rather than lymphadenopathy.
CNS involvement occurs in 30% of PTLD (1% in Non-Hodgkin lymphoma in the general population) and graft involvement is 30%.
Prophylaxis:
-EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
-Balanced immunosuppressive medications.
-Reduction of Immunosuppressive medications with viral re-activation.
-Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
Treatment:-
1-Reduction of immunosuppression .
RI can reverse 20%-80% of patients with PTLD, especially decreasing CNI group and withdrawal of antimetabolites such as azathioprine or Mycophenolate mofetil (MMF) and With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered, we should monitor the graft function, to detect any manifestation of acute rejection.
2-Rituximab therapy.
Rituximab is a chimeric m Ab mouse-human against CD20 and most PTLDs express CD20 but 20 to 30% of all PTLD are CD20 negative and the overall response to Rtx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases. Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5%.
3-Chemotherapy.
Indications of Immune chemotherapy include: Burkett’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
Safety and efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen every 3 wk and G-CSF support have been elucidated in the PTLD-1 sequential treatment (ST) trial.
The PTLD-2 sequential treatment (ST) trial demonstrated the efficacy of Rituximab monotherapy for those who are low-risk and respond well to the rituximab monotherapy and those who are at higher risk or non-responders will receive sequential chemotherapy (CHOP).
The response rate approached 88%, with 70% of cases with any response achieving a complete response at the end of the therapeutic programme.
4-Adoptive immunotherapy.
Strong EBV-specific cellular immune response is induced by EBV-specific cytotoxic lymphocytes and the major risk of this therapeutic modality is GVHD development.
5-Outpatient care.
1-Monitoring of EBV viral titers weekly, in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
2-Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
3-Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
4-Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
5-Therapeutic options should be tailored as per multidisciplinary team discussion.
6-The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality.
Re-transplantation and PTLD recurrence.
One-year disease free survival is necessary after control of PTLD before re-transplantation.
There are strategies that limit the recurrence of PTLD after re-transplant such as waiting two years after successful PTLD management, TR should experience Epstein–Barr nuclear antigen IgG positivity before retransplantation, Low/absent EBV viral load is recommended at the time of retransplantation with close monitoring of TRs with persistently high EBV viral load is advised.
Regarding the immunosuppression, ATG induction significantly triggers the risk of lymphoma evolution as compared to other agents, using of triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered.
Future strategies.
1. Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib)
2. Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]; SRL and everolimus
3. Proteasome inhibition (Bortezomib)
4. Radioimmunotherapy , (90Yibritumomab, tiuxetan)
5. Checkpoint inhibitors (Pembrolizumab, nivolumab)
6. Anti-CD30 therapy (Brentuximab vedotin)
CONCLUSION.
PTLD is one of the serious complications post KTX, need high suspicion for diagnosis and most of cases related to EBV and mainly respond to reduction of immunosuppression , re-transplant with special consideration carries a good response and low risk of PTLD recurrence.
Level of evidence: V (a narrative review article).
Introduction:
Post-transplant lymphoproliferative disorders (PTLD) are one of the essential malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT), and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells may get infected by Epstein-Barr virus (EBV) either by:
(1) Post-transplant viral reactivation.
(2) Primary EBV infection
Risk factors:
(1) SOT
(2) Allogenic HSCT
(3) the presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution
(4) Oncogenic EBV
Pathogenesis:
EBV-positive TRs, the development of PTLD can be attributed to the immunosuppressive-induced decline in the T-cell immune surveillance. EBV can integrate into regular B-cell programs leading to the proliferation
and transformation of these cells
EBV-positive vs. EBV-negative PTLD::
T-cell subtype PTLD (usually EBV-ve) is a rare tumor and presents with manifestations that are dissimilar to those of T-cell lymphoma in immune-competent subjects.
Classification:
(1) Three nondestructive PTLDs: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD
Clinical presentation:
Pyrexia (57%), weight loss (9%), neurological manifestations (13%), nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%), and infectious mononucleosis-like syndrome that could be fulminant (19%)
Differential diagnosis::
Streptococcal infections or Infectious mononucleosis.
Time to PTLD for different transplanted organs: The time to PTLD is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR
EBV monitoring for preemptive therapy:
An estimation of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy.
Prophylaxis:
Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function have also been recommended.
TREATMENT OF PTLD:
RI reduced immunosuppressive medication
Rituximab therapy
Chemotherapy.
Adoptive immunotherapy
Outpatient care:
: (1) Weekly monitoring of EBV viral titers
(2) While viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression
(3) Serial physical examination,
(4) Optimum balance between PTLD management and avoidance of acute allograft rejection is crucial
(5) Therapeutic options should be tailored as per multidisciplinary team discussion
(6) The initial therapeutic step is RI or cessation of immunosuppression
Future strategies:
(1) Bruton’s tyrosine kinase (BTK) inhibition
(2) Inhibition of PI3K and mTOR
(3) Proteasome inhibition
(4) Radioimmunotherapy
(5) Checkpoint inhibitors.
(6) Anti-CD30 therapy
Prognosis
The outcome of PTLD patients has significantly improved owing to the advent of new lymphoma-specific protocols as well as the better supportive care
level of study : v
Thank you
Please summarise this article :
1- the cumulative intensive immunosuppression.
2- the oncogenic virus, EBV
1- Reduction of immunosuppression: the cornerstone of management.
2- Rituximab : it is indicated in the following types:
a- Non-destructive PTLD.
b- Polymorphic PTLD.
c- Monomorphic diffuse large B-cell lymphoma -like PTLD that is not responsive to reduction of immunosuppression.
3- Chemotherapy: it is indicated in the following types :
a- Burkitt’s lymphoma.
b- Hodgkin’s lymphoma.
c- peripheral T- cell lymphoma.
d- 1ry CNS lymphoma.
e- B-cell PTLD that is not responding to either reduction of immunosuppression or Rituximab.
4- Other modalities:
a- adaptive immunotherapy.
b- outpatient care.
c- risk-stratified sequential therapeutic approach.
d- anti-viral therapy.
e- Radiotherapy.
What is the level of evidence provided by this article?
Thank you
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Introduction
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation. It develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance. B cells get infected by Epstein-Barr virus (EBV) either by: (1) Post-transplant viral reactivation; and (2) Primary EBV infection, through the donated organ or via environmental exposure. The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year. On the other hand, PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative.
The immunosuppressive burden has an important role in PTLD evolution. Lymphoma presents 21% of all malignancies in SOT recipients as compared to 4% and 5% in immunocompetent individuals. Tissue diagnosis is crucial for PTLD diagnosis, in addition to clear evidence of EBV DNA, RNA.
The mainstay of PTLD primary management is reduction of immunosuppression. Complete cessation of the immunosuppressive drugs may be necessary to stop the disease progression. However, RI is not always feasible; a potential risk of allograft loss or graft dysfunction has to be considered particularly for vital organ transplants.
Another therapeutic options include surgical excision, anti-viral agents, local radiotherapy, intravenous immunoglobulin (IVIG), chemotherapeutic agents, monoclonal antibodies and cytotoxic T lymphocytes with variable success.
Clinical presentation: Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Salient features: PTLD may present as a local or disseminated disease. Clinical manifestations include: Pyrexia, weight loss, neurological manifestations, nodal lesions, gastrointestinal manifestations, pulmonary manifestations and infectious mononucleosis-like syndrome that could be fulminant.
An associated high EBV viral load by PCR should make one suspect PTLD. The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
Prophylaxis: Primarily, EBV serostatus of both donor and recipient should be recognized before donor selection. EBV-negative candidates is better receiving grafts from EBV-negative donors whenever available. A fine-tuning the immunosuppressive burden to as low as clinically possible. Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression. Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
TREATMENT OF PTLD:
The mainstay of primary PTLD management is reduction of immunosuppression. Reduction of immunosuppression can reverse 20%-80% of patients with PTLD. It is plan includes 50% reduction of calcineurin inhibitors doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil, despite the lack of evidence demonstrating any relation between MMF and PTLD development.With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
Rituximab therapy:
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen, leading to B cell depletion. Rituximab has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification:
(1) Non destructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. (375 mg/m2 body-surface area, weekly for 4 wk.
Chemotherapy Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and reduction of immunosuppression.
Adoptive immunotherapy Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells.
Re-transplantation and PTLD recurrence Feasibility of re-transplantation after successful management of PTLD has been reported in particular cases; however, one-year disease free survival is necessary after control of PTLD before re-transplantation.
Thank you
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Epidemiology
SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma). On the other hand, a reported incidence of PTLD in 3.2% of HSCT recipients has been observed in multicenter studies
Risk factors
(1) SOT: the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors therefore it is highest in intestinal, ht, lung transplant compared with kidneys.
(2) Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney.
(3) Oncogenic EBV: EBV may alter cell growth via several mechanisms:
A) EBV may induce highly regulated growth transformation.
B) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
C) EBV induced proliferating cells may permit these proteins to by-pass immune control
D) Growth alterations with the right levels of expression of cell targets
Pathogenesis
EBV-positive TRs: the development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immune surveillance and hence this immune defence mechanism compromised, B cell undergoes unlimited transformation and the evolution of lymphoma.
PTLD in EBV-negative hypotheses: CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes. ( Table 1)
WHO histological Classification 2017
(1) Non-destructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD
2) Polymorphic PTLD
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types)
(4) classic Hodgkin’s lymphoma-like PTLD. (Table 2)
Clinical presentation:
Clinical pic: varies from vary from symptomless lesions to fulminating disease. 50 % fever and nodal lesions, 25 % GI and IMN, 10 % Wt loss, neuro and pulmonary
Onset: Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology; whereas Burkitt’s lymphoma and Hodgkin’s disease are late events.
EBV monitoring for preemptive therapy:
The risk of EBV+ve PTLD relatd to Type of transplant organ, time elapsed until diagnosis of post-transplant PTLD and EBV serological status of both recipient and donor before transplant.
An estimation of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy. It has been observed that TR with PTLD usually expresses an increased EBV viral load as compared to PTLD free TR. This higher viral load invites more risk for PTLD evolution.
Pitfalls: cut-off values are not clear, sources of samples are not universal, absence of standard points of time to perform the monitoring that reflected poor positive and negative predictive of EBV viral load.
“Cell-free plasma EBV DNA” has been reported as a better marker of EBV activity
Preemptive strategies: RI, rituximab therapy, and adoptive transfer of EBV specified T cells for high-risk group of PTLD patients (not defined)
Prophylaxis:
EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
A fine-tuning the immunosuppressive burden to as low as clinically possible.
Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression.
High risk groups: Preemptive/prophylactic antiviral therapy, Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam, monitoring EBV viral load, preemptive RI with rising titers, and close monitoring of allograft function have been also recommended .
TREATMENT OF PTLD
RI: RI plan includes 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF). TR can be restaged within two to four weeks in contrary to lymphoma staging in immunocompetent patients. Acute rejection rate of 37%. Less response with EBV -ve cases. Complete lack of response observed in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV)
Rituximab therapy standard ttt for the following stages: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
Chemotherapy: for the following: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
Adoptive immunotherapy: Infusion of donor lymphocytes, to achieve adoptive immunotherapy. Has risk of GVHD.
Outpatient care
(1) High risk: weekly monitor. Low risk: Monthly then every three monthly
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
Prognosis: 70 % complete remission with median survival 6.6 years. IPI is a prognostic scoring system that includes the following: age, performance attitude, stage, LDH, and number of extra-nodal locations.
Re-transplantation and PTLD recurrence
To limit the possibility of PTLD recurrence the following recommendations are worth noting:
1- Time to retransplant: Approximately two years of time should elapse after successful PTLD management.
2- EBV:
· TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation.
· Low/absent EBV viral load is recommended at the time of retransplantation.
· Close monitoring of TRs with persistently high EBV viral load is advised.
· Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence . Ganciclovir has been suggested for this purpose.
3- Role of immunosuppression: RI/withdrawal of immunosuppression has been the cornerstone of PTLD management.
Induction therapy:
– ATG vs IL-2 receptor antagonists: The T cell-depleting agents should be excluded from the induction strategies with IL-2 receptor antagonists appeared to have the first priority.
– Rituximab in induction therapy: Rtx may be introduced as an element of desensitization regimen in high-risk TR.
Maintenance immunosuppression:
Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered.
MMF: Considering the safety of MMF in regard to PTLD evolution, MMF can be included safely in the immunosuppressive protocols with no more added risk.
mTOR inhibitors: Their role in PTLD development remains debatable. These agents may inhibit the development of lymphomas in vitro, but their clinical application in human still warrant the proper evidence.
4- Graft PTLD: Is very intriguing and usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative.
5- Monoclonal gammopathy: Whilst the presence of monoclonal gammopathy may indicate incompletely remitted PTLD, its complete resolution is an obvious indicator of complete remission.
6- Origin of PTLD (donor vs recipient): better outcome in TRs with “donor” lymphomas, it is an important therapeutic guide in using cytotoxic T cell infusions in PTLD management.
Thank you
Please summarise this article
Introduction:
Post-transplant lymphoproliferative disorders (PTLD), are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT). Occurs due uncontrolled B cell proliferation due to blunted immunological surveillance.
EBV infects B cell by: (1) Post-transplant viral reactivation. (2) through the donated organ or environmental.
Risk factors:
1. Solid organ transplantation: more common in multiorgan transplantation, thoracic transplants and intestinal Tx.
2. Allogenic hematopiotic stem cell transplants: more common in less HLA matched Tx, umblical cord Tx.
3. Previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney.
4. Oncogenic EBV: – expression of its growth inducing proteins.
– Induction of the potent oncogenes; LMP1 and LMP2.
– EBV variant/HLA types combination permit these proteins to by-pass immune control.
– Growth alterations.
Pathogenesis:
EBV+ PTLD: Fewer genomic abnormalities, mostly B-cell proliferative lesions, “Non-germinal” center B-cell, more common in the first year of transplant, Almost all cases of HSCT (100%) are EBV positive,
EBV- PTLD: Share many genomic/ transcriptmic features with diffuse large B-cell lymphoma in Immunocompetent patients, mostly T-cell proliferative lesions, “Germinal center B-cell type”, less common with peak 10 years after transplantation.
Prognosis/response to therapy in adults; a considerable proportion of both EBV+ve and -ve PTLD respond to RI as a sole intervention.
Future studies Whole-exome/genome wide sequencing and studies of role of EBV-associated microRNAs, may further define PTLD pathogenesis with more precise molecular-genomic classification of both EBV+ve and EBV-ve PTLD.
Classifications:
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
Constitutional symptoms: fever, wt. loss, neurological deficit.
Lymphnode enlargement, GI manifestations, pulmonary symptoms, and fulminant form of infectious mononucleosis.
Differential diagnosis:
All infections cause lymphadenopathy, pharyngitis, and fever.
Treatment of PTLD:
1. Reduction or discontinuation of immunosuppressive medication.
2. Rituximab.
3. Chemotherapy.
4. Surgical.
5. Adoptive immunotherapy.
Outpatient care:
Weekly monitoring of EBV viral titers in higher risk patients, while monthly followed by three monthly monitoring for low risk groups.
Viral load monitoring.
– Frequent clinical examination, graft function evaluation, and imaging.
– Monitoring for rejection while on treatment as the risk of graft loss reaches 40%.
– Multidisciplinary team work up, evaluation and followup.
– The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality.
New therapeutic medications:
– Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib).
– Inhibition of PI3K and mTORi.
– Proteasome inhibition (Bortezomib).
– Radioimmunotherapy.
– Checkpoint inhibitors (Pembrolizumab, nivolumab).
– Anti-CD30 therapy (Brentuximab vedotin).
Prognosis:
The outcome improved as a result of improved lymphoma treatment.
70% of PTLD patients had achieved a complete remission with median survival of approximately 6.6 years.
Re-transplantation:
Two years elapsed before re-transplant in PTLD cured patients.
Transplant recipient with EBV+ IgG before re-transplantation.
Low/ absent viral load before transplantation.
Graft PTLD removal curative.
Immunosuppression:
– Induction with basilixumab not ATG.
– Desensitization with rituximab.
– Triple therapy (CNI, MMF and steroids) with lowest therapeutic drug levels.
– Use of m-TOR inhibitors in maintenance IS
Monoclonal gammopathy may indicate incompletely remitted PTLD.
Identification of PTLD (donor vs recipient) may help in disease control, type of recurring disease, and future treatment plan.
Conclusion:
PTLD are now better understood, new treatment therapeutic option is under investigational studies, and rarely recurs in re-transplantation with proper monitoring.
Multidisciplinary team is mandatory in PTLD management and followup.
What is the level of evidence provided by this article?
Level of evidence V – erratic review
Thank you
SUMMARY:
Introduction:
After solid organ and allogeneic hematopoietic stem cell transplants, recipients of transplants are more susceptible to developing cancer. Posttransplant lymphoproliferative disorders (PTLD) cover a broad range of illnesses, from benign lymphoid tissue proliferation to overt malignancy with aggressive behavior. The cumulative immunosuppressive load and the Epstein-Barr virus’s carcinogenic potential are the two primary risk factors for PTLD. The latter is a significant pathognomonic force in the progression of PTLD.
The treatment of PTLD includes reduction of immunosuppression, rituximab therapy, either isolated or in combination with other chemotherapeutic agents, adoptive therapy, surgical intervention, antiviral therapy and radiotherapy.
Risk factor includes: Solid organ transplantation, highest in lung and lowest in kidney transplantation also in allogenic HSCT, the incidence is higher in the use of T -cell depleting agents compare to non T cell depleting agent and oncogenic EBV.
Clinical presentations: It can vary from asymptomatic to fulminant disease with multi-organ involvement. It includes pyrexia, weight loss, neurological lesion, nodal involvement, GIT manifestations, pulmonary manifestation, infectious mononucleosis-like symptoms.
Treatment options of PTLD:
Future Strategies in treatments:
Re-transplantation and PTLD recurrence:
Successful re-transplantation is feasible after a failed allograft due to PTLD by considering the following factors
Conclusion
PTLD is a disease of immunosuppression. Recent progress in our understanding of the underlying pathophysiology of PTLD as well as the role of EBV has led to a better management strategy.
Level of evidence: Level V
Thank you
Please summarise this article
INTRODUCTION
-Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT).
-PTLD may manifest either as localized lesion or as systemic disease.
Epidemiology of PTLD
-There is increased risk which expressed as “standardized incidence ratios” (SIRs) i.e., the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort).
Risk factors
Risk factors are, reportedly, varied according to the type of the transplant organ: (1) SOT: The amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors.
(2) Allogenic HSCT: PTLD incidence is primarily related to the degree of HLA
matching with consequent introduction of T-cell depleting agents prior to transplant.The late PTLD is largely determined by cumulative immunosuppressive burden. Compared to EBV seropositive TRs, the seronegative patients in SOT are more vulnerable to develop PTLD with an increased estimated risk of 10-75.
(3) It is noteworthy to mention that the presence of previous exposure to the
immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution.
(4) Oncogenic EBV .
Classification
– Depending mainly on histopathological classification, diagnosis of PTLD can be categorized according to WHO 2017 Classification, as follows: (1) Three nondestructive PTLD: plasmacytic hyperplasia,
florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2)Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation
Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.An allograft dysfunction may ensue due to graft involvement. Lowering the threshold for PTLD diagnosis is crucial, as TR may
present with nonspecific symptoms (e.g., fever, asthenia).
EBV monitoring for preemptive therapy
This higher viral load invites more risk for PTLD evolution.
Prophylaxis
Primarily, EBV sero-status of both donor and recipient should be recognized before donor selection. EBV-negative TR is better receiving grafts from EBV-negative donors whenever available. A fine-tuning the immunosuppressive burden to as low as clinically possible. Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression.Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
TREATMENT OF PTLD
1-Reduction immunosuppression :
2-Rituximab therapy
3-Chemotherapy
4-Adoptive immunotherapy
Outpatient care
(1) Weekly monitoring of EBV viral titers[81] in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
(5) Therapeutic options should be tailored as per multidisciplinary team discussion.
(6) The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality.
Prognosis
Outcome of PTLD patients has greatly improved owing to the advent of new
lymphoma-specific protocols as well as to the better supportive care. Seventy percent the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years .
Re-transplantation and
Feasibility of re-transplantation after successful management of PTLD has been
reported in particular cases; however, one-year disease free survival is necessary after control of PTLD before re-transplantation[
What is the level of evidence provided by this article?
Level 5
Thank you
1. Please summarise this article
Introduction
Epidemiology
Risk factors for PTLD:
SOT:
HSCT:
The degree of increased PTLD risk can be categorized as follows:
The role of IS agents:
The “donor kind” and the “T-cell depleting technique” were the two most important variables in the progression of PTLD. Seronegative patients have a higher estimated risk of 10-75 of developing PTLD compared to EBV seropositive TRs.
Previous exposure to IS load (during treatment of the primary renal disease in the native kidney)
Oncogenic EBV: EBV may alter cell growth via several mechanisms.
Pathogenesis:
Role of EBV
EBV-positive VS EBV-negative PTLD:
Classification (WHO 2017):
EBV infection is seen in:
Clinical presentation:
Differential diagnosis:
Time to PTLD for different transplanted organs:
EBV monitoring for preemptive therapy:
Prophylaxis:
Treatment of PTLD:
RI
Rituximab therapy
Chemotherapy
Adoptive immunotherapy
Outpatient care
Future strategies (efficacy remains to be validated via RCTs):
Prognosis
Re-transplantation & PTLD recurrence
6. Monoclonal gammopathy: its complete resolution is an obvious indicator of
complete remission.
7, Identification of the tumor source (donor vs recipient) is essential for future
therapeutic plans. Olagne et al, reported a trend to a better outcome in TRs with
“donor” lymphomas.
========================
2. What is the level of evidence provided by this article?
Level V
Thank you. How long the patient needs to wait after PTLD clearance?
Summary of the article
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
PTLD include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissues to frank malignancy with aggressive behavior.
PTLD; risk factors:
· The cumulative immunosuppressive burden.
· The oncogenic impact of the Epstein-Barr virus, through several mechanisms:
a) With lack of immune recognition, EBV may induce highly regulated growth transformation with expression of all of its growth inducing proteins.
b) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
c) EBV induced proliferating cells as well as EBV variant/HLA types combination may permit these proteins to bypass immune control and go unrecognized.
d) Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA.
PTLD; incidence in transplantation
1. Adults with SOT
· 0.8%- 2.5% in kidney transplant recipients (KTR).
· 0.5%-5.0% in pancreatic TRs.
· 1.0%-5.5% in liver TRs.
· 2.0-8.0% in heart TRs.
· 3.0-10.0% in lung TRs.
· ≤ 20% in multi-organ and intestinal TRs.
2. Allogenic HSCT: PTLD incidence is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant.
· zero in patients who received cyclophosphamide for GVHD.
· > 20% with selective T-cell depletion.
· Umbilical-cord transplantation (4%-5%).
· Transplant from unrelated donors (4%-10%).
· Transplant from matched, related donors (1%-3%).
PTLD;Classification:
1. Early vs late onset PTLD.
2. Histopathological categorization according to WHO 2017 Classification:
a) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
b) Polymorphic PTLD.
c) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
d) classic Hodgkin’s lymphoma-like PTLD.
3. EBV +ve vs EBV-ve PTLD (there is a lack of clear distinction between clinical consequences of different EBV serotypes and their response to therapy);
· An associated EBV infection could be currently seen in almost all TRs with non- destructive PTLD.
· EBV infection is seen in > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD.
· EBV infection is seen in 50% of monomorphic PTLD.
PTLD; diagnostic approach
· Relevant history and clinical examination. EBV serostatus, transplant organ type (SOT vs HSCT) and duration of transplant.
· The EBV-encoded RNA (EBER) in-situ hybridization assessment is mandatory for all the cases.
· Histopathologic configuration.
· Prompt staging for PTLD via application of the currently used staging for lymphoma.
PTLD; Clinical presentation
PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
· Salient features: Pyrexia (57%), weight loss (9%), neurological manifestations (13%), nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant (19%).
· An allograft dysfunction may ensue due to graft involvement.
· The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands.
PTLD; Differential diagnosis
Any high-risk TR who presents with pyrexia, pharyngitis and cervical lymphadenopathy would make one consider other diagnoses:
· Streptococcal infections.
· Infectious mononucleosis.
PTLD; Management
1. reduction of immunosuppression.
· RI can reverse 20%-80% of patients with PTLD.
· RI plan includes 50% reduction of CNI, in addition to withdrawal of the antimetabolites(azathioprine or MMF).
· With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
· A complete lack of response to RI has been observed in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage III/IV).
2. Rituximab therapy, either isolated or in combination with other chemotherapeutic agents.
· RTX has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
· The dose of RTX monotherapy is 375 mg/m2 body-surface area, weekly for 4 weeks.
· Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5%.
3. Chemotherapy:
· indications of Immunochemotherapy include Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to RTX and RI.
· Overall response rate approached 88% when using R-CHOP + G-CSF + anti-PJP prophylaxis.
4. Antiviral therapy; Ganciclovir has been suggested for this purpose.
5. Adoptive therapy.
· Infusion of donor lymphocytes, to achieve adoptive immunotherapy.
· EBV-specific cytotoxic lymphocytes (CTLs) is promising but the risk of GVHD is a major risk.
· Expanded EBV-specific cytotoxic lymphocytes (CTLs) have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD.
· Recent approaches include adoptive transfer of “pamidronate-expanded T cells” and Tac-resistant, engineered CTLs has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load.
6. Radiotherapy.
7. Surgical intervention.
8. Future strategies:
· Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib).
· Inhibition of PI3K(Idelalisib) and mTORi(SRL and everolimus).
· Proteasome inhibition(Bortezomib).
· Radioimmunotherapy, (90Yibritumomab, tiuxetan).
· Checkpoint inhibitors(Pembrolizumab, nivolumab).
· Anti-CD30 therapy (Brentuximab vedotin).
PTLD Prophylaxis:
· Recognition of EBV serostatus of both donor and recipient.
· A fine-tuning the immunosuppressive burden to as low as clinically possible.
· Preemptive/prophylactic antiviral therapy in potentially high-risk groups.
· Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration.
· Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers.
· Close monitoring of allograft function.
PTLD and re-transplantation
· one-year disease free survival is necessary after control of PTLD before re-transplantation.
· TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before re-transplantation.
· An anti-EBV indicator of robust cytotoxic response) before re-transplantation.
· Low/absent EBV viral load is recommended at the time of re-transplantation.
· Close monitoring of TRs with persistently high EBV viral load is advised.
· Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence.
· Induction therapy: The following agents are considered: (a) ATG vs IL-2 receptor antagonists. (b) Rituximab in induction therapy.
· Maintenance immunosuppression: to avoid the intense state of immunosuppression, therefore, the lowest safe dosages monitored by target trough levels should be considered.
The level of evidence provided by this article
This is a narrative review article with level of evidence grade 5.
Thank you. How long the patient needs to wait after PTLD clearance?
Introduction
PTLD is most common post transplant malignancy after skin cancers. It is caused by uncontrolled proliferation of B cells due to weakened immune system. Most of the PTLD is caused by EBV positive B cells in the first year of transplant. PTLD can manifest as a localized lesion or a multisystem disease. Tissue diagnosis is essential for PTLD along with EBV-PCR. The mainstay of treatment of PTLD is reduction in immunosuppression but rejection must be monitored.
Epidemiology of PTLD (standardized incidence ratios):
The increased risk of PTLD is expressed as “standardized incidence ratios” (SIRs) i.e., the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort).
Risk Factors:
1. The amount of lymphatic tissue in transplanted organ and the degree of immunosuppression are key factors in increasing risk of PTLD. In kidney transplant recipients the risk of PTLD is 0.8-2.5%.
2. Weakened immune system is an instigator for infection related cancers, such as EBV positive PTLD.
Pathogenesis:
Role of EBV:
Due to weakened immune system, EBV mediated integration and proliferation of B cells goes unchecked leading to PTLD. The pathogenesis of EBV negative PTLD is less evident and may be due to other immunomodulator viruses such as CMV, or due to the type and degree of immunosuppression.
WHO 2017 Classification:
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
It can present as a localized or as a fulminant disseminated multiorgan disease.
1. Pyrexia (57%)
2. weight loss (9%),
3. neurological manifestations (13%),
4. nodal lesions (38%),
5. gastrointestinal manifestations (27%),
6. pulmonary manifestations (15%)
7. infectious mononucleosis-like syndrome that could be fulminant (19%).
An associated high EBV viral load by PCR should make one suspect PTLD.
Common sites:
A. Lymph nodes,
B. liver,
C. lung,
D. kidney,
E. bone marrow,
F. gastrointestinal tract (GIT), spleen,
G. central nervous system (CNS),
H. tonsils and salivary glands.
Risk of EBV+ve PTLD depends on:
1. Type of transplant organ,
2. Time elapsed until diagnosis of post-transplant PTLD,
3. EBV serological status of both recipient and donor before transplant.
An estimation of the viral load via EBV-PCR is necessary to monitor pre-emptive PTLD therapy. It has been observed that transplant recipients with PTLD usually expresses an increased EBV viral load. Regarding preemptive therapy, cut-off values are not clear, sources of samples are not universal and there is absence of standard points of time to perform the monitoring.
Ideally EBV negative recipient should receive organ from EBV negative donor. Prophylactic anti-viral therapy can be considered in certain high-risk groups.
Treatment:
Reduction of immunosuppression:
1. 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA).
2. Withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF).
3. Apart from glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
Monitor response for 2-4 weeks.
Rituximab therapy:
Rituximab can be used in:
(1) Non-destructive PTLD,
(2) Polymorphic PTLD, and
(3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
Chemotherapy, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone):
Indications of Immunochemotherapy include:
1. Burkitt’s lymphoma,
2. Hodgkin’s lymphoma,
3. Peripheral T-cell lymphoma,
4. Primary CNS lymphoma and other uncommon lymphomas.
5. B-cell PTLD unresponsive to Rtx and RI.
Adaptive Immunotherapy in EBV positive PTLD refractory to the above-mentioned treatment modalities.
Prognosis
Poor prognostic criteria include the following:
1. Monoclonality,
2. Negative EBV serology,
3. Primary CNS involvement,
4. Tumour originated from T-cell,
5. Performance status ≥ 2,
6. Chemotherapy-based therapy (plus RI), and,
7. Multiple involved locations
Re-transplantation:
Re-transplantation can be considered after successful control of PTLD as the risk of recurrence of PTLD after re-transplantation is low. A minimum of one year may be considered before re-transplantation.
Level of Evidence: V
Thank you.
SUMMARY
Introduction
Post-transplant lymphoproliferative disorders are among the most common malignancy following solid organ transplantation and hematopoietic stem cell transplantation. EBV, which has been associated with PTLD, infects a B cell either by reactivation of dormant infected B cells as a result of severe immune suppression or from a transplanted organ.
It is of note that most of the PTLD (>85%) either locally or systemically usually present in the first year following organ transplantation
Epidemiology of PTLD
Since 1969 when pen et al first described five cases of PTLD, awareness about the disease has been on the rise due to the following suggested reasons;
Risk factor
WHO 2017 Classification of PTLD
Clinical presentation
It can vary from symptomless to fulminant disease with multi-organ failure.
Treatment of PTLD
Future Strategies in treatments
Re-transplantation and PTLD recurrence
Successful re-transplantation is feasible after a failed allograft due to PTLD by considering the following factors
Conclusion
PTLD, is largely a disease entity driven mostly by EBV and an increase in the use of immunosuppressive medications and this has helped in the understanding of appropriate prevention and management of the disease.
The level of evidence is 5
Thank you.
III.Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches
Abstract
====================================================================
Introduction
===================================================================
Epidemiology of PTLD
====================================================================
Risk factors
====================================================================
Pathogenesis
====================================================================
Classification:
WHO divides PTLD into four categories:
====================================================================
Clinical presentation:
Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
====================================================================
Differential diagnosis:
Time to PTLD for different transplanted organs:
B-Time elapsed until diagnosis of post-transplant PTLD
C-And EBV serological status of both recipient and donor before transplant.
====================================================================
Prophylaxis:
===================================================================
Treatment of PTLD
RI
Rituximab therapy
Chemotherapy
====================================================================
Adoptive immunotherapy
====================================================================
Outpatient care
====================================================================
Prognosis
====================================================================
Re-transplantation and PTLD recurrence
====================================================================
Conclusion
====================================================================
the level of evidence is V
Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). EBV (50%).
Thank you. How long the patient needs to wait after PTLD clearance?
One-year disease free survival is necessary after control of PTLD before re-transplantation.
Many thanks Prof.Halawa
Post-transplant immunosuppression can cause major complications including post-transplant lymphoproliferative diseases (PTLD). Epstein-Barr virus (EBV) has a major role in PTLD development, however EBV-negative patients are frequent. Reducing immunosuppression is crucial to treating PTLD. Transplant doctors should be aware of this complication, especially in patients who had immunosuppression for primary renal illness. Early diagnosis requires high suspicion. Rituximab, chemotherapy, antivirals, adoptive therapy, and surgery are treatments.
Risk Factors
A- Solid organ transplantation: lowest in KTR 0.8%-2.5%, maximum in multi-organ and intestinal TRs 20%.
1-HSCT: T cell depletion agent
2-Umbilical-cord transplantation RR 4%-5%
3- Unrelated donor transplant RR 4%-10%
4- Match-related donor transplant RR 1%-3%
C—Immunosuppressive load. Induction therapy affects early-onset PTLD, however, Immunosuppressive load determines late PTLD.
D- Oncogenic EBV may affect cell development in numerous ways:
1- Immune recognition deficiency
2- Environmental conditions induce powerful oncogenes.
3- EBV-induced proliferating cells and variant/HLA types may allow these proteins to bypass immune regulation and go unidentified.
4- Growth changes
Role of EBV: For years, PTLD formation was linked mostly to EBV infection, however, current data reveal that as much as 50% PTLD in SOT are not accompanied by EBV infection. For EBV-positive TRs, the development of PTLD can be linked to immunosuppressive-induced reduction in the T-cell immuno-surveillance.
Classification based on numerous variables:
1- According to the period of onset, PTLD is divided into Early and Late Onset.
2- Based on histopathological classification according to WHO 2017 Classification, as follows:
3- Gene expression profile and immunohistochemistry staining
Clinical picture
Variations in clinical presentation of PTLD range from asymptomatic lesions to fulminant illness with multi-organ failure.
EBV monitoring for preventative therapy:
Viral load by PCR of peripheral blood EBV DNA is required for monitoring preventative PTLD therapy.
Challenges: there are no cutoff values, no universal sources of samples, and there is no standard monitoring time.
Compared to EBV DNA extracted from peripheral blood mononuclear cells, “cell-free plasma EBV DNA” has been described as a more accurate indicator of EBV activity.
Treatment
All patients with PTLD should get early therapy that includes immunosuppression reduction unless issues with graft rejection or graft-versus-host disease make this approach impossible.
Rituximab is an effective chimeric anti-CD20 monoclonal antibody that binds to CD-20 antigen and causes B lymphocytes to be eliminated through a variety of processes, including phagocytosis (macrophages), complement-mediated cytotoxicity, and natural killer cells (antibody-dependent cell-mediated toxicity) (antibody-dependent cell-mediated toxicity).
Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and other uncommon lymphomas are among the cancers that can be treated with immunochemotherapy.
PTLD in HSCT patients, which is primarily caused by donor cells, has been reported to be controlled by adoptive immunotherapy using donor lymphocyte infusion.
Retransplantation
After 1-2 years without PTLD disease, retransplantation may be an option.
Induction therapy should not have any substances that kill T cells, so IL2 receptor antagonists are the best choice. Rituximab can be used to start treatment in high-risk patients.
The lowest safe doses of triple therapy should be used for maintenance therapy.
There is a place for giving ganciclovir to people with high viral loads as a preventive measure. Should, if possible, have low or no viral loads.
The use of mTORi is debatable.
Level of evidence: V review article
Thank you.
;
Epidemiology of PTLD ;
———————————————————————————-
The increased risk is expressed as “standardized incidence ratios” (SIRs) , the incidence of lymphoma in transplant cohort divided by its incidence in general population (non-transplant cohort). SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients.
Risk factors;
——————————————————————————-
1-The amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors.
2-PTLD incidence is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant.
3-The presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution.
4-Oncogenic EBV: EBV may alter cell growth via several mechanisms .
Pathogenesis;
————————————-
The role of EBV :
1-The development of PTLD can be attributed to immunosuppressive-induced decline in the T-cell immune-surveillance.
2-EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells.
Classification:
————————————————-
depending mainly on histopathological classification, diagnosis of PTLD can be categorized according to WHO 2017 Classification, as follows:
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD .
Gene-expression profile and immunohistochemical staining have been used to classify the diffuse large B-cell lymphoma in immunocompetent subjects depending on the cell of origin into;
1-“germinal center” B cell .
2-“non–germinal” center B cell.
In PTLD, EBV+ve cases are mostly non-germinal center B-cell type, in contrary to the EBV-ve cases that are more likely to be “germinal center B-cell type”.
Clinical presentation:
———————————————————————–
PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure . Clinical manifestations include:
1-Pyrexia (57%) .
2- weight loss (9%) .
3-neurological manifestations (13%)
4-nodal lesions (38%) .
5-gastrointestinal manifestations (27%) .
6-pulmonary manifestations (15%) .
7-infectious mononucleosis-like syndrome that could be fulminant (19%) .
8-An allograft dysfunction may ensue due to graft involvement. Lowering the threshold for PTLD diagnosis is crucial, as TR may present with nonspecific symptoms (e.g., fever, asthenia).
9-An associated high EBVviral load by PCR should make one suspect PTLD.
10-The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands .
Differential diagnosis:
——————————————————
Any high-risk TR who presents with pyrexia, pharyngitis and cervical lymphadenopathy would make one consider other diagnoses e.g., streptococcal infections or Infectious mononucleosis .
Time to PTLD for different transplanted organs:
—————————————————————————–
1-The time to PTLD is longest for the heart recipients and shortest for the lung and heart/lung in pediatric TR.
2-Early PTLD is often of diffuse large B-cell or other B-cell lymphoma histology.
3- Burkitt’s lymphoma and Hodgkin’s disease are late events .
EBV monitoring for preemptive therapy:
——————————————————————–
.
1-An estimation of the viral load via PCR amplification of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy.
A- It has been observed that TR with PTLD usually expresses an increased EBV viral load as compared to PTLD free TR.
B- Higher viral load invites more risk for PTLD evolution.
2- Cell-free plasma EBV DNA;
Compared to the reliability of EBV DNA via peripheral-blood mononuclear cells, the “cell-free plasma EBV DNA” has been reported as a better marker of EBV activity .
Considering a suitable preemptive approach should be confined to the high-risk group of PTLD patients, however, the precise definition of the cohort of patients at high risk has not been established yet .
Prophylaxis:
————————————————
1-Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
2-Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
3- Monitoring EBV viral load in a high-risk case and considering preemptive RI with rising titers, and close monitoring of allograft function have been also recommended .
TREATMENT OF PTLD;
—————————————————————————————–
1-RI ;
1-RI can reverse 20%-80% of patients with PTLD.
2-Compared to EBV positive disease, the EBV negative cases are less responsive to RI However, a complete lack of response to RI has been observed in old aged patients (> 50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann
Arbor stage III/IV) .
3-RI plan includes ;
a-50% reduction of calcineurin inhibitors .
b- Withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF) .
c-With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
4-Monitoring allograft function is mandated during the trial of RI to recognize any manifestations of early rejection.
Rituximab therapy ;
1-Rtx has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
2-The overall response to Rtx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases . Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5% .
3- In the PTLD-1 trial the complete remission rate approached 25% after standard induction augmented by another four doses of 3 weekly Rtx (low-risk patients).
4- in comparison with the group of TRs with complete remission with Rtx followed by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), the low-risk group in the cohort receiving risk-stratified sequential expressed longer disease-free survival at 3 year, despite no change in overall survival .
Chemotherapy;
——————————————————-
1-Indications of Immunochemotherapy include:
1- Burkitt’s lymphoma .
2- Hodgkin’s lymphoma .
3- peripheral T-cell lymphoma .
4- primary CNS lymphoma .
5- Other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
2-Safety and efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen every 3 wk and G-CSF support have been elucidated in the PTLD-1 trial .
3- A risk-stratified sequential therapeutic approach has been admitted in the second part of this trial as follows: Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy.
4- Considering an excellent outcome reported of this trial, a
reduction of the immunosuppressive load and risk-stratified sequential therapy are widely considered the standardized care of polymorphic and monomorphic diffuse large B-cell lymphoma-like PTLD (regardless to EBV status) after SOT.
Adoptive immunotherapy;
————————————————————
1-Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD.
2-A variety of recent approaches has been admitted as new therapeutic options for PTLD with no need to decrease the immunosuppressive load e.g.,
A-adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells”.
B-Tac-resistant, engineered CTLs .
Outpatient care;
————————————————–
In light of serial follow up of the EBV viral load in identifying the patients at risk and in monitoring the response to therapy, the following steps have been suggested:
(1) Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
(5) Therapeutic options should be tailored as per multidisciplinary team discussion.
(6) The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality .
Future strategies;
———————————————-
A list of newer therapeutic medications has been proposed . However, their efficacy remains to be validated via randomized controlled trials:
(1) Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib) .
(2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor).
(3) Proteasome inhibition (Bortezomib) .
( 4 ) Radioimmunot herapy , (90Yibritumomab, tiuxetan) .
(5) Checkpoint inhibitors (Pembrolizumab, nivolumab)
(6) Anti-CD30 therapy[86] (Brentuximab vedotin) .
Re-transplantation and PTLD recurrence;
——————————————————————————-
To limit the possibility of PTLD recurrence the following recommendations are worth noting:
(1) Time to retransplant:
————————————–
Approximately two years of time should elapse after successful PTLD management.
(2) EBV:
—————————-
The following recommendations is currently suggested in the literature:
(a) TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation.
(b) Low/absent EBV viral load is recommended at the time of retransplantation.
(c) Close monitoring of TRs with persistently high EBV viral load is advised.
(d) Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence. Ganciclovir has been
suggested for this purpose.
(3) Induction therapy: The following agents are considered:
—————————————————————————-
(a) ATG vs IL-2 receptor antagonists: The T cell-depleting agents should be excluded from the induction strategies with IL-2 receptor antagonists appeared to have the first priority.
(b) Rituximab in induction therapy: Rt may be introduced as an element of desensitization regimen in high-risk TR. Rtx has been used before in bone marrow or heart TR with seriously high EBV loads in order to inhibit EBV proliferation within lymphocytes, consequently limiting the risk of PTLD development .
(4) Maintenance immunosuppression:
——————————————————
(a) Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered.
(b) MMF: Considering the safety of MMF in regard to PTLD evolution, MMF can be included safely in the immunosuppressive protocols with no more added risk.
(c) mTOR inhibitors: Their role in PTLD development remains debatable. These agents may inhibit the development of lymphomas in vitro, but their clinical application in human still warrant the proper evidence.
(d) Graft PTLD: Is very intriguing ( and usually has a good prognostic outcome, furthermore, graft nephrectomy is almost curative.
(5) Monoclonal gammopathy:
——————————————–
The presence of monoclonal gammopathy may indicate incompletely remitted PTLD, its complete resolution is an obvious indicator of complete remission.
(6) Origin of PTLD (donor vs recipient):
—————————————————–
Identification of the tumor source is crucial for future therapeutic plans and recognition of the biology of the next PTLD.
.
What is the level of evidence provided by this article?
Level V
Thank you. How long the patient needs to wait after PTLD clearance?
Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches.
1. This is a review article.
2. Summary:
Incidence and Risk factors:
Risk factors are, reportedly, varied according to the type of the transplant organ. For SOT: In adults, the incidence of PTLD has been reported to range from 0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs, 1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ and intestinal TRs. These figures suggest that the amount of lymphatic tissue in an allograft and the degree of immunosuppression are key factors.
Compared to EBV seropositive TRs, the seronegative patients in SOT are more vulnerable to develop PTLD with an increased estimated risk of 10-75%.
Two peaks of PTLD incidence have been observed, first peak: In the first post-transplant year (mostly EBV seropositive), and second peak: Usually present 5-15 years after transplant (mostly EBV seronegative).
Pathogenesis Role of EBV: For decades, PTLD development was attributed mainly to EBV infection, however, recent reports suggest that as many as 50% PTLD in SOT are not accompanied by EBV infection.
Diagnosis of PTLD can be categorized according to WHO 2017 Classification, as follows: (1) Three non-destructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD. (2) Polymorphic PTLD. (3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). And (4) classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation: Clinically, PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
Differential diagnosis: Any high-risk TR who presents with pyrexia, pharyngitis and cervical lymphadenopathy would make one consider other diagnoses e.g., streptococcal infections or Infectious mononucleosis.
TREATMENT OF PTLD
The mainstay of primary PTLD management is to ameliorate the immunosuppressive burden, so that EBV-specific cellular immunity can be partially restored with no additional risk of acute rejection. RI can reverse 20%-80% of patients with PTLD. RI plan includes 50% reduction of calcineurin inhibitors (CNI), either tacrolimus (Tac) and cyclosporine (CyA) doses in addition to withdrawal of the antimetabolites such as azathioprine or mycophenolate mofetil (MMF), despite the lack of evidence demonstrating any relation between MMF and PTLD development . With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered. Considering their early response, TR can be restaged within two to four weeks in contrary to lymphoma staging in immunocompetent patients. Monitoring allograft function is mandated during the trial of RI to recognize any manifestations of early rejection. An acute rejection rate of 37% has been observed in a prospective trial entailed the RI strategy as a sequential plan for post-SOT PTLD therapy .
Compared to EBV positive disease, the EBV negative cases are less responsive to RI.
Other therapy includes:
Rituximab therapy: However, Rtx has been approved as a standard therapeutic agent in PTLD for three types of the WHO classification: (1) Nondestructive PTLD, (2) Polymorphic PTLD, and (3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI. The overall response to Rtx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission has been observed in 20%-55% of cases.
Chemotherapy Indications of Immunochemotherapy include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and R.
A risk-stratified sequential therapeutic approach has been admitted in the second part of this trial as follows: Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy.
Adoptive immunotherapy Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells. The major risk of this therapeutic modality, however, is GVHD development.
Outpatient care:
In light of serial follow up of the EBV viral load in identifying the patients at risk and in monitoring the response to therapy, the following steps have been suggested:
(1) Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) Whilst viral load drop denotes a response to therapy, persistently high or continuous rise in viral load indicates disease development or progression.
(3) Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of comprehensive clinical picture that includes EBV viral load assessment. The latter does not necessarily correlate with PTLD status.
(4) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
(5) Therapeutic options should be tailored as per multidisciplinary team discussion.
(6) The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality.
Prognosis
Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care. Seventy percent of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years.
Re-transplantation and PTLD recurrence
Feasibility of re-transplantation after successful management of PTLD has been reported in particular cases; however, one-year disease free survival is necessary after control of PTLD before re-transplantation.
Thank you
PTLD are one of the most important malignancies after solid organ transplantation AND
HBCT.
Usually observed in the first post-transplant year
Due to B cell proliferation
:
B cells may get infected by Epstein-Barr virus (EBV) either by:
(1) Post-transplant viral reactivation.
(2) Primary EBV infection, through the donated organ or via environmental exposure
.
T-cell proliferation is less, most EBV negative.
Epidemiology of PTLD:
Increased awareness of PTLD prevalence:
Better diagnostic technology, older age of donors and recipients, increased awareness
of this disorder, the advent of new immunosuppressive strategies and introduction of the
haplo-identical.
Standardized incidence ratios:
SIRs of in SOT, 10 (non.-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma)
PTLD in 3.2% of HSCT.
Risk factors:
1- SOT:
0.8%- 2.5% in kidney transplant recipients (KTR), 0.5%-5.0% in pancreatic TRs,
1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in
multi-organ and intestinal TRs
2-Allogenic HSCT:
Degree of HLA matching with consequent introduction of T-cell depleting agents prior
to transplant.
The type of induction therapy has a fundamental role in the early developed PTLD, the
one that develops late PTLD is largely determined by cumulative immunosuppressive
burden.
(1) HSCT (zero in patients who received cyclophosphamide for GVHD and > 20% with
selective T-cell depletion); (2) Umbilical-cord transplantation (4%-5%); (3) Transplant
from unrelated donors (4%-10%); and (4) Transplant from matched, related donors
(1%-3%).
(3) Previous exposure to the immunosuppressive:
During treatment of the primary renal disease in the native kidney.
(4) Oncogenic EBV;
1-Induce highly regulated growth transformation with expression of all of its growth
inducing protein.
2)-Induction of the potent oncogenes e.g., LMP1 and LMP2.
3- Proliferating cells as well as EBV variant/HLA types combination may permit these
proteins to by-pass immune control and go unrecognized.
4- Growth alterations with the right levels of expression of cell targets and viral and
cellular mRNA.
Pathogenesis:
Role of EBV positive:
Integrate into normal B-cell program leading to proliferation and transformation of these
cells and the evolution of lymphoma.
PTLD in EBV-negative:
50% PTLD in SOT are EBV negative, several hypotheses have been postulated e.g.,
CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent
antigenic triggering, hit-and-run hypothesis i.e., EBV commences the pathogenic process
leading to the development of PTLD and then vanishes.
Classification:
WHO 2017 Classification:
(1) Three nondestructive PTLD:
Plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) Classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
Salient features:
PTLD may present as a local or disseminated disease. In either form, the tumor can
behave aggressively in a rapidly progressive manner.
Pyrexia , weight loss .
Neurological manifestations .
Nodal lesions .
Gastrointestinal manifestations .
Pulmonary manifestations .
Infectious mononucleosis-like syndrome that could be fulminant .
An allograft dysfunction may ensue due to graft involvement.
Lowering the threshold for PTLD diagnosis is crucial, as TR may present with
nonspecific symptoms (e.g., fever, asthenia).
An associated high EBV viral load by PCR should make one suspect PTLD.
Most common locations of PTLD:
Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract , spleen, central
nervous system , tonsils and salivary glands,
EBV monitoring for preemptive therapy:
Monitor preemptive PTLD therapy.
positive and negative predictive of EBV viral load values for both SOT (28%-100% and
75%-100%, respectively) and allogeneic HSCT (25%-40% and 67%-86%, respectively)
Prophylaxis:
EBV-negative TR is better receiving grafts from EBV-negative donors
.
A fine-tuning the immunosuppressive burden to as low as clinically possible.
Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI .
Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also
considered.
Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also
recommended.
monitoring EBV viral load in a high-risk case and considering preemptive RI with rising
titers, and close monitoring of allograft function have been also recommended.
TREATMENT OF PTLD:
RI can reverse 20%-80% of patients with PTLD.
RI plan includes 50% reduction of calcineurin inhibitors ,in addition to withdrawal of the
antimetabolites .
Critically ill cases withdrawal of all immunosuppressive medications With the exception
of glucocorticoids should be considered.
Monitoring allograft function is mandated during the trial of RI to recognize any
manifestations of early rejection, An acute rejection rate of 37%.
EBV negative cases are less responsive to RI.
a complete lack of response to RI has been observed in old aged patients (> 50 years),
bulky lesions (> 7 cm), as well as in advanced stages of the disease (Ann Arbor stage
III/IV).
Rituximab therapy :
Rtx is a potent chimeric anti-CD20.
tx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition
to RI, approached 44%-79% with a complete remission has been observed in 20%-55%
of cases.
the PTLD-1 trial (prospective, multicenter trial including post-SOT PTLD), the complete
remission rate approached 25% after standard induction augmented by another four
doses of 3 weekly Rtx (low-risk patients)
Chemotherapy :
Indications of Immunochemotherapy include:
Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS
lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and
RI.
Safety and efficacy of Rtx (375 mg/square meter/week/4 wk), followed by CHOP regimen
every 3 wk and G-CSF support have been elucidated in the PTLD-1 trial
A risk-stratified sequential therapeutic approach has been admitted in the second part of
this trial as follows: Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF
support in cases with no complete response to isolated Rtx therapy. Overall response
rate approached 88%, with 70% of cases with any response achieved a complete
response at the end of therapeutic program. Of note, post-R-CHOP supportive G-CSF
was mandated in all patients with anti-Pneumocystis jirovecii prophylactic therapy
Adoptive immunotherapy:
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to
manage PTLD in HSCT patients that is primarily originating from donor cells.
Outpatient care :
(1) Weekly monitoring of EBV viral titers in higher risk patients.
(2) Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(3) Whilst viral load drop denotes a response to therapy, persistently high or continuous
rise in viral load indicates disease development or progression.
(4) Serial physical examination, radiology testing and monitoring allograft function should
be viewed as a part of comprehensive clinical picture that includes EBV viral load
assessment. The latter does not necessarily correlate with PTLD status.
5) balance between PTLD management and avoidance of allograft acute
rejection .
6) Therapeutic options per multidisciplinary team discussion.
(6) The initial therapeutic step is RI or cessation of immunosuppression, after which
further therapeutic options is tailored according to the response and clonality.
Prognosis:
Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-
specific protocols as well as to the better supportive care.
Seventy percent of the PTLD-1 patients had achieved a complete remission with median
survival of approximately 6.6 years.
level of evidence V.
Thank you
Introduction: 21% of malignancies post solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) are post transplant lymphoproliferative disorders (PTLD) which occur due to blunted immune surveillance causing uncontrolled B cell proliferation and infection by Epstein-Barr virus (EBV). More than 85% of the cases occur within first year post-transplant. T cell related PTLD is less common, and usually EBV-negative. Tissue histopathology, and evidence of EBV (DNA or protein material) is crucial for diagnosis of PTLD.
Epidemiology: In SOT, the standardized incidence ratio (SIR) of PTLD is high, being 10 for non-Hodgkin’s lymphoma and 4 for Hodgkin’s lymphoma. In HSCT, PTLD incidence is 3.2%. Time to PTLD in children is minimum for lung and lung/heart transplants, while maximum is for heart transplant patients. Diffuse large B-cell PTLD present early while Burkitt’s and Hodgkin’s disease present late.
Risk factors: They include type of SOT (maximum with multiorgan and intestinal transplant, and minimum with renal transplant), donor type and use od T cell depleting strategies in HSCT, history of prior immunosuppressive use, and EBV.
2 peaks of PTLD have been observed – early PTLD (in first year post-transplant, mostly with EBV, and second peak 5-15 years post-transplant, mostly EBV-negative). Early PTLD has been associated with induction immunosuppression, and late PTLD is associated with cumulative immunosuppression dose.
Pathogenesis: In EBV-positive PTLD, immunosuppressive induced reduced T-cell immune-surveillance in presence of integration of EBV in B cell leading to unchecked B cell proliferation causes PTLD. In EBV-negative PTLD, the mechanisms postulated include infections like cytomegalovirus (CMV), prolonged immunosuppression, and allograft-driven persistent antigenic triggering.
Classification: WHO classifies PTLD into 4 different types, namely non-destructive PTLD (100% EBV positive – plasmacytic hyperplasia, follicular hyperplasia, and infectious mononucleosis, IMN like PTLD), polymorphic PTLD (>90% EBV positive), monomorphic PTLD (50 % EBV-positive – B cell type, T cell type, and natural killer cell type), and classic Hodgkin’s lymphoma (>90% EBV positive).
Clinical presentation: Symptoms include fever (57%), lymphadenopathy (38%), gastrointestinal features (27%), IMN like syndrome (19%), pulmonary manifestations (15%), central nervous system (CNS) manifestations (13%), and loss of weight (9%). Graft dysfunction can be seen.
Differential diagnosis: Any patient with fever, weight loss, pharyngitis and cervical lymphadenopathy should be considered for streptococcal infections or IMN.
Prophylaxis: EBV serology of both donor and recipient should be known prior to transplant. EBV-negative recipient should receive organ from EBV-negative donor. Pre-emptive/ prophylactic antiviral therapy in high-risk groups and maintenance of high anti-EBV antibody titres using intravenous immunoglobulin (IVIG) is recommended.
Treatment of PTLD: It includes
a) Reduction of immunosuppression (RIS- reduce calcineurin inhibitors by 50%, stop antimetabolites): Can reverse 20-80% PTLD. EBV-negative, age more than 50, bulky lesions (>7 cm), and Ann Arbor stage III and IV are less responsive. Acute rejection can occur in upto 37%.
b) Rituximab: 4 weekly doses of rituximab are given in nondestructive PTLD, polymorphic PTLD, and monomorphic diffuse large B cell lymphoma like PTLD non-responsive to RIS. It has as response rate of 44-79% with complete remission in 20-55%, which further increases to 34-60% on using 4 more doses.
c) Chemotherapy: It is used for B-cell PTLD non responsive to RIS and rituximab, Burkitt’s’ lymphoma, Hodgkin’s lymphoma, peripheral T cell lymphoma, and primary CNS lymphoma. It includes regimes like Rtx + CHOP (rituximab with doxorubicin, cyclophosphamide, vincristine, and prednisolone) every 3 weeks for 4 cycles. It should be accompanied by GCSF (Granulocyte colony stimulating factor) and pneumocystis jirovecii prophylaxis.
d) Adoptive immunotherapy: It includes using donor lymphocyte infusion and EBV-specific cytotoxic lymphocytes (CTLs) in autologous as well as donor-derived PTLD.
Outpatient care post-transplant includes regular physical examination, radiology, allograft function monitoring, and monitoring of EBV viral titres.
Prognosis: International prognostic index (IPI) is used for prognosis. 70% complete remission with median survival of 6.6 years has been seen with use of newer treatment protocols. Poor prognosis is associated with monoclonality, EBV-negative serology, primary CNS involvement, T-cell origin tumor, performance status ≥2, chemotherapy based therapy, and >site involvement.
Re-transplantation and PTLD recurrence: One year disease free survival is necessary before re-transplant (wait for 2 years), presence of EBV-IgG positive status, low/absent EBV viral load, close monitoring of EBV viral load, long-term prophylactic anti-viral therapy (Ganciclovir), Avoid T-cell depleting agents as induction therapy, avoid intense immunosuppression (MMF safe, mTOR inhibitor use is debatable)
Conclusion: PTLD is due to immunosuppression, hence first step in treatment is reduction of immunosuppression. Multidisciplinary involvement is required for optimal management. It is rare to recur after re-transplant.
2. What is the level of evidence provided by this article?
Narrative review: Level of evidence – Level 5
Thank you. How long the patient needs to wait after PTLD clearance?
Thank you Professor.
Waiting period should be minimum 1 year, preferably 2 years.
1- Summary of the study:
A review article sowed the clinical features and management of PTLD.
1- The amount of lymphoid tissue in the graft and degree of IS ( more in intestinal
and muliorgan tx , then lung, then heart, then liver and least incidence in renal
TX)
2-Immunosuppression: induction play a role in early PTLD and cumulative IS
status is responsible for delayed PTLD
3- Previous exposure to IS during CKD
4- EBV:
a- reactivation
b- new infection: more in seronegative recepient and children.
1- Time to re-transplant: Approximately two years of time should elapse after successful PTLD management
2- EBV:
a- Recipient should experience Epstein–Barr nuclear antigen IgG positivity
b- Low/absent EBV viral load is recommended at the time of re-transplantation.
c- Close monitoring of TRs with persistently high EBV viral load is advised
d- Anti-viral therapy: Long-term prophylactic antiviral therapy with serial estimation of
EBV viral load is crucial to limit the incidence of PTLD recurrence.
3- Immunotherapy:
a- ATG vs IL-2 receptor antagonists: The T cell-depleting agents should be
excluded from the induction strategies with IL-2 receptor antagonists
appeared to have the first priority.
b- Rituximab induction may be introduced as an element of desensitization
regimen in high-risk TR.
c- Maintainance triple therapy. Maintain the lowest safe dosages monitored by
target trough levels should be considered
d- MMF is safe
e- mTOR inhibitors: Their role in PTLD development remains debatable
f- Complete resolution of monoclonal gammopathy is an obvious indicator of
complete remission
II- level of evidence: V
Thank you
Post transplantation Lymphoproliferative disorder: Current concepts and future therapeutic approaches.
Introduction:
PTLD is most common in post-SOT and HSCT, due to B cell uncontrolled proliferation, as a result of immune suppression.
Most cases are due to EBV-associated infection, and it can be:
Usually occur within the first year post-transplant and it is a common one, mostly EBV associated, and represents 85% of cases.
Rare cases can occur late up to 10% and it can be EBV- negative and it could be T-cell proliferation.
It can be:
Recipients should be aware of this possible complication, and an effort should be done to minimize the incidence and to find a way to a total cure.
The cornerstone of treating PTLD is immunosuppressant reduction.
Risk factors:
EBV oncogenicity:
Pathogenesis:
Classification:
Clinical presentation:
Most common sites of involvement of PTLD:
Differential diagnosis:
Prophylaxis:
Treatment:
Future strategy:
Prognosis:
Re-transplantation and PTLD recurrence:
Conclusion:
PTLD is the disease of immunosuppression.
Identification of risk factor, adjustment of IS dosage, understand the underline pathology, and advances in future treatment, selection of R/D, serial follow up, planning of re transplantation are all vital in dealing with such comorbid condition.
Level of evidence:
Article review ((III)).
Thank you
Why level 3?
See my response below.
thank u prof.
Review Article
Level 5
III. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approachesPlease summarise this article
*The objective of this study:
To show the incidence, clinical pointer, prophylactic measures in addition to current and future therapeutic approach of this overwhelming disorder.
Introduction:
* PTLD are frequent malignancies post- sold organ and hematopoietic stem-cell transplantation, due to uncontrolled B cell proliferation as a result of abrupt in immunological surveillance.
* The B cells may get infected by (EBV) in post-transplant viral reactivation; or due to primary infection.
*Great numbers of PTLD cases more than 85% are developed in the first year following transplantation.
*PTLD due to T-cell proliferation was developed in fewer cases and is mostly EBV-negative.
*PTLD may manifest either as localized lesion or as systemic disease.
* Tissue diagnosis is mandatory for PTLD diagnosis, as well as clear identification of EBV DNA, RNA, or protein material.
The risk factors:
According to the type of the transplant organ:
(1) SOT:
The amount of lymphatic tissue in an allograft and the degree of immunosuppression are important factors.
(2) Allogenic HSCT:
The degree of HLA matching with consequent introduction of T-cell depleting agents before transplantation.
(3) The presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney is an unnoticed risk factor for PTLD evolution.
(4) Oncogenic EBV
EBV may alter cell growth via several mechanisms: growth transformation ,induction of the potent oncogenes, by-pass immune control and go unrecognized. And growth alterations with the right levels of expression of cell targets and viral and cellular mRNA.
The pathogenesis:
*50% PTLD in SOT are not contributed to EBV infection.
*For EBV-positive PTLD, can be attributed to immunosuppressive-induced decline in the T-cell immunesurveillance.
* EBV-negative patients is less evident.CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis.
*EBV-positive vs EBV-negative PTLD: In the light of molecular-genomic data of diffuse large B-cell lymphoma subtype, a range of distinguishing features have been identified to discriminate between EBV+ve and EBV-ve PTLD.
Classification:
Depending on histopathological classification, diagnosis of PTLD can be categorized according to WHO 2017
Classification, as follows:
(1) Three nondestructive PTLD: plasmacytic hyperplasia,
florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2)Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell
types).
(4) classic Hodgkin’s lymphoma-like PTLD.
Clinical presentation:
*It is vary from symptomless lesions to fulminating disease with multi-organ failure.
*Clinical manifestations include: Pyrexia , weight loss, CNS symptoms, nodal lesions, GIT, pulmonary manifestations and infectious mononucleosis-like syndrome.
* An allograft dysfunction may ensue due to graft involvement.
* Lowering the threshold for PTLD diagnosis is crucial, as TR may present with nonspecific symptoms (e.g., fever, asthenia). An associated high EBV viral load by PCR may suspect PTLD.
* The most common locations of PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone marrow, (GIT), spleen, (CNS), tonsils and salivary glands.
Differential diagnosis:
Any high-risk TR who presents with pyrexia, pharyngitis and
cervical lymphadenopathy
The treatment of PTLD:
*The important step of management of PTLD reduction of immunosuppression (RI), it can reverse 20%-80% of patients.
*RI plan includes 50% reduction of (CNI), in addition to withdrawal of the antimetabolites.
* With the exception of glucocorticoids, withdrawal of all immunosuppressive medications in critically ill cases should be considered.
* TR can be restaged within two to four weeks in
contrary to lymphoma staging in immunocompetent patients. Monitoring allograft function is mandated during the trial of RI to recognize any manifestations of early rejection.
*Compared to EBV positive disease, the EBV negative cases are less responsive to RI.
*Absent of response to RI occurred in old aged patients (>
50 years), bulky lesions (> 7 cm) and in advanced stages of the disease.
Rituximab therapy:
Rtx has been approved as a standard therapeutic agent in PT: (1) Nondestructive PTLD
(2) Polymorphic PTLD
(3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
The complete response can be interpreted as three associated benefits:
Better overall survival, extended time to progression, and better progression-free survival.
Chemotherapy:
*The indications of Immunochemotherapy:
Burkett’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
* Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with
G-CSF support in cases with no complete response to isolated Rtx therapy.
Adoptive immunotherapy:
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT, with a high risk of GVHD.
Outpatient care:
*Weekly monitoring of EBV viral titers in higher risk patients.
*Monthly monitoring initially followed by three monthly monitoring for low risk groups.
*Persistently high or continuous rise in viral load indicates disease development or progression.
* Serial physical examination, radiology testing and monitoring allograft function should be viewed as a part of
comprehensive clinical picture that includes EBV viral load assessment.
* Therapeutic options should be tailored as per multidisciplinary team discussion.
*The initial therapeutic step is RI or cessation of immunosuppression, after which further therapeutic options is tailored according to the response and clonality.
The prognosis:
*Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care.
70% of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years.
CONCLUSION:
*PTLD is a disease of immunosuppression, so understanding it is pathophysiology and the role of EBV has led to a better management.
*PTLD recurrence has been rarely reported after re transplantation that requires careful planning of immunosuppression.
* Improving moleculargenomic technology has had its impact on upgrading our diagnostic and therapeutic strategies that will be reflected in improved recipient’s outcome.
What is the level of evidence provided by this article?
Level of evidence is level V
Thank you
Summary
Introduction
Post-transplant lymphoproliferative disorders (PTLD) one the commonest cause of malignancies after solid organ transplantation (SOT) Lymphoma accounts for 21% of all malignancies in SOT recipients as compared to 5% in immunocompetent individuals. most of PTLD cases (> 85%) are usually observed in the first post-transplant year,
commonly, it is associated with B-lymphocyte proliferation and it is associated with EBV infection either pre or posttransplant. less commonly, PTLD is related to T cell proliferation mostly in the absence of EBV infection
Epidemiology of PTLD
“Standardized incidence ratios” (SIRs) i.e., the incidence of lymphoma in transplant cohort divided by its incidence in general population used to express the incidence.
SIRs of 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) have been reported among SOT recipients in comparison to the HSCT where the incidence is 3.2% of recipients in multicenter studies.
Risk factors
A- SOT : amount of lymphatic tissue in different organ
Degree of immunosuppression with the peak incidence in the 1st year post transplantation ((mostly EBV seropositive )owing to the type of induction immunosuppression used and the one that develops late ( mostly EBV negative )PTLD is largely determined by cumulative immunosuppressive burden
B- HSCT: The most crucial contributing factors for PTLD evolution were the “donor type” as well as the “T-cell depleting strategy”
Pathogenesis
Role of EBV : EBV is prevalent in adult population by more than 90% infection acquired during childhood where it get attach to B lymphocyte through specific site ( CD21 ) and stimulate the cell protein factory to produce its antigens (3 nuclear antigen and three surface membrane protein) that stimulate Cytotoxic T lymphocyte to control the infection . hence the virus within the infected slave B lymphocyte enter in latent phase inside lymphoid tissue so long the immune system is potent . under any weakness of immune system ( HIV infection or solid organ transplantation SOT) latent antigenic machine inside B lymphocyte will be active and can cause lymphoproliferative disease
An associated EBV infection could be currently seen in almost all TRs with nondestructive PTLD, in > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD, and in only 50% of monomorphic PTLD (Figure 4). Pathologically, monomorphic PTLD cannot be discriminated from lymphomas in immunocompetent patient
Classification : : according to WHO 2017 Classification
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). And
(4) classic Hodgkin’s lymphoma-like PTLD
Clinical presentation: vary from symptomless lesions to fulminating disease with multi-organ failure.
Onset either with local or systemic disease
Course: variable and disease may has a rapidly progressive course
Manifestations include
Pyrexia (57%).
weight loss (9%).
neurological manifestations (13%).
nodal lesions (38%).
, gastrointestinal manifestations (27%).
pulmonary manifestations (15%).
and infectious mononucleosis-like syndrome that could be fulminant (19%)
Differential diagnosis
Other causes of lymphadenopathy either local or generalized
Prophylaxis:
Identification of EBV sero-status of both donor and recipient should be recognized before donor selection.
EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
Adjustment of the immunosuppressive burden to as low as clinically possible.
Ealy detection and treatment of Reactivation of other viruses, e.g., CMV or BK should trigger initiation of RI since viral application of other viruses might herald over-immunosuppression.
Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
Maintenance of high titers anti-EBV antibodies via IVIG/Cyto Gam administration is also recommended
Treatment
A- Reduction of immunosuppression it can reverse 20%-80% of patients with PTLD
Either
– withdrawal of MMF or Azathiopine
– Reduction of CNI by 50%
– Or withdrawal all immunosuppressive leaving steroids in criticall ill patients
Note:
– Close monitoring for acute rejection
– a complete lack of response to RI has been observed in :
– old aged patients (> 50 years),
– bulky lesions (> 7 cm),
– in advanced stages of the disease (Ann Arbor stage III/IV)
B- Rituximab therapy ( in addition to RI): if PTLD not responding to RI in the 3 class of WHO classification mentioned above
– Complete remission in 20%-55% of cases
– Response is observed in 44%-79% of PTLD cases
– Administration as 4 weekly dosesof 375 mg/m2
– Another 4 weeks doses can improve the response
C- Chemotherapy indications are:
– Burkitt’s lymphoma,
– Hodgkin’s lymphoma,
– peripheral T-cell lymphoma,
– primary CNS lymphoma and other uncommon lymphomas,
– and B-cell PTLD unresponsive to Rtx and RI
– Can be used sequentially with rituximab in addition to other supportive treatment like antibiotic ( for associated infection ) and granulocyte colony-stimulating factors (G-CSF)
D- adoptive immunotherapy
through Infusion of donor lymphocytes, Expanded EBV-specific CTLs have been an effective therapeutic option in autologous (recipient-derived PTLD) as well as in donor-derived PTLD
E- out patient care
Therapeutic options should be tailored as per multidisciplinary team discussion.
(1) monitoring of EBV viral titer
– weekly in in higher risk patients.
– Monthly monitoring initially followed by three monthly monitoring for low risk groups.
(2) Serial physical examination, radiology testing and monitoring allograft function
(3) Optimum balance between PTLD management and avoidance of allograft acute rejection is crucial.
New startiges
1. Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib)
2. Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]
3. Proteasome inhibition (Bortezomib)
4. Radioimmunotherapy (90Yibritumomab, tiuxetan)
5. Checkpoint inhibitors (Pembrolizumab, nivolumab)
6. Anti-CD30 therapy (Brentuximab vedotin)
Re-transplantation
Many transplant physicians recommend 12 to 24 mo after complete PTLD remission, before commencing a new kidney transplant
The following are of concern:
1- EBV: The following recommendations is currently suggested in the literature:
(a) TR should experience Epstein–Barr nuclear antigen IgG positivity (an anti-EBV indicator of robust cytotoxic response) before retransplantation.
(b) Low/absent EBV viral load is recommended at the time of retransplantation.
(c) Close monitoring of TRs with persistently high EBV viral load is advised.
(d) Anti-viral therapy: Long-term prophylactic antiviral therapy, Ganciclovir has been suggested for this purpose
2- Immunosuppressive
Induction therapy: ATG and IL-2 receptor antagonists
– induction with ATG significantly triggers the risk of lymphoma evolution as compared to other agents .
– IL-2 receptor antagonists however, may provide two benefits, first, a lower risk of PTLD development, and, second, TRs are more amenable to avoid long-term excessive immunosuppression after retransplantation.
Maintenance immunosupresssion
– The target in regard to maintaining immunosuppression is to avoid the intense state of immunosuppression so that the recovered immune system can promote the evolution of the anti-EBV cytotoxic T lymphocyte, thereby, hampering EBV-triggered B cell proliferation
– Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered
Conclusion
“Risk-stratified sequential” therapeutic approach with monitoring for acute rejection and use of other modalities may include adoptive immunotherapy and outpatient care. Investigational agents that’re currently under trials have been shown above.
level of evidence is V
Thank you
PTLD: Current concepts and future therapeutic approaches
Summary
· PTLD is a well-known complication after SOT due to cumulative effect of immunosuppressive and oncogenic properties of EBV infection(either reactivation or 1ry infection) leading to uncontrolled proliferation of infected B cells in 90 % of cases, while in 10 % who are EBV-ve (proliferation of T cells).
· Standardized incidence ratios” (SIRs): the incidence of lymphoma in transplant cohort divided by its incidence in general population and it equals 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) among SOT recipients
· Transplant team should be aware of this complication, particularly in patients who were exposed to large cumulative dose of immunosuppression during treatment of immune mediated original kidney diseases.
· Diagnosis is based on tissue pathology plus evidence of EBV (PCR).
· Available ttt are reduction of immunosuppression, antiviral, rituximab either monotherapy or followed by chemotherapy (CHOP).
· Risk factors:
o Type of organ transplantation (highest risk in intestine then heart and lung (according to the amount of lymphoid tissue in transplanted organ.
o Use of T cell depleting agents as ATG induction therapy, has high risk.
o EBV serostatus prior to transplantation, R-/D+ as in pediatric transplantation.
· Testing for EBV in transplant recipients depends on PCR, not serology, as humoral immune response in such immunocompromised individuals may be affected and antibodies be undetected.
· PCR has 2 limitations: no standard ideal sample (serum, whole blood or peripheral lymphocytes) and no clear cut off level to start ttt.
· Clinical manifestations include generalized constitutional manifestations ads fever, weight loss and may be pure peripheral lymphadenopathy in 10 % of cases, while nodal involvement in 38% of cases, CNS and graft involvement each in 30% of cases.
· Prevention: Use of EBV-ve donor for -ve recipients, chemoprophylaxis against CMV infection which can help or increase risk of PTLD (together with EBV), surveillance of the high-risk group for PTLD.
· Treatment:
o Reduction of immunosuppression (RIS): stop MMF and AZA , decrease CNI by 30-50% with close monitoring of remission of tumor within 2-4 weeks + surveillance of early signs of acute rejection.
o Rituximab:
§ Used if no complete remission is achieved after RIS.
§ old aged patients (>50 years), bulky lesions (> 7 cm), as well as in advanced stages of the disease (AnnArbor stage III/IV).
§ Effective as monotherapy in nondestructive PTLD, polymorphic PTLD, and, monomorphic diffuse large B-cell lymphoma-like PTLD
o Sequential chemotherapy (CHOP) cycle every 21 days. Indicated in Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI with variable results
o Adoptive immunotherapy as EBVSTs. In recurrent /relapsed cases with EBV+ve.
o Monitoring during therapy:
§ Tumor regression by follow up radiology.
§ Graft function and surveillance for rejection.
§ FU of EBV viral load (Weekly monitoring of EBV viral titers in higher risk patients. Monthly monitoring initially followed by three monthly monitoring for low risk groups).
§ Although viral titer does not always correlate with PTLD activity, persistent high or rising titer may indicate none responsive or worsening disease.
o Future therapy (under trials):
o Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib):
o mTORi SRL and everolimus: robust immunosuppressive impact, introduction in PTLD therapy still controversial.
o Proteasome inhibition (Bortezomib): Particularly efficacious in the early presented PTLD post allogeneic HSCT.
o Radioimmunotherapy
o Yibritumomab, tiuxetan): Apparent efficacy seen only in a small pilot trial.
o Checkpoint inhibitors (Pembrolizumab, nivolumab): Cytotoxic T lymphocyteassociated antigen 4 pathway:
o Anti-CD30 therapy (Brentuximab vedotin): Expression of CD30 in 85% of all PTLD subtypes: only limited to case reports.
Level of evidence: narrative review (level V).
Thank you
Introduction
Risk factors for post-transplant malignancy
Clinical presentation (diagnosis needs high index of suspicion)
Classification
Prevention of PTLD
Management of PTLD (challenging and needs multidisplinary team)
A- Modulation of immunosuppression
B- Specific treatment
Protocol
What is the level of evidence provided by this article?
Thank you
● PTLD are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT)
● It is a result of uncontrolled B cell proliferation
● The majority of PTLD (> 85%) are usually observed in the first post-transplant year. ● PTLD as a result of T-cell proliferation is less and is mostly EBV-negative.
● Lymphoma accounts for 21% of all malignancies in SOT recipients as compared to 4% and 5% in immunocompetent individuals respectively in men and women
● SIRs of lymphoma is 10 (non-Hodgkin’s lymphoma) and 4 (Hodgkin’s lymphoma) among SOT recipients.
● The incidence of PTLD is 0.8% – 2.5% in adult kidney transplant recipients and 0.5%-5.0% in pancreatic ,1.0%-5.5% in liver TRs, 2.0-8.0% in heart TRs, 3.0-10.0% in lung TRs, and ≤ 20% in multi-organ andintestinal TRs
● Risk factors :
☆ The amount of lymphatic tissue in an allograft
☆ The degree of immunosuppression
☆ Use of T-cell depleting strategies
Impaired immune surveillance for EBV , HIV
☆ The “donor” type
☆ The primary EBV infection especially in pediatric age group.
● Two peaks of PTLD incidence have been observed:
◇ first : the first post-transplant year (mostly EBV seropositive)
◇ second : 5-15 years after transplant (mostly EBV seronegative).
☆ Pesence of previous exposure to the immunosuppressive load
(4) Oncogenic EBV:
1- lack of immune recognition
2- Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
3- EBV induced proliferating cells
4- Growth alterations with the right levels of expression of cell targets and viral and cellular mRNA
● Molecular plus serological methods (anti VCA IgG )combination may allow early detection of EBV
● EBV integrate normal B-cell program leading to proliferation and transformation of these cells.
● pathogenesis of PTLD in EBV-negative patients is :
* CMV or another viral infection
* prolonged immunosuppression
* allograft-driven persistent antigenic triggering, hit-and-run hypothesis
● T-cell subtype PTLD (usually EBV-ve)
● Classification of PTLD:
* plasmacytic hyperplasia
* Polymorphic PTLD.
* Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
* classic Hodgkin’s lymphoma-like PTLD.
● > 90% of patients with polymorphic PTLD and Hodgkin’s lymphoma–like PTLD associated EBV infection and in only 50% of monomorphic PTLD
● PTLD-EBV+ve are mostly non-germinal center B-cell type, in contrary to EBV-ve that are more likely to be “germinal center B-cell type
● PTLD manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
● An allograft dysfunction may due to graft involvement.
● An associated high EBV viral load by PCR should make one suspect PTLD
● The most common locations of PTLD involvement are :
Lymph nodes, liver, lung, kidney, bone marrow, gastrointestinal tract (GIT), spleen, central nervous system (CNS), tonsils and salivary glands .
● Differential diagnosis:
▪︎Streptococcal infections
▪︎Infectious mononucleosis
● The risk of EBV+ve PTLD is related to three factors:
* Type of transplant organ
* Time until diagnosis of post-transplant PTLD
* EBV serological status of both recipient and donor before transplant
● pitfalls in preemptive strategy monitoring:
☆ Cut-off values are not clear
☆ Sources of samples are not universal
☆ Absence of standard points of time to perform the monitoring.
● preemptive strategies to limit the risk of PTLD development
• RI
• rituximab therapy
• adoptive transfer of EBV-specified T cells. ● Prophylaxis:
☆ EBV sero-status of both donor and recipient should be recognized before donor selection.
☆ EBV-negative TR is better receiving grafts from EBV-negative donors whenever available.
☆ A fine-tuning the immunosuppressive burden to as low as clinically possible.
☆ Preemptive/prophylactic antiviral therapy in potentially high-risk groups should be also considered.
Maintenance of high titers anti-EBV antibodies via IVIG/CytoGam administration is also recommended.
● TREATMENT OF PTLD
● RI :
☆ The mainstay of PTLD management
☆ RI can reverse 20%-80% of patients with PTLD
☆ RI plan includes
▪︎50% reduction of CNI
▪︎withdrawal antimetabolites
▪︎exception of glucocorticoids
▪︎withdrawal of all immunosuppressive medications in critically ill cases should be considered.
☆ Monitoring allograft function during RI to recognize early rejection.
☆ EBV negative are less responsive to RI Compared to EBV positive
☆ lack of response to RI observed in
▪︎Old aged patients (>50 years)
▪︎Bulky lesions (> 7 cm)
▪︎Advanced stages ( stage III/IV)
● Rtx treatment :
☆ A standard therapeutic agent in three of PTLD types :
(1) Nondestructive PTLD
(2) Polymorphic PTLD
(3) Monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
● Chemotherapy Indications include: ▪︎Burkitt’s lymphoma
▪︎Hodgkin’s lymphoma
▪︎Peripheral T-cell lymphoma
▪︎Primary CNS lymphoma
▪︎Uncommon lymphomas
▪︎B-cell PTLD unresponsive to Rtx and RI
☆ Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy.
☆ Overall response rate 88%
● Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown
to manage PTLD in HSCT patients that is primarily originating from donor cells.
● The major risk is GVHD development
● Expanded EBV-specific CTLs have been an effective therapeutic
● Outpatient care
☆ Weekly monitoring of EBV viral titers in higher risk patients.
☆ Monthly monitoring initially followed by three monthly monitoring for low risk groups
☆ load drop denotes a response to therapy
☆ persistently high or continuous rise in viral load indicates disease development or progression
☆ Serial physical examination
☆ keep balance between PTLD management and avoidance of allograft acute rejection
☆ Therapeutic options should be tailored as per multidisciplinary team discussion.
● Future strategies
(1) Bruton’s tyrosine kinase (BTK) inhibition
(Ibrutinib): Virtually active in GVHD and allograft rejection remarkably active in activated B cells (ABC) type diffuse large B cell lymphoma (DLBCL)
(2) Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)] SRL and everolimus
(3) Proteasome inhibition (Bortezomib)
(4) Radioimmunotherapy
(5) Checkpoint inhibitors
(6) Anti-CD30 therapy (Brentuximab vedotin) Expression of CD30 in 85% of all PTLD subtyps
● Prognosis
☆ 79 % of the PTLD-1 patients had achieved a complete remission with median survival of approximately 6.6 years
☆ IPI is a prognostic scoring system that includes the following:
* Patient’s age
* performance attitude
* current stage
* lactate dehydrogenase (LDH)
* number of extra-nodal locations.
☆ poor prognostic
▪︎Monoclonality
▪︎negative EBV serology
▪︎primary CNS involvement
▪︎tumor originated from T-cell, ▪︎performance status ≥ 2
▪︎chemotherapy-based therapy (plus RI)
▪︎multiple involved locations
● Recommendations to limit the PTLD recurrence :
(1) Time to retransplant: two years should elapse after successful PTLD management
(2) positive Epstein–Barr nuclear antigen IgG in TR before retransplantation.
(3) Low/absent EBV viral load at the time of retransplantation.
(4) Close monitoring of TRs with high EBV viral load
(5) Long-term prophylactic antiviral therapy as Ganciclovir
(6) Exposure to immunosuppression in
retransplantation after PTLD cure remains controversial
(7) The T cell-depleting agents should be excluded from the induction strategies with priority to IL-2 receptor antagonists (8) Rituximab in induction therapy
(9) Maintenance immunosuppression: The lowest dosages Of maintenance therapy
(10) mTOR inhibitors: their clinical application in human still warrant the proper evidence
● Graft PTLD usually has good prognostic outcome and graft nephrectomy is almost curative
● Level : 5
Thank you
Please summarise this article
Introduction
PTLD are one of the most important malignancies after SOT and HSCT due to uncontrolled B cell proliferation
EBV can infect B cells by either post-transplant viral reactivation or primary EBV infection (donor organ or environmental exposure)
Most cases of PTLD (> 85%) are usually observed in the first post-transplant year
PTLD T-cell is less common and mostly EBV-negative
The magnitude of cumulative immunosuppressive burden has a crucial role in PTLD evolution
PTLD may manifest clinically as localized lesion or as systemic disease
The aim of the study is to discuss the prevalence, clinical clues, prophylactic measures, and the current and future therapeutic strategies of this devastating disorder
Risk factors
According of type of immunosuppression:
1. SOT: the incidence of PTLD is 0.8%2.5% in KTR, ≤ 20% in multi-organ and intestinal TRs. The amount of lymphatic tissue the degree of immunosuppression are the key factors
2. Allogenic HSCT: the incidence of PTLD is primarily related to the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant
3. Previous exposure to the immunosuppressive load during treatment of the primary renal disease
4. Oncogenic EBV
Pathogenesis
Role of EBV:
EBV-positive TRs: immunosuppressive-induced decline in the T-cell immunesurveillance. EBV can integrate into normal B-cell program leading to proliferation and transformation of these cells
PTLD in EBV-negative patients: pathogenesis is not clear (CMV or another viral infection, prolonged immunosuppression, allograft-driven persistent antigenic triggering, hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes)
EBV-positive vs EBV-negative PTLD:
EBV-positive PTLD (Fewer genomic abnormalities, mostly B-cell proliferative lesions, non-germinal center B-cell, more common (first peak), less risk compared to seronegative TR, and almost all cases of HSCT (100%) are EBV positive)
EBV-negative PTLD (share many genomic/ transcriptmic features with diffuse large B-cell lymphoma in immunocompetent patients, mostly T-cell proliferative lesions, germinal center B-cell type, less common (second peak), seronegative SOT pediatric TR are more vulnerable to develop PTLD with increased estimated risk of 10-75, and in SOT, both EBV positive and negative are present)
Classification
WHO 2017 histopathological classification:
1. Three nondestructive PTLD (plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD). Almost all associated with EBV
2. Polymorphic PTLD. EBV in > 90% of patients.
3. Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). EBV in only 50%
4. Classic Hodgkin’s lymphoma-like PTLD. EBV in > 90% of patients
Clinical presentation
Vary from symptomless lesions to fulminating disease with multi-organ failure. PTLD May present as a local or disseminated disease. Symptoms include: Pyrexia (57%), weight loss (9%), neurological manifestations (13%), nodal lesions (38%), gastrointestinal manifestations (27%), pulmonary manifestations (15%) and infectious mononucleosis-like syndrome that could be fulminant (19%)
The most common locations of PTLD involvement are: Lymph nodes, liver, lung, kidney, bone marrow, GIT, spleen, CNS, tonsils and salivary glands
EBV monitoring for preemptive therapy
Should be confined to the high-risk group (viral load via PCR)
Prophylactic antiviral
EBV-negative TR is better receiving grafts from EBV-negative donors (do EBV serology)
Should be considered in potentially high-risk groups (negative recipient, positive donor)
Monitoring of EBV viral load and considering preemptive RI with rising titers, with close monitoring of allograft function
Treatment
RI
The cornerstone of management is to ameliorate the immunosuppressive burden
RI can reverse 20%-80% of patients with PTLD
50% reduction of CNI, in addition to withdrawal of the antimetabolites (azathioprine or MMF)
In critically ill patients, withdrawal of all immunosuppressive medications should be considered with the exception of glucocorticoids
Monitoring allograft function (acute rejection in 37% in a prospective trial)
EBV negative cases are less responsive to RI
No response to RI in old aged patients (> 50 years), bulky lesions (> 7 cm), and advanced stages of the disease (Ann Arbor stage III/IV)[60]
Rituximab (Rtx)
A potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen, leading to B cell depletion
Approved for three types of the WHO classification: nondestructive PTLD, Polymorphic PTLD, and monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI
Response to Rtx monotherapy (375 mg/m2 body-surface area, weekly for 4 wk, single agent) in addition to RI, approached 44%-79% with a complete remission in 20%-55% of cases. Adding 4 doses of Rtx, can raise the rate of complete remission to 34%-60.5%
Chemotherapy
Indications of Immunochemotherapy include Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
Sequential therapeutic approach: Rtx + CHOP (R-CHOP) given over 3 wk for 4 cycles with G-CSF support in cases with no complete response to isolated Rtx therapy. Overall response rate approached 88%, with 70% of cases with any response achieved a complete response at the end of therapeutic program
Adoptive immunotherapy
Infusion of donor lymphocytes or EBV-specific cytotoxic lymphocytes (CTLs) to abort the EBV-driven proliferation of B cells in EBV-associated PTLD (in HSCT)
The major risk is GVHD
Recent approaches: adoptive transfer of “pamidronate-expanded Vγ9Vδ2 T cells” and Tac-resistant, engineered CTLs
Outpatient care
To identify patients at risk and monitoring response of therapy:
5. High risk: monitor weekly. Low risk: monthly initially followed by three monthly
6. Viral load drop indicates therapy response; persistent high or increase load denotes disease development or progression
7. Serial physical examination, radiology and monitoring allograft function
8. Optimize balance between PTLD management and avoidance of allograft rejection
9. Therapeutic options through MDT discussion
10. The initial therapeutic step is RI or cessation of immunosuppression and further therapeutic options accordingly
Future therapies
1. Bruton’s tyrosine kinase (BTK) inhibition (Ibrutinib)
2. Inhibition of PI3K and mTORi [Idelalisib (PI3K inhibitor)]
3. Proteasome inhibition (Bortezomib)
4. Radioimmunotherapy (90Yibritumomab, tiuxetan)
5. Checkpoint inhibitors (Pembrolizumab, nivolumab)
6. Anti-CD30 therapy (Brentuximab vedotin)
Prognosis
70% of the PTLD-1 patients: complete remission (median survival of 6.6 years)
IPI prognostic scoring system includes the following: Patient’s age, performance attitude, current stage, LDH, and number of extra-nodal locations
Poor prognostic criteria include: Monoclonality, negative EBV serology, primary CNS involvement, tumor originated from T-cell, performance status ≥ 2, chemotherapy-based therapy (plus RI), and, multiple involved locations
Re-transplantation and PTLD recurrence
Wait for at least one year after complete remission
To reduce PTLD recurrence:
1. Time to retransplant ( 2 years after successful PTLD treatment)
2. EBV: TR should experience Epstein–Barr nuclear antigen IgG positivity before retransplantation. Low/absent EBV viral load is recommended at the time of retransplantation. Close monitoring of TRs with persistently high EBV viral load is advised. Long-term prophylactic antiviral therapy with serial estimation of EBV viral load is crucial to limit the incidence of PTLD recurrence (Ganciclovir)
3. Immunosuppression: PTLD is disease of post-transplant immunosuppression. The fundamental trigger for PTLD evolution is the magnitude of immunosuppressive intensity
4. Induction therapy: T cell-depleting agents should be excluded. ATG induction significantly triggers the risk of lymphoma evolution
5. Maintenance immunosuppression: avoid the intense state of immunosuppression. Triple therapy (CNI, MMF and steroids) use is very common in the current post-transplant maintenance therapy, therefore, the lowest safe dosages monitored by target trough levels should be considered. MMF can be included safely in the immunosuppressive protocols with no more added risk. The role of mTOR inhibitors in PTLD development remains debatable. These agents may inhibit the development of lymphomas in vitro, but their clinical application in human still warrant the proper evidence. Graft PTLD usually has a good prognostic outcome; furthermore, graft nephrectomy is almost curative.
6. Monoclonal gammopathy: complete resolution of monoclonal gammopathy indicates complete remission
7. Origin of PTLD (donor vs recipient): guide using cytotoxic T cell infusions in PTLD management. The outcome is better in TRs with “donor” lymphomas
Conclusion
PTLD is a disease of immunosuppression
Better management relies on understanding the pathophysiology of PTLD and the role of EBV
Although PTLD recurrence is rare, it requires careful plan of strategies
Molecular genomic technology has a great impact on diagnostis and therapeutic strategies with improvement of recipient’s outcome
Close contact with hemato-oncology team is fundamental
What is the level of evidence provided by this article?
Level V (narrative review)
Thank you
1- SUMMARY OF REVIEW;.
–INTRODUCTION;.
Post-transplant lymphoproliferative disorders (PTLD) are lymphoid and/or plasmacytic proliferations that occur as a result of immunosuppression in the setting of solid organ or allogeneic hematopoietic cell transplantation.
These conditions lie along a continuum of disease and are categorized by the World Health Organization PTLD classification system .
PTLDs are among the most serious complications of transplantation.
-EPIDEMIOLOGY;.
-INCIDENCE
–PTLD is the most common malignancy complicating solid organ transplantation (excluding nonmelanoma skin cancer and in situ cervical cancer), accounting for approximately 20 percent of all cancers.
In contrast, PTLD accounts for a minority of secondary cancers following allogeneic hematopoietic cell transplantation (HCT).
-RISK FACTORS
-The principal risk factors underlying the development of PTLD are the degree of T cell immunosuppression and the Epstein-Barr virus (EBV) serologic status of the recipient. Additional risk factors include time post-transplant, recipient age, and ethnicity
-PATHOGENESIS
EBV-positive disease — In most affected patients, PTLD is an Epstein-Barr virus (EBV)-positive B cell proliferation occurring in the setting of immunosuppression and decreased T cell immune surveillance.
–PATHOLOGIC FEATURES
The diagnosis of PTLD is based upon the evaluation of histologic, immunophenotypic, and genetic studies.
The World Health Organization classification of tumors of the hematopoietic and lymphoid tissues uses morphologic, immunophenotypic, genetic, and clinical features to define four main categories of PTLD:
●Plasmacytic hyperplasia and infectious mononucleosis-like PTLD
●Florid follicular hyperplasia
●Polymorphic PTLD
●Monomorphic PTLD
●Classic Hodgkin lymphoma-like PTLD
-DIAGNOSIS
An accurate diagnosis of PTLD requires a high index of suspicion. Radiologic evidence of a mass, or elevated serum markers (such as increased lactate dehydrogenase [LDH] levels) are suggestive of PTLD;
positive positron emission tomography (PET) scanning also favors the diagnosis.
A tissue biopsy, preferably an excisional biopsy, with review by an expert hematopathologist, is required to ensure an accurate diagnosis.
Diagnosis of central nervous system or cardiac lymphoma is particularly difficult
TREATMENT
Reduction in immunosuppression
RIS should be incorporated into the initial management of all patients with PTLD unless concerns regarding graft rejection or graft-versus-host disease make this approach unfeasible.
Rituximab therapy
Rituximab (Rtx) is a potent chimeric anti-CD20 monoclonal antibody that binds CD-20 antigen, leading to B cell depletion via several mechanisms e.g., phagocytosis (macrophages), complement mediated cytotoxicity, and through natural killer cells (antibody-dependent cell-mediated toxicity).
Chemotherapy Indications of Immunochemotherapy include:
Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI
Adoptive immunotherapy
Infusion of donor lymphocytes, to achieve adoptive immunotherapy, has been shown to manage PTLD in HSCT patients that is primarily originating from donor cells
PROGNOSIS
Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care.
70% of the PTLD patients had achieved a complete remission with median survival of approximately 6.6 years.
2-What is the level of evidence provided by this article?
This article is a narrative review (level of evidence is V).
Thank you
Introduction
PLTD is a common malignancy post SOT and HSCT,it occurs due to uncontrolled growth of B cell.EBV usually infect B cells either primarily or by reactivation ,it is noticed in the first year post transplant. PTLD of T Cell origin is less common and is EBV negative.
The immunosuppressive load has a direct effect on PLTD occurrence.
In SOT lymphoma accounts for 21% of all malignancies.
PTLD could be localised or systemic disease.
High index of suspicion is needed for the diagnosis ,with histopathology and EBV DNA , RNA or protein material.
The main treatment is RI which carries graft loss risk , surgical clearance, anti-viral agents, local radiotherapy, IVIG, chemotherapeutic agents, monoclonal antibodies and cytotoxic T lymphocytes.
PTLD epidemiology
PTLD incidence is 3.2% in HSCT recipients and it’s recognition has increased due to advanced technology, increase of the donor and recipient age and new immunosuppressive regimens as well as haploidentical HSCT.
Risk factors
-SOT: Multiorgan and intestinal transplant has the highest incidence while kidney transplant has the lowest.
-Allogenic HSCT: HLA degree of matching and the T cell depleting agents affects the risk, where the more the matching the lower is the risk and the risk was low with broad lymphocyte depleting agents.
EBV negative recipients are more susceptible to develop PTLD, early occurrence is with EBV positive recipients while late occurrence is associated with EBV negative cases.
-Immunosuppressive exposure in primary renal disease therapy before transplantation increase immunosuppression burden.
-Oncogenic EBV causes growth transformation, initiation of oncogenes, bypass immune control, cell targets, viral and cellular mRNA expression.
Molecular and serological methods together early detection of EBV
Pathogenesis
50% of PTLD are EBV negative with unclear specific pathogensis.
In EBV positive cases ,defective T cell surveillance through immunosuppressives is implicated.
EBV-positive vs EBV-negative PTLD
There is no clear difference but some differences can be noted
EBV negative: has features similar to diffuse large B-cell lymphoma in immunocompetent patients, mostly T cell lesion of germinal B cell center type ,less prevalent , common with seronegative SOT in pediatrics.
EBV positive :is more common , of B cell origin of non germinal center type ,prevalent with HSCT
Early versus Late onset PTLD
Early onset represent the majority of PTLD cases ,it is usually associated with EBV positive cases, with graft involvement and is non destructive , donor derived ,less common to be Monomorphic subtypes and bortezomib can be useful after allogeneic HSC also Induction therapy has a role.
Late onset is less prevalent ,mostly EBV negative with extra nodal involvement more than graft affection, with high incidence of late onset Hodgkin’s lymphoma after allogeneic HSCT and cumulative immunosuppressives have an important role.
WHO 2017 classified PTLD into 3 non destructive PTLD , Polymorphic ,Monomorphic , classic Hodgkin’s lymphoma-like PTLD.
EBV-encoded RNA (EBER) in-situ hybridization evaluation is mandatory for PTLD diagnosis .
Clinical picture varies from being asymptomatic to multiorgan failure
Time to PTLD for different transplanted organs
It is longest for the heart recipients and shortest for the lung and heart/lung transplantation in pediatric . Early PTLD is commonly diffuse large B-cell while late PTLD is usually Burkitt’s
lymphoma and Hodgkin’s disease
EBV monitoring for preemptive therapy
It has limitations and suffer lack of standardised recommendations
Type of transplant organ, time elapsed till post-transplant PTLD and EBV serological status before transplant are 3 factors that affect EBV positive PTLD occurrence.
High EBV load increases PTLD risk. Cell-free plasma EBV DNA is a good marker of EBV activity
Prophylaxis
Donor and recipient viral status has to be screened before selection where EBV negative donors have to be selected for EBV negative recipients as much as applicable .
Immunosuppression load has to be decreased as much as possible to balance immunosuppression and rejection possibility .
RI is a strategy when ever viral reactivation is recognised along with vaccination for high risk cases with maintenance of high titer of anti-EBV antibodies as well as monitoring viral load level.
PTLD treatment
-RI
It can be effective in 20-80% of PTLD cases. It includes decrease of 50% of CNI doses and stopping antimetabolites meanwhile for severe cases all immunosuppressives need to be suspended except glucocorticoids.
Tracing allograft function is crucial .EBV negative PTLD is less likely to respond to RI.
-Rituximab therapy
It is used as standardised treatment for non destructive PTLD, Polymorphic PTLD and Monomorphic diffuse large B-cell lymphoma-like PTLD unresponsive to RI
Rituximab monotherapy with RI can achieve 44%-79% complete remission detected in 20%-55% of cases also adding 4 doses of Rituximab can increase remission rate.
Comparing those patients with patients receiving RCHOP ,the low risk candidates had nearly the same over all survival but better disease free survival at 3 years .
-Chemotherapy
Is used for Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and B-cell PTLD unresponsive to Rituximab and RI.
Chemotherapy treated PTLD cases whom experienced poor outcome was due to therapy related mortality meanwhile mortality was reduced with efficient supportive treatment and GCSF usage .
RCHOP therapy with GCSF had acceptable outcomes in PTLD 1 trial.
Adoptive immunotherapy
Managing PTLD of donor’s origin by the donors lymphocytes are applied in HSCT opposite to PTLD occurring in SOT . EBV specific cytotoxic T lymphocytes can be used but GVHD is the main side effect.
Expanded EBV-specific CTLs were used in treatment of recipient-derived PTLD and donor-derived PTLD.
Outpatient care
– monitor of EBV viral load for high risk cases weekly and for low risk monthly monitor at first then every 3 months
–monitor response to therapy through viral load tracing
– Serial physical exam, radiological evaluation and monitoring allograft function
-Balancing therapeutic modalities and rejection risk is mandatory
-MDT is crucial to create an individualized therapy
-RI is the first treatment option
Future strategies under trial
· Bruton’s tyrosine kinase (BTK) inhibition is estimated to have a therapeutic role in GVHD and allograft rejection,DLBCL.
· Inhibition of PI3K and mTORi in PTLD
· Bortezomib in the early PTLD post allogeneic HSCT.
· Radioimmunotherapy under trial
· Checkpoints inhibitors are adviced only in trials due to the accompanied side effects
· Anti-CD30 therapy was used in case reports
Prognosis
Improved due to using lymphoma specific strategies and advanced supportive care. 70% of PTLD cases had complete remission with median survival of 6.6 years.
IPI is the scoring system currently applied.
Re-transplantation and PTLD recurrence
1-2 year of disease free survival after PTLD therapy is mandatory before re-transplantation.
Anti-EBV partially acquired immunity was hypothesised as a possible protective
mechanism.
To reduce recurrence risk it is recommended
o 2 years of time interval after PTLD complete remission .
o EBV : Epstein–Barr nuclear antigen IgG positivity indicates immunity before re transplantation, low EBV viral load before pretransplant, monitoring transplant with high viral load and antiviral therapy.
o Immunosuppression burden is a major risk for PTLD .
o Induction therapy; need to include IL2R antagonist instead of ATG, Rituximab can be used as desensitisation protocol
o Maintenance therapy : the lowest targeted trough levels of the triple therapy is recommended; MMF is considered safe while m TORI is controversial, and for graft PTLD , graft nephrectomy is curative.
o Monoclonal gammopathy indicates complete remission if completely resolved .
o Donor PTLD vs recipient PTLD: tumor source detection is essential for therapeutic protocols.
Conclusion
Immunosuppression is the main risk for PTLD . Discovering the pathogenesis and EBV role improved the therapeutic options thereby the prognosis.
-Level of evidence is V
Thank you
Introduction:
Risk factors:
Pathogenesis:
WHO classification of PTLD:
Prophylaxis measures to reduce PTLD incidence:
Treatment of PTLD:
Follow-up of EBV viral load:
Future treatment strategies:
Recommendations to reduce risk of PTLD recurrence:
level of evidence is 4.
Thank you, It is level 5, not level 4.
Summarise.
Introduction
PTLD is a common malignancy following solid organ and hematopoietic stem cell transplantation.
Majority of the cases it is caused by uncontrolled B cell proliferation due to compromised immunosurveillance. However in rare cases it can be caused by T cell proliferation and in this cases it is EBV negative.
In over 80% of the cases it occurs in the first year post-transplantation.
The B cell are infected by EBV either through primary infection from the donated organ or from post-transplant reactivation.
Risk factor depends with the organ donated. Solid organ transplant highest risk associated with graft with highest lymphatic tissue and degree of immunosuppression. While hematopoietic stem cell transplant depends with the HLA matching and use of T cell depleting agents prior to transplantation.
Pathogenesis:
EBV seropositive disease: the virus integrates itself into the B cell leading to proliferation and transformation. The B cells proliferate due to lack of T cell mediated immune surveillance.
EBV negative disease: pathogenesis less clear but could be due to other viruses like CMV.
Classification
WHO classifies PTLD into four categories:
For non-destructive, polymorphic >90% and classic Hodgkins lymphoma like PTLD are associated with EBV, while monomorphic only 50% are associated.
Clinical presentation
Ranges from asymptomatic to constitutional symptoms including weight loss, pyrexia to multi-systemic disease that may involve the cns, git, lungs and spleen.
Treatment
First line is reduced immunosuppression which induces remission in 20-80% of cases. The CNIs are reduced by 50% and the antimetabolites are withdrawn.
Steroids should be maintained.
There is a role of withdrawing all immunosuppressive and maintaining only steroids in acute illness.
Should have graft monitoring to detect any early signs of rejection.
EBV negative PTLD is less responsive to reduced immunosuppression.
Rituximab indicated in nondestructive, polymorphic and monomorphic PTLD unresponsive to reduced immunosuppression.
4 weekly doses followed by additional 4 doses have a complete remission rate of 34-60%.
Chemotherapy is indicated in unresponsive to rituximab and reduced immunosuppression.
CD20 positive PTLD should combine rituximab with chemotherapy.
Monitoring to maintain a balance between the reduced immunosuppressive and the cytotoxic and immunosuppressive effect of the chemotherapeutic agents.
Adoptive immunotherapy has a role in hematopoietic stem cell transplantation whereby there is infusion of donor lymphocytes to induce a EBV specific cellular immune response.
Prognosis
Improved prognosis with better lymphoma specific protocol and supportive care.
Retransplantation
There is a role of retransplantation after 1-2 years free of PTLD disease.
Induction therapy should ideally be free of T cell depleting agents hence IL2 receptor antagonists preferred. Rituximab may be used for induction in patients at high risk.
Maintenance therapy should be triple therapy with the lowest safe doses possible.
There is a role of giving prophylactic antivirals- ganciclovir in patients with high viral loads. Ideally should have low/absent viral loads.
MTOR inhibitors use debatable.
Level of evidence
Level V its a narrative review.
Thank you. Well done
Introduction:
Epidemiology of PTLD:
Risk factors
A- SOT: the incidence is lowest in KTR 0.8%- 2.5% , and highest among multi-organ and intestinal TRs ≤ 20%.
B- Allogenic HSCT:
1- HSCT : use of T cell depletion agent
2- Umbilical-cord transplantation RR 4%-5%
3- Transplant from unrelated donors RR 4%-10%
4- Transplant from matched related donors RR 1%-3%
C- Immunosuppressive load.
-The type of induction therapy has a role in the early developed PTLD.
-Late PTLD is largely determined by cumulative immunosuppressive burden.
D- Oncogenic EBV: it may alter cell growth via several mechanisms:
i. Lack of immune recognition
ii. Induction of the potent oncogenes via environmental factors.
iii. EBV induced proliferating cells as well as EBV variant/HLA types may permit these proteins to by-pass immune control and go unrecognized.
iv. Growth alterations.
Pathogenesis
Role of EBV:
· CMV or another viral infection
· Prolonged IS
· Allograft-driven persistent antigenic triggering,
· Hit-and-run hypothesis i.e., EBV commences the pathogenic process leading to the development of PTLD and then vanishes.
Classification:
A- Time of occurrence: Early and late onset PTLD.
B- Histopathological classification according to WHO 2017 Classification, as follows:
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD. EBV infection seen in almost all TRs
(2)Polymorphic PTLD. EBV seen in in > 90% of patients
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types). EBV seen in only 50%.
(4) classic Hodgkin’s lymphoma-like PTLD.
C- Gene-expression profile and immunohistochemical staining for DLBCL.
Clinical presentation:
– Clinically, can be localized lesion or as systemic disease.
– It manifestations vary from symptomless lesions to fulminating disease with multi-organ failure.
– In either form, it can behave aggressively in a rapidly progressive manner.
– Clinical manifestations include:
– Nonspecific symptoms: asthenia Pyrexia, weight loss and infectious mononucleosis-like syndrome.
– Organ involvement : neurological manifestations, nodal lesions, gastrointestinal, pulmonary manifestations.
– Graft involvement: graft dysfunction.
Time to PTLD for different transplanted organs:
-Longest for the heart recipients
-Shortest for the lung and heart/lung in pediatric TR.
-Early PTLD is often of B-cell lymphoma histology; whereas Burkitt’s lymphoma and Hodgkin’s disease are late event.
EBV monitoring for preemptive therapy:
– Viral load via PCR of peripheral blood EBV DNA is mandated to monitor preemptive PTLD therapy.
-Challenges: no cut-off values, no universal sources of samples, and time to perform the monitoring is not standard.
– Compared to the reliability of EBV DNA via peripheral-blood mononuclear cells, the “cell-free plasma EBV DNA” has been reported as a better marker of EBV activity.
Prophylactic measures:
– EBV-negative TR is better receiving grafts from EBV-negative donors whenever possible.
– Fine-tuning the immunosuppressive burden to as low as clinically possible.
– RIS when reactivation of other viruses ( CMV, BK) identified.
– High risk group: preemptive/prophylactic antiviral therapy via IVIG/CytoGam.
– Close monitoring of EBV viral load and allograft function.
TREATMENT OF PTLD
RI
– It is the mainstay of therapy to restore immune surveillance.
– the EBV negative cases are less responsive to R.
– RI can reverse 20%-80% of patients with PTLD.
– RI includes: CNI reduction by 50% , along with withdrawal of the antimetabolites and maintain glucocorticoids
-In critically ill cases should consider withdrawal of all IS medications except glucocorticoids.
– Monitoring allograft function for rejection.
Rituximab therapy
-It binds CD-20 antigen, leading to B cell depletion via several mechanisms.
-CD20 +ve B-cell PTLD approached 75% of TR.
– Used in addition to RI.
– The overall response to Rtx monotherapy approached 44%-79%.
Chemotherapy
– Indications include: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma and other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
– Rtx should be included in all CD-20 +ve cells.
– TRM greatly improved after the advent of supportive care G-CSF and PJP prophylactic.
Adoptive immunotherapy
-Robust EBV-specific immune response is induced by EBV-specific cytotoxic lymphocytes(CTLs)
-The major risk is GVHD development.
Investigational agents that are currently under trials.
Outpatient care:
– Weekly monitoring of EBV viral titers in higher risk patients.
– Monthly monitoring initially followed by three monthly monitoring for low risk groups.
– Persistently high or continuous rise in viral load indicates disease development or progression.
– Serial physical examination, radiology testing and monitoring allograft function
Therapeutic options is tailored as per MDT discussion.
Prognosis
– 70% of the PTLD-1 patients had achieved a CR with median survival of approximately 6.6 years.
– Multiple prognostic factors present.
Re-transplantation and PTLD recurrence;
– PTLD recurrence has been rarely reported after re-transplantation.
– one-year disease free survival is necessary after control of PTLD before re-transplantation
– The following recommendations to limit the possibility of recurrence:
(1) wait time to re-transplant: 12 to 24 months after CR.
(2) EBV: TRs should experience EBV nuclear antigen IgG positivity, Low/absent EBV viral load at the time of re-Tx, Close
monitoring of TRs with persistently high EBV viral load is advised. Long-term prophylactic antiviral therapy Ganciclovir
(3) Role of immunosuppression: the induction with IL-2 receptor antagonists appeared to have the first priority, include RTx in induction, avoid intense state of IS, use the lowest safe dosages
Level of evidence: 5 narrative review.
Thank you. Well done. What do you mean by TRM?
Please explain the abbreviations.
My apologies
TRM ;therapy related mortality
Post-transplantation lymphoproliferative disorders:
Current concepts and future therapeutic approaches
INTRODUCTION
▪︎ Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplant (HSCT), and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance.
▪︎B cells may get infected by Epstein-Barr virus (EBV) either by:
(1) Post-transplant viral reactivation
(2) Primary EBV infection,
▪︎The majority of PTLD cases (> 85%) are usually observed in the first post-transplant year.
▪︎ PTLD as a result of T-cell proliferation is seen much less commonly and is mostly EBV-negative.
▪︎PTLD may manifest either as localized lesion or as systemic disease.
▪︎Histopathology is crucial for PTLD diagnosis, in addition to a clear evidence of EBV DNA, RNA, or protein material.
◇ Risk factors of PTLD:
(1) In SOT: the amount of lymphatic tissue in the allograft and the degree of immunosuppression.
(2) In allogenic HSCT: the degree of HLA matching with consequent introduction of T-cell depleting agents prior to transplant.
(3) The presence of previous exposure to the immunosuppressive load during treatment of the primary renal disease in the native kidney
(4) Oncogenic EBV.
EBV may alter cell growth via several mechanisms:
(1) May induce highly regulated growth transformation with expression of all of its growth inducing proteins.
(2) Induction of the potent oncogenes e.g., LMP1 and LMP2 via environmental factors.
(3) EBV induced proliferating cells as well as EBV variant/HLA types combination may permit these proteins to by-pass immune control and go unrecognized.
(4) Growth alterations
◇ Pathogenesis
Role of EBV: 50% PTLD in SOT are not accompanied by EBV infection.
For EBV-positive TRs, the development of PTLD can be attributed to IS -induced decline in the T-cell immunesurveillance.
▪︎ EBV can integrate into normal B-cell program leading to proliferation
and transformation of these cells.
▪︎ Pathogenesis of PTLD in EBV-negative patients is less evident.
◇ Classification:
A. Early and late onset PTLD
B. Depending mainly on histopathological classification
(1) Three nondestructive PTLD: plasmacytic hyperplasia, florid follicular hyperplasia, and infectious mononucleosis-like PTLD.
(2) Polymorphic PTLD.
(3) Monomorphic PTLD (B-cell, T-cell, or natural killer-cell types).
(4) classic Hodgkin’s lymphoma-like PTLD.
C. An associated EBV infection could be currently seen in almost all TRs with nondestructive PTLD.
◇ Clinical presentation
1. Symptomless lesions
2. Fulminating disease with multi-organ failures
Salient features: PTLD may present as a local or disseminated disease.
▪︎Clinical manifestations include: Pyrexia, weight loss , neurologica manifestations, nodal lesions, GIT manifestations, pulmonary manifestations and infectious mononucleosis-like syndrome that could be fulminant.
▪︎An allograft dysfunction may.
▪︎An associated high EBV viral load by PCR should make one suspect PTLD.
▪︎The most common locations of
PTLD involvement are as follows: Lymph nodes, liver, lung, kidney, bone
marrow, GIT, spleen, CNS, tonsils & salivary glands.
◇ Differential diagnosis:
Any high-risk TR who presents with pyrexia, pharyngitis and cervical lymphadenopathy.
◇ TREATMENT OF PTLD
▪︎ Reduction of immunosuppression is the cornerstone of PTLD management.
▪︎ Rituximab therapy is indicated in nondestructive PTLD, polymorphic PTLD, and, monomorphic diffuse large B-cell lymphoma-like PTLD not responding to RI.
▪︎ Chemotherapy is indicated for: Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, and B-cell PTLD unresponsive to Rtx/RI with variable results.
▪︎ However, “risk-stratified sequential” therapeutic approach seems to be promising. Other modalities may include adoptive immunotherapy and outpatient care.
Prognosis
▪︎ Outcome of PTLD patients has greatly improved owing to the advent of new lymphoma-specific protocols as well as to the better supportive care.
◇ CONCLUSION
▪︎ PTLD is a disease IS.
▪︎Recent progress in understanding of
the underlying pathophysiology of PTLD as well as the role of EBV has led to a bettermanagement.
▪︎PTLD recurrence has been rarely reported after re-transplantation.
▪︎ Close liaison with hemato-oncology team of key importance since the lessons learnt from lymphoma management in the general population can be applied to the management
of patients who develop PTLD.
◇ Level of evidence: V
Thank you. Well done
Thanks prof Ahmed
Introduction: Post-transplant lymphoproliferative disorders (PTLD) are among the important malignant complications following solid organ (SOT) and hematopoietic stem-cell transplantation (HSCT). There is uncontrolled B proliferation caused by lack of immune-surveillance. Around 85% of cases are seen in the first year and mostly EBV-positive PTLD of B cell origin. T cell PTLD is much less common compared to B cell PLTD.
Epidemiology: Incidence is 0.8 to 2.5% in kidney transplant, 0.5-0.5% pancreatic,1 to 5% liver, 2 t0 8% heart, 3 to 10 % lung and < 20% intestinal TRs
Risk factors:
1.Solid Organ Transplantation (SOT)
2.Allogenic HSCT
3.Previous exposure to immune-suppressive drugs in the native kidney
4.Oncogenic EBV
Pathogenesis:
1.EBV-positive PTLD: EBV infection results in uncontrolled B cell proliferation
-B cell transformation
2.EBV-negative PTLD: may CMV or other viruses, immune-suppression
-chronic antigenic stimulation
3.WHO classification: Early lesions e.g., Infectious mononucleosis, polymorphic, monomorphic, and classical lymphoma PLTD
Clinical features: may be non-specific, mostly extra-nodal disease, and systemic involvements including CNS, lung and the gut. PTLD may present with allograft dysfunction.
Prophylaxis: the best is EBV-negative D t to EBV-negative R, EBV viral load and preemptive/prophylactic antiviral for high-risk groups
Treatment of PLTD:
1.Reduction of immune-suppression; stop or reduce CNIs/anti-metabolites
2.Rituximab: in low-risk group the response rate may be 44 to79%
3.Chemotherapy: indicated for those who fail to respond to RTX or frank lymphoma
-Many regimens e.g., CHOP
4.Adoptive immunotherapy: this is based on removing cytotoxic lymphocytes
-After genetic modification then give them back to the patient for immune-response
-It also uses donor lymphocytes infusion which may result in GVHD
Prognosis: early diagnosis is associated with better outcomes and high index of suspicious is required for getting good prognosis. Prognostic scoring system include age, number of the extra-nodal location, performance attitude, current stage, and LDH.
Re-transplantation: it is advisable to wait for one year after completion of treatment.
-Avoid ATG?
-Keep lowest possible dose of immune-suppression
-Low/absent EBV viral load at the time of transplantation
-Antiviral prophylaxis: Ganciclovir was considered for this aim.
-EBV-PCR serial monitoring
-MMF is safe
-mTORi: may be?
This was narrative review article, level 5
Thank you. Well done
Thanks prof
Summary :
INTRODUCTION:
Uncontrolled B cell proliferation owing to weakened immunological monitoring causes post-transplant lymphoproliferative diseases (PTLD), one of the most common malignancies after solid organ transplantation (SOT) and hematopoietic stem-cell transplantation (HSCT).
Epstein-Barr virus (EBV) could get into B cells through viral reactivation after the transplant or from the donor organ or environment. 85% of PTLD instances occur in the first year post-transplant.
T-cell proliferation-induced PTLD is rare and EBV-negative. PTLD evolution depends on the accumulated immunosuppressive burden. Lymphoma made up 21% of all cancers in SOT patients, but only 4% and 5%, respectively, in immunocompetent men and women. PTLD may be localized or systemic.
Risk factors :
are said to differ depending on the type of transplanted organ:
(1) SOT, (2) Allogenic HSCT, (3) Immunosuppressive load exposure, (4) Oncogenic EBV
Pathogenesis:
EBV: For decades, PTLD formation was predominantly linked to EBV infection, however, current findings reveal that as many as 50% of SOT PTLD are not associated with EBV.
-Immunosuppressive-induced T-cell immune surveillance decrease causes PTLD in EBV-positive TRs. EBV may integrate into the B-cell program and cause proliferation and transformation.
Patients without EBV exhibit reduced PTLD. Several theories have been put forward, such as the “hit-and-run” theory, chronic immunosuppression, allograft-driven persistent antigenic triggering, and CMV or another viral infection.
Classification:
WHO 2017 classifies PTLD as follows:
Clinical presentation:
Clinical manifestations of PTLD range from symptomless lesions to fulminating illness with multi-organ failure. Pyrexia, weight loss, neurological symptoms, nodal lesions, gastrointestinal and pulmonary symptoms, infectious mononucleosis-like syndrome, and graft involvement may cause allograft dysfunction. Since TR might cause vague symptoms, the PTLD diagnosis must be lowered (e.g., fever, asthenia).
Treatment of PTLD:
RI
Improving the immunosuppressive load is the main goal of primary PTLD therapy. This is done so that EBV-specific cellular immunity can be partially restored without raising the risk of acute rejection. RI may cure 20% to 80% of PTLD patients.
Tacrolimus (Tac) and cyclosporine (CyA) dosages are reduced by 50% as part of the RI plan, and antimetabolites such as azathioprine or mycophenolate mofetil (MMF) are discontinued.
Rituximab therapy
Rituximab (RTX), a powerful chimeric anti-CD20 monoclonal antibody, binds to CD-20 antigen and kills B cells through phagocytosis (macrophages), complement-mediated cytotoxicity, and natural killer cells (antibody-dependent cell-mediated toxicity).
Chemotherapy
Indications of immunochemotherapy include Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma, primary CNS lymphoma, other uncommon lymphomas, and B-cell PTLD unresponsive to Rtx and RI.
Adoptive immunotherapy:
Adoptive immunotherapy with donor lymphocytes may treat donor-cell-derived PTLD in HSCT patients. The PTLD in SOT TRs is different. EBV-specific CTLs elicit a strong cellular immunological response. This therapy’s main danger is GVHD.
Re-transplantation and PTLD recurrence:
The possibility of re-transplantation after successful management of PTLD has been reported in particular cases; however, one-year disease-free survival is necessary after control of PTLD before re-transplantation.
PTLD recurrence has been rarely reported after re-transplantation, which requires careful planning of immunosuppression.
What is the level of evidence provided by this article?
Narrative review, Level V
Thank you. Well done
1. Please summarise this article
Introduction:
– Post-transplant lymphoproliferative disorders (PTLD) is the second most common malignancy in adult recipients post solid organ transplantation.
– Transplant clinicians must have a high index of suspicion of the symptoms and signs of PTLD to allow early detection and appropriate management.
– The cumulative immune suppression state and the Epstein-Barr virus (EBV) infection represents the most critical risk factors for developing PTLD. Therefore, reducing immune suppression represents the first line of management of this condition to allow normal T- cell surveillance.
Pathogenesis:
The exact pathogenesis of PTLD is uncertain. However, several hypotheses were introduced:
· EPV-positive PTLD is thought to be secondary to the incorporation of the DNA of the EPV into the B-cell DNA, producing abnormally proliferating cells resistant to natural apoptosis. A normal T-cell function is essential to eliminate these cells. The marked immune suppression will result in the failure of the immune surveillance function of T-cells and the development of PTLD.
· EPV-negative PTLD is another subgroup of PTLD. Possible pathogenesis includes an old, undocumented EBV infection that is not detectable anymore, another undetermined viral infection, or persistent antigenic stimulation and profound immune suppression.
Classification of PTLD:
There are different classifications of the PTLD, which differ in their morphology, immunophenotypic, and response to treatment. PTLD can be categorized in one of the following categories:
– Plasmacytic hyperplasia and infectious mononucleosis-like PTLD
– Florid follicular hyperplasia
– Polymorphic PTLD
– Monomorphic PTLD
– Classic Hodgkin lymphoma-like PTLD
Clinical presentation:
The clinical picture varies from asymptomatic cases to the aggressive fulminant form with multi-organ affection. Therefore, a high index of suspicion is required during the evaluation of non-specific symptoms such as fever, weight loss, and lymphadenopathy.
Treatment options for PTLD:
o Reduction of immune suppression:
One suggested protocol is to lower the dose of CNI by 50% with the complete withdrawal of anti-metabolites. In severe cases all immune suppressive drugs should be stopped apart from steroids.
o Rituximab:
It is a monoclonal antibody against CD-20, which will cause B-cell depletion. Therefore, it can be used together with the reduction of immune suppression in mild cases and those with polymorphic PTLD that expresses CD20.
o Chemotherapy:
Its indications include Hodgkin’s lymphoma, Burkitt’s lymphoma, primary CNS lymphoma, peripheral T-cell lymphoma and B-cell PTLD unresponsive to Rituximab.
o Adoptive immunotherapy:
This means the use of uses EBV-specific cytotoxic T lymphocytes to attack the EPV-positive PTLD cells or the use of donor lymphocyte infusion in the setting of PTLD post-hematopoietic cell transplantation. The major complication of adoptive immunotherapy is acute and chronic graft-versus-host disease (GVHD).
Follow-up response to treatment:
EPV viral load is usually used for follow-up response to treatment (it is expected to drop significantly in those who respond to treatment and to be rising in the case of non-responders).
Regular physical examination, radiological investigations and monitoring of the allograft function should be planned individually during the treatment course.
Prognosis:
IPI is a prognostic scoring system used by many haematologists and oncologists to recognize the prognostic attitude in aggressive lymphoma. It includes the patient’s age, performance attitude, current stage, lactate dehydrogenase (LDH), and the number of extra-nodal locations.
The prognosis of PTLD has improved compared to the previous decades due to the implementation of new tumour-specific startigies and better supportive care. Complete remission was achieved in 70% of cases included in the PTLD-1 study, with median survival of about 6.6 years.
Re-transplantation options:
– Patients who were cured of PTLD can be listed for subsequent transplantation after at least one year (and better if two years) of complete cure.
– EPV viral load should be evaluated regularly to detect any significant viral replication early.
– The use of Ganciclovir as an anti-EPV has been suggested.
– The goal will be to balance adequate immune suppression and lowering the risk of PTLD recurrence.
– Lymphocyte-depleting agents should be avoided during the induction phase of immune suppression, and the IL-2 receptor antagonist is the alternative induction agent.
– Rituximab use during the induction was tried in cases of cardiac transplantation for recipients with high EPV viral load.
– Carefully planned maintenance immune suppression in the form of mTOR inhibitor, MMF and steroids may be safe and beneficial.
2. What is the level of evidence provided by this article?
This article is a narrative review article which makes its level of evidence is 5.
Thank you. Well done
Due to blunted immunological Surveillance there is uncontrolled B cell proliferation in PTLD.
B cells get infected by EBV during –
Viral reactivation post transplant
Primary infection via donated organ or by environmental exposure.
> 85 % of PTED cases occur in the first year post transplant.
PTLD due to Tell proliferation is uncommon and mostly E BV negative.
Cumulative immunosuppression burden plays a role in PTLD evolution.
PTLD can present as a localised lesion or systemic disease.
Risk factors –
Solid organ transplant
Allogeneic H SCT
Previous exposure to immunosuppression
Oncogenic EBV
Pathogenesis –
E BV integ rates into normal B cell program.
There is immunosuppression induced decline In Tell surveillance.
leads to uncontrolled B cell proliferation.
other factors –
CMV and other viral infection
allograft driven persistent antigenic stimulation
prolonged immunosuppression
hit and run hypothesis
o EBV positive PTLD
Mostly B cell
fewer genetic abnormality
More common
Less risk compared to seronegativeTR
All cases post HSCT are EBV positive
o EBV negative PTLD
Shares genomic features with diffuse large Bell lymphoma
Mostly Tcell
Less common
Seronegative SOT TR are more vulnerable
In SOT both EBV positive and negative are present.
o classification –
Non destructive PTLD – plasmacystic hyperplasia, Florid follicular hyperplasia, infectious mononucleosis like PTLD
Polymorphic PTLD
Monomorphic PTLD ( Bcell, Tcell, NK type )
classic Hodgkin lymphoma like PTLD
o Clinical Presentation
Fever
Weight loss
Neurological manifestation
Nodal lesion
gastrointestinal manifestation
Pulmonary Manifestation
infectious mononucleosis like syndrome
Allograft dysfunction
Concomitant increased EBV load
o PTLD involvement seen in –
lymph rode
Liver
Lung
Kidney
bone marrow
git
spleen
CNS
tonsils
salivary gland
o D/D
Streptococcal infection
Infectious mononucleosis
when pt present with Fever, pharyngitis and cervical lymph node.
Time to PTLD is longest for heart recipient.
Early PTLD is usually diffuse large B cell lymphoma.
Burkitts and Hodgkins lymphoma are late events.
o Pre emptive therapy by EBV monitoring
PPV of EBV viral load in SOT is 28%- 100%
NPV of EBV viral load in SOT is 75% – 100%
cell Free plasma EBV DNA load better than EBV DANA load in peripheral blood mononuclear cells.
o Prophylaxis –
Monitoring EBV viral load
Recognising Serostatus of donor and recipient pre transplant
Missional needed immunosuppression.
Iv Ig/ Cytogam can be used.
Treatment –
o Reduction of immunosuppression
withdraw anti metabolites
Reduce CNI done by 50%
In critically ill withdraw all except steroids.
Monitor allograft function
Acute rejection Rate of 37%
EBV negative cases are less responsive to RI
Lack of response to RI seen in –
old aged > 50years
bulky lesions > 7cm
Advanced stage of disease Ann Arbor 3/4.
o Rituximab
Indicated in –
Non destructive PTLD
Polymorphic PTLD
Monomorphic DL BCL not responding to RI
375 mg/m2 weeky x 4 doses
o chemotherapy
Indications –
Burkitts lymphoma
Hodgkins lymphoma
peripheral T cell lymphoma
primary CNS lymphoma
other uncommon lymphoma
Bcell PTLD unresponsive to Rituximab and RI.
o Adoptive immunotherapy
EBV specific cytotoxic lymphocytes.
Infusion of donor lymphocyte in HSCT
o Outpatient care
In high risk –
Monitor EBv titre weekly
In low risk
Monitor EBV titre monthly, then 3 monthly
Serial physical examination
Radiology assessment
Allograft function assessment
o Future Strategy
Ibrutinib- BTK inhibition
PI3k inhibitor
M TORi
Bortezomib
Checkpoint inhibitor
Radio immuno therapy
Anti – CD 30 therapy
o Prognosis
70% of patients in PTLD1 achieved CR
Median survival of 6.6years
o Retransplantation and PTLD recurrence
12-24 months wait period before retransplant
TR should hance EBV Ig G positivity
low or absent EBV load
ganciclovir lovin therapy long term with EBV load monitoring
Induction – IL-2 receptor antagonist prefered.
Rituximab can be used as an induction agent.
Triple maintenance immuno suppression can be given
Role of MTORi
Identification of tumour Source is important.
Early PTLD
EBV positive
graft involvement
Rarely extranodal
Mostly donor desired
Monomorphic type less likely
More common
Late PTLD
EBV negative
graft involvement rare
Extra nodal disease common
Elevated LDH
Less prevalent
level of evidence-5