II. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Lymphoproliferative disorders account for 21% of all cancers of SOT. The majority of cases are derived from B lymphocytes and are EBV associated. Incidence of PTLD in renal transplant is about 0.8 to 2.5 %.
PTLD are subclassified into four histopathological categories
.. Non- destructive
.. Polymorphic
.. Monomorphic
.. Classical Hodgkin lymphoma
Diagnosis and staging
* surgical excisional or incisional biopsy is recommended to establish diagnosis. If it is not possible, a core needle biopsy is an alternative.
* PET -CT is recommended for staging. If it is not available, CT can be used .
Management of PTLD
1. Reduction of immunosuppression
* Reduction of immunosuppression by stopping Azathioprine and MMF and reduction of CNI by 30 to 50 % with maintaining corticosteroids is recommended when possible with monitoring of graft function.
* Early disease response assessment ( at 2 to 4 weeks ) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond.
2.Rituximab +/- chemotherapy
* Rituximab monotherapy is recommended for patients with CD20 positive PTLD who fail to respond adequately to RIS as initial therapy
* Four further three weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission after four cycles of weekly standard dose rituximab.
* Four cycles of R-CHOP-21 immunotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard dose rituximab or who clinically progress during these four cycles.
*Rituximab plus R-CHOP-21 is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise.
*Cardiac and renal function follow up.
3.Radiotherapy
* In localized disease, radiotherapy may be offered concurrently with RIS.
*Treatment with anti-viral agents, IVIG is not recommended outside clinical trials.
4. Therapy for replased or refractory PTLD
* patients that relapse post-R-CHOP should be carefully selected for intensive second line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
* Treatment of PTLD with EBV specific CTLs should be considered where available with R/R EBV positive PTLD.
5.Supportive care
G- CSF is recommended for patients receiving chemotherapy and pneumocystitis Jirovecii pneumonia.
Diagnosis and staging
excision biopsy samples are recommended
Patients with PTLD require a comprehensive pre-treatment evaluation
Staging should be recorded using the Ann Arbor classification or the Lugano classification
following Positron Emission Tomography–Computed Tomography (PET-CT)
The role of PET-CT in the staging of PTLD is less well defined when compared to lymphoma
PET-CT detected additional sites of disease in 28% of cases, resulting in upstaging in 15% when compared to CT alone.
End-of-treatment PET-CT appears to have moderate sensitivity (71%) and specificity (73%)
●Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
●Where this is not possible, a core needle biopsy is an alternative (1A).
● Staging with a CT is recommended in all patients where PET-CT is not available (1A).
●Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
●All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
●All diagnostic material should be reviewed by a haematopathologist (1A).
●Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
●Staging with a CT is recommended in all patients where PET-CT is not available (1A).
●Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Management of PTLD Immunosuppression reduction
●Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
●Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab +/chemotherapy
●Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
●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 (1B).
●Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
●Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
●Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
● PET-CT should be considered for interim and endof-treatment response assessment where available (1C).
Radiotherapy
● Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C). In localised disease, radiotherapy may be offered concurrently with RIS (2C).
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
●Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD
●Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
●Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C). Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Other recommendations
●It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
●Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
●Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
●Local radiotherapy +/corticosteroids with RIS where f itness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
●Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
●G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
● Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
This article is an updated guideline of the recommendations for the front-line management of adult patients with an established diagnosis of post-transplant lymphoproliferative disease.
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
” Staging with a CT is recommended in all patients where PET-CT is not available (1A).
” Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
” All diagnostic material should be reviewed by a haematopathologist (1A).
” Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
” Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
” 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 (1B).
” Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
” Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
” Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
PET-CT should be considered for interim and endof-treatment response assessment where available (1C). Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
” In localised disease, radiotherapy may be offered concurrently with RIS (2C).
” Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B)
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
” Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C)
” It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
” Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
” Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy withrituximab in suitable patients depending on adequate organ function and comorbidity (1C).
” Local radiotherapy +/-corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
” Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
PTLD is the second most common malignancy in SOT, with the lung having the highest rate.
It needs a high index of clinical suspicion, biopsy to confirm the diagnosis,CT scan and PET scan for staging.
PTLD types are four: 1. Classic Hodgkin lymphoma 2. Non-destructive 3. Polymorphic 4. Monomorphic (the worst type)
Management of PTLD: 1. The base of treatment is the reduction of immunosuppression. Stop MMF, reduce CNIs (30-50%) associated with graft function monitoring and evaluating its response at 2-4 weeks and if no response was observed, further treatment is indicated 2. Rituximab monotherapy for CD20-positive PTLD with a standard weekly dose for four cycles of rituximab. 3. If fail to respond to monotherapy, four cycles of R-CHOP-21 immuno-chemotherapy are recommended. 4. Rituximab plus anthracycline-based therapy (typically R-CHOP-21) combined with a reduction of Is in aggressive lymphoma with critical organ compromise. 5. Assessment of cardiac and renal function 6. PET scan to evaluate treatment. 7. Radiotherapy: for selected patients with specific histologic subtypes if localized, at the same time of IS reduction.
Therapy for relapsed or refractory PTLD: -Patients that relapse after R-CHOP should be selected for intensive second-line chemotherapy followed by autologous stem cell transplant (2B)
Introduction: Lymphoproliferative disease is the second most common malignancy after SOT due to immunosuppression and EBV-related infection, with the highest rate among lung TX. Diagnosis: 1. Excisional biopsy and if not possible core needle biopsy 2. Staging by CT scans when PET scan is not available. 3. PET scan when available for staging. PTLD types are four: 1. Classic Hodgkin lymphoma 2. Non-destructive 3. Polymorphic 4. Monomorphic (the worst type) Multidisciplinary approach: MDT with a hemato-oncology specialist, an organ transplant physician radiologist recommended, and a hematopathologist. Adverse risk factors: · Poor performance status · EBV negative tumor · Older age · Graft involvement · Monomorphic histology · CNS or BM involvement · Higher LDH and lower albumin Management of PTLD: 1. The base of treatment is the reduction of immunosuppression. Stop MMF, reduce CNIs (30-50%) associated with graft function monitoring and evaluating its response at 2-4 weeks and if no response was observed, further treatment is indicated 2. Rituximab monotherapy for CD20-positive PTLD with a standard weekly dose for four cycles of rituximab. 3. If fail to respond to monotherapy, four cycles of R-CHOP-21 immuno-chemotherapy are recommended. 4. Rituximab plus anthracycline-based therapy (typically R-CHOP-21) combined with a reduction of Is in aggressive lymphoma with critical organ compromise. 5. Assessment of cardiac and renal function 6. PET scan to evaluate treatment. 7. Radiotherapy: for selected patients with specific histologic subtypes if localized, at the same time of IS reduction. · Treatment of relapsed or refractory PTLD: autologous stem cell TX ± adoptive immunotherapy · CNS-PTLD: 1. Combination chemotherapy with rituximab after IS reduction 2. Local radiotherapy with corticosteroids 3. EBV-specific VST for EBV-positive ones. · Retransplantation: after at least one year but maybe a longer period.
PTLD represents around 21% of cancers of SOT recipients. Management of PTLD:
-Reduction in immunosuppression by stopping azathioprine and MMF .
-Reduction of CNIs by 30–50% .
-Maintaining or reducing corticosteroids.
-Early disease response assessment .
-Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
-Four further three-weekly cycles of Rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose Rituximab (1B).
-Four cycles of R-CHOP-21chemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ! 3) after four cycles of weekly standard-dose Rituximab or who clinically progress during these four cycles (1B).
-Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C). Therapy for relapsed or refractory PTLD:
-Patients that relapse after R-CHOP should be selected for intensive second-line chemotherapy followed by autologous stem cell transplant (2B).
Post-transplant lymphoproliferative disease is a spectrum of disorders that come from lymphoid proliferations that occur as a result of immunosuppression following SOT. These lymphoid proliferations might be caused by the transplant itself or by immunosuppression. In SOT recipients, lymphoproliferative disorders account for 21% of all malignancies, whereas in immunocompetent populations, the same disorders account for between 4% and 5% of all cancers.1 Adult SOT recipients have an increased risk of developing PTLD, which is the second most prevalent malignancy after skin cancer and is associated with a considerable mortality rate due to cancer.1 The age of the patient, the type of transplant, and the level of immunosuppression all have an impact on the incidence that is recorded. In the past, it was claimed that PTLD was diagnosed in patients at the highest rate during the first year after receiving a transplant.
Diagnosis and staging
It can be difficult to establish a tissue diagnosis of PTLD, and any diagnostic material should be supported by relevant clinical information, such as the date of the transplant, the immune suppression regimen, and the organ type. Excision biopsy samples are advised whenever possible since they allow for correct PTLD sub-classification and provide sufficient material for later auxiliary examinations.
Prognostic scoring
There is no prognostic grading system that is specific to PTLD that is universally acknowledged by physicians. This is due to the fact that the majority of prognostic scores comprised a diverse range of risk factors, a wide variety of patients or treatments, and were either retrospective or conducted by a single institution. However, a number of adverse risk variables have been discovered in several prognostic scoring systems. These risk factors include poor performance status, an EBV-negative tumor, graft involvement, monomorphic histology, older age, central nervous system (CNS) or bone marrow involvement, elevated lactate dehydrogenase (LDH), and hypoalbuminemia.
Reduction of immunosuppression
According to the patient’s clinical presentation and the severity of the disease, the American guidelines advise following a different course of treatment.
As can be seen in Table III, a similar methodology was utilized in a prospective trial of sequential RIS that was carried out according to the clinical picture by the Southwest Oncology Group (SWOG) using Protocol S9239. At the time, this methodology was regarded as the gold standard. Historically, some standards suggest halting full immune suppression in certain therapeutic conditions. However, this should not be done unless specifically directed to do so by the transplant team, nor should it be done unless it is absolutely required.
Rituximab +/# chemotherapy
Primary therapy for patients with monomorphic CD20-positive B-cell peripheral T-cell lymphoma
The most common type of PTLD has a CD20-positive, B-cell monomorphic histology, which is similar to that of DLBCL (see the next section for information on how to treat another subtype).
A monoclonal anti-CD20 antibody called rituximab can be used to treat people with polymorphic PTLD or monomorphic PTLD that looks like DLBCL who have not responded to first-line RIS treatment. This treatment has become the standard of care. The international phase II PTLD-1 trial39 found that four cycles of weekly intravenous rituximab at standard dose (375 mg/m2) followed by four cycles of standard-dose CHOP-21 chemotherapy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide; 1.4 mg/m2 vincristine; 50 mg/m2 prednisolone) every 21 days along with mandatory G-CSF worked best.
The low-risk category was refined further in the ongoing PTLD-2 research by taking into account the initial response to rituximab monotherapy as well as the IPI at the time of diagnosis. These findings were based on the data that were available from PTLD-1 and PTLD-1/3. Patients who achieve a complete remission (CR) following the first four cycles of rituximab monotherapy and patients whose illness progression index (IPI) is 0–2 and who obtain a partial remission at interim staging are considered to have a low chance of their disease progressing further. This method increases the number of patients with PTLD who only require rituximab monotherapy. It also has a good chance of reducing grade 3–4 leucopenia, infection, and ultimately the TRM while keeping the OS the same.
Radiotherapy
There is a lack of clarity on the function of radiotherapy in the overall treatment of PTLD. 7–25% of cases had radiotherapy incorporated into their initial management, and retrospective, non-randomized, heterogeneous case series include patients who were treated largely with RIS and/or chemotherapy.
According to the findings of a retrospective study, people with limited-stage illness, regardless of the histological subtype, are able to get durable CRs following surgical resection or radiotherapy, typically in conjunction with concomitant RIS.
Polymorphic CD20-positive B-cell PTLD
There is a paucity of data available about the management of polymorphic CD20-positive B-cell PTLD; hence, these cases have been incorporated into the PTLD-1 trial. As a result, the same approach that is used for the treatment of monomorphic CD20-positive B-cell PTLD is used for these cases as well.28,30,39 Polymorphic PTLD can very rarely overlap with Hodgkin lymphoma PTLD, in which case the treatment would be the same as what is mentioned in the Hodgkin lymphoma PTLD section.
Therapy for relapsed or refractory PTLD
There are no prospective data available to advise the treatment of patients who have refractory or relapsed PTLD (also known as R/R PTLD). Case reports from a variety of histological subtypes make up the entirety of the evidence base. R-CHOP is a method that is sensible and logical to use with patients who do not respond to treatment with rituximab.23,24,79 If relapse after rituximab monotherapy happens at a late stage, one option that can be investigated is a sequential approach similar to that used in front-line therapy.
Adoptive immunotherapy
EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy could be a new way to treat PTLD that is positive for EBV while lowering or getting rid of the chance of graft rejection at the same time. EBV-specific CTLs make a T-cell immune response to these abnormal B cells by using either the recipient’s own cells to make autologous EBV-directed CTLs or a bank of partially HLA-matched EBV-specific CTLs. This action removes the threat that the abnormal B cells pose.
Burkitt lymphoma-like PTLD
There are several differences that may be seen between Burkitt-like PTLD and sporadic Burkitt lymphoma, despite the fact that there are many similarities between the two. There is a significant correlation with EBV, and there is also a relationship with 11q abnormalities in patients who show typical histological characteristics but do not have a clear MYC rearrangement. Both of these associations are found in patients.
Plasmablastic and plasma-cell myeloma PTLD
There is a paucity of data on these subtypes to recommend a standardized approach, and therefore it is reasonable to treat as for the plasmacytoid dyscrasia disease in immunocompatibility. RIS should be incorporated into the management algorithm.
Hodgkin lymphoma PTLD
Classical Hodgkin lymphoma-type peripheral T-lymphoid nodule lymphoma (HL-PTLD) is uncommon, and there is a dearth of data regarding the most effective treatment. Patients diagnosed with PTLD are often barred from participation in clinical trials, which instead rely heavily on data collected from case series.The data collected by SEER-Medicare at the population level in the United States reveal that HL-PTLD develops rather late, at a median of 88 months after SOT.
Extra-nodal marginal zone lymphoma – PTLD
It is anticipated that exposure to SOT doubles or perhaps triples a person’s risk of developing extra-nodal marginal zone lymphoma.Gastric involvement is the most common manifestation of MALT lymphoma, but there have also been reports of the cancer spreading to the colon and the small intestine in rare instances.
There is a wide variety of treatment algorithms, and they are not well standardized. In rare cases, EBV-positive MALT lymphoma might develop in the skin; in these cases, RIS treatment might be effective in the first stages of the disease.
Supportive care
Significant TRM has been documented in patients with PTLD who were treated with combined immunochemotherapy. There have been reports of as much as a 50 percent mortality rate following infection in these patients. Therefore, the use of G-CSF as the main prophylaxis in this patient population is acceptable and recommended.
It is recommended that prophylactic administration of G-CSF be considered whenever there is a risk of febrile neutropenia (FN) that is higher than 20% for any and all planned cycles of treatment. Age is a significant risk factor for developing FN, which can be mitigated to some extent by receiving G-CSF treatment.
Re-transplantation
After PTLD has been successfully controlled, re-transplantation may be an option to consider because there is a low likelihood of the disease returning following re-transplantation. 69 patients who underwent re-transplantation had satisfactory results, according to the findings of an investigation by the Organ Procurement and Transplant Network and the United Network.
After a mean follow-up of nearly two years, all of the patients were still alive, and 89% of the grafts had some level of functionality. The recurrence of PTLD following retransplantation was shown to be uncommon, with only one patient acquiring the condition after two years, according to more recent research that included 52 patients.
Recommendation
The clinical need as well as the type of organ will determine whether or not re-transplantation is performed. Before re-transplantation, a wait of at least one year may be considered, although it’s possible that a longer time frame may be required.
This article handling the updated guideline and recommendations
for management of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT) in adults.
Lymphoproliferative disorders represents 21% of all cancers of SOT recipients, in contrast to only 4–5% within the immunocompetent population.
Most of the cases at the first year with another peak at 10 years.
The diagnosis is by tissue biopsy for accurate PTLD sub-classification.
A detailed evaluation is needed before treatment. Recommendations
” Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Where this is not possible, a core needle biopsy is an alternative (1A).
” Staging with a CT is recommended in all patients where PET-CT is not available (1A).
” Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma Management of PTLD : 1- Immunosuppression reduction
Recommendations
” Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended
in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
” Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
2- Rituximab +/- chemotherapy
Recommendations
” Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
” Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab (1B).
” Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
” Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive
lymphoma with critical organ compromise (1B).
3 Radiotherapy
4- Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Recommendations
” Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
” In localised disease, radiotherapy may be offered concurrently with RIS (2C).
” Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
5- Adoptive immunotherapy
Recommendations
” Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remissin is acheived (2B). for uncommon types of PTLD:
Recommendations
” It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
” Treatment of less common forms of PTLD with standard- of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
” Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
” Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
” Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
6- Supportive care
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
PTLD is a complication of immunosuppressive medications in solid organ transplant recipients which is the second common malignancy and accounts for 21% of all malignancy in those recipients. PTLD usually occur in the first-year post-transplantation.Diagnosis of PTLD can be difficult especially getting a tissue biopsy, staging of PTLD is important for classification and arranging for further treatment.
Poor prognostic factors of PTLD include the following:1-Poor performance status and older age of the patient.2-EBV negative tumor.3-PTLD involving the graft.4-Mono-morphic histology.5-PTLD involving CNS or Bone Marrow.6-PTLD associated with high LDH.
Treatment options for PTLD:a-Reduction of immune-suppression.b-Supportive care: use G-CSF for primary prophylaxis against febrile neutropenia.b-Rituximab +/-Chemotherapy: for polymorphic and mono-morphic CD20-positive B-cell PTLD.c-Radiotherapy: undefined role.d-Treatment of refractory and relapsing PTLD: use R-CHOP chemotherapy is a reasonable option.e-Adoptive immunotherapy: EBV-CTL immunotherapy is a treatment option for EBV +ve PTLD, this treatment reduces the risk of graft rejection.f-Burkitt’s lymphoma like PTLD: is strongly associated with EBV.g-Plasmablastic and plasma cell myeloma PTLD: is managed with standard approach.h-Hodgokin’s lymphoma PTLD: occurs late at 88 months post-transplant.i-Re-transplantation can be considered after PTLD therapy because the risk of recurrence is low and at least one year to wait before re-transplantation is recommended.
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.1 In adult SOT recipients, PTLD is a common malignancy after skin cancer and is asso- ciated with a significant cancer-related mortality.1 The reported incidence varies according to patient age, transplant type and the degree of immunosuppression. Historically, PTLD has been reported to occur most frequently in the first year following transplantation.
Diagnosis and staging
Establishing a tissue diagnosis of PTLD can be challenging and all diagnostic material should be accompanied by rele- vant clinical information including the date of transplant, immune suppression regimen and organ type. Where possi- ble, excision biopsy samples are recommended to enable accurate PTLD sub-classification and to provide sufficient material for subsequent ancillary investigations.
Prognostic scoring
There is no universally accepted prognostic scoring system specific for PTLD. This is a result of most prognostic scores included varying risk factors, heterogeneous patients or treat- ments and often being retrospective or single-institution ser- ies. However, a number of adverse risk factors have been identified in various prognostic scoring systems including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia
Reduction of immunosuppression
The American guidelines recommend an alternative approach according to the clinical picture and the extent of the disease.
A prospective study of sequential RIS accord- ing to the clinical picture conducted by the Southwest Oncology Group (SWOG) on Protocol S9239 had a similar approach, which was then considered best practice32 as shown in Table III. Historically, some guidelines suggest stopping all immune suppression in certain clinical scenarios. However, this should only be done with guidance from the transplant team and only if absolutely necessary.
Rituximab +/# chemotherapy
Front-line therapy for monomorphic CD20-positive B-cell PTLD
The commonest form of PTLD has a CD20-positive, B-cell monomorphic histology similar to DLBCL (see later sections for management of another subtype.
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 unre- sponsive to initial RIS. The international phase II PTLD-1 trial39 established sequential therapy of four cycles of weekly intravenous rituximab at standard dose (375 mg/m2) fol- lowed by four cycles of standard-dose CHOP-21 chemother- apy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1!4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF).
Based on the data available from PTLD-1 and PTLD-1/3 the low-risk group was refined further in the ongoing PTLD-2 study taking into account the initial response to rituximab monotherapy and the IPI at diagnosis. Patients with a low risk of disease progression are defined as those who achieve a CR after the first four courses of rituximab monotherapy and those with an IPI of 0–2 who achieve a partial remission at interim staging. This strategy increases the number of PTLD patients who only require rituximab monotherapy and is likely to reduce grade 3–4 leucopenia, infection and subsequently the TRM, but retaining a similar OS.
Radiotherapy
The role of radiotherapy as a component of treatment for PTLD is undefined. Retrospective, non-randomised heteroge- neous case series include patients treated predominantly with RIS and/or chemotherapy, with 7–25% of cases having radio- therapy included in their initial management.
A retro- spective analysis suggested that adults with limited-stage disease, regardless of the histological subtype, can obtain dur- able CRs after surgical resection or radiotherapy, usually with concurrent RIS.
Polymorphic CD20-positive B-cell PTLD
Data on the management of polymorphic CD20-positive B- cell PTLD are limited, and these cases have been included in the PTLD-1 trial. Therefore, they are treated with the same algorithm as monomorphic CD20-positive B-cell PTLD as described above.28,30,39 Rarely, polymorphic PTLD can have an overlap with Hodgkin Lymphoma PTLD and thus the management would be as described in the Hodgkin Lym- phoma PTLD section.
Therapy for relapsed or refractory PTLD
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD. The evi- dence base is limited to case reports across various histologi- cal subtypes. In patients who are unresponsive to rituximab, using R-CHOP is a reasonable and logical approach.23,24,79 A sequential approach as in front-line ther- apy can be considered if relapse post rituximab monotherapy occurs late.
Adoptive immunotherapy
EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV- positive PTLD whilst avoiding the risk of graft rejection. EBV-specific CTLs utilise either the recipient’s own cells to generate autologous EBV-directed CTLs or a bank of par- tially HLA-matched EBV-specific CTLs to generate a T-cell immune-mediated response to these abnormal B cells.
Burkitt lymphoma-like PTLD
Burkitt-like PTLD has many features in common with spo- radic Burkitt lymphoma, but some differences can be observed. A strong association with EBV is described,93 along with an association with 11q aberrations in patients present- ing with typical histopathological features but without a demonstrable MYC rearrangement.
Plasmablastic and plasma-cell myeloma PTLD
There is a paucity of data on these subtypes to recommend a standardised approach and therefore it is reasonable to treat as for the plasmacytoid dyscrasia disease in the immunocom- petent. RIS should be incorporated in the management algo- rithm.
Hodgkin lymphoma PTLD
Classical Hodgkin lymphoma-type PTLD (HL-PTLD) is rare and data on optimal therapy are lacking. Patients with PTLD are typically excluded from clinical trials with data largely from cases series.78,101,102 SEER-Medicare population-level US data suggest that HL-PTLD occurs late, at a median of 88 months post SOT.
Extra-nodal marginal zone lymphoma – PTLD
SOT is estimated to increase the risk of extra-nodal marginal zone lymphoma by two- to threefold.The predominant site of involvement of MALT lymphoma is gastric, although isolated cases of colonic and small-bowel involvement are described.
Treatment algorithms are heterogeneous and poorly standardised. Occasionally EBV-positive MALT lym- phoma occurs in the skin and may respond well to RIS in the first instance.
Supportive care
Significant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection. It is therefore appropriate to use G-CSF as primary prophylaxis in this patient group.
Prophylactic administration of G-CSF if the risk of febrile
neutropenia (FN) is >20% for all planned cycles of treatment.
should be considered. Age is an important risk factor.
for developing FN which can partly be prevented by G- CSF.
Re-transplantation
Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re-trans- plantation is low. The Organ Procurement and Trans- plant Network/United Network analysis reported favourable outcomes in 69 patients who underwent re-transplantation.
all patients were alive and 89% of grafts were functioning after a mean fol- low-up of approximately two years. A more recent review of 52 patients reported that recurrence of PTLD after re-trans- plantation was rare, with only one patient developing PTLD at two years.
Recommendation
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be consid- ered before re-transplantation, but a longer period may be needed (2C).
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative .
Staging with a CT is recommended in all patients where PET-CT is not available .
Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma .
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians .
All diagnostic material should be reviewed by a haematopathologist .
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy .
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 .
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles .
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise ,
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected .
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes .
” In localised disease, radiotherapy may be offered concurrently with RIS Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials .
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved .
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD .
Patients with relapsed/refractory PTLD should be offered clinical trials where available .
It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management .
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity .
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity .
Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD .
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed .
This Article is is an updated guideline and details the recommendations for the front-line management of adult patients with an established diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation. Diagnosis and staging:
surgical excisional or incisional biopsy is should be done to confirm the diagnosis. If not a core needle biopsy is an option (1A).
All patients must have a CT where PET-CT is not available (1A).
If PET-CT is available should be utilized for staging in line with the recommendation for FDG-avid lymphoma (1B) Multidisciplinary approach to care:
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haematopathologist (1A) Management of PTLD: Reduction of immunosuppression:
Stop azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, for all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) should be done to those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B). Rituximab +/- chemotherapy:
Rituximab monotherapy should be given for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
4 further 3-weekly cycles of rituximab are given to patients who obtain CR or complete metabolic remission (CMR) (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab (1B).
4 cycles of R-CHOP-21 immunochemotherapy are given to patients who fail to obtain CR or CMR (with Deauville ≤ 3) after 4 cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B)
Radiotherapy: Its role uncertain. Antivirals, intravenous immunoglobulin and interferon-alpha treatment:
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
In localized disease, radiotherapy may be offered con[1]currently with RIS (2C). ” Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD:
There is no data to guide the treatment. Adoptive immunotherapy:
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B)
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C). Post-transplant lymphoproliferative disease affecting the central nervous system:
It is recommended that all patients with the less com[1]mon forms of PTLD be considered for RIS as part of their initial management (1C).
Treatment of less common forms of PTLD with stan[1]dard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C). ” Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C). Supportive care:
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B). Re-transplantation:
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C). Level of evidence is 1
This document provides updated guidelines for the front-line management of adult patients with post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT). PTLD is a spectrum of disorders resulting from lymphoid proliferations that occur due to immunosuppression following SOT. PTLD is a common malignancy in adult SOT recipients and is associated with significant cancer-related mortality. Accurate diagnosis and staging are crucial for patient management. A surgical biopsy is recommended to establish a diagnosis, and staging with PET-CT is recommended where available. A multidisciplinary approach to care is necessary considering various factors, including histological subtypes, clinical stage, and SOT function.
PTLD Management of post-transplant lymphoproliferative disorder (PTLD) is challenging due to the rarity of the disease and its histological heterogeneity. Reduction in immunosuppression is the first-line treatment for low-risk PTLD patients with early lesions, low-stage disease, and non-bulky disease.
Response should be assessed within 2-4 weeks, and alternative strategies should be initiated for non-responders. Close monitoring for rejection of the solid organ transplant is essential in these patients. Reduction in immunosuppression should be considered in conjunction with other therapies for high-risk patients with aggressive PTLD.
Recommendations include reducing immunosuppressive medications, assessing early disease response, and close monitoring of graft function under the guidance of the transplant physician.
RITUXIMAB For patients with monomorphic CD20-positive B-cell PTLD who fail to respond to initial reduction in immunosuppression (RIS), rituximab is recommended as the standard of care. The international phase II PTLD-1 trial established sequential therapy of four cycles of weekly intravenous rituximab at standard dose followed by four cycles of standard-dose CHOP-21 chemotherapy every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF). Patients who achieve complete remission (CR) or complete metabolic remission (CMR) with rituximab monotherapy may receive further four doses of rituximab and stop therapy. For patients who do not respond adequately, further chemotherapy options are available with caution to avoid treatment-related mortality. PET-CT is recommended for interim and end-of-treatment response assessment where available.
RADIOTHERAPY The role of radiotherapy in the treatment of PTLD is undefined, and it is often included in initial management for 7-25% of cases. Localised monomorphic DLBCL and Hodgkin lymphoma PTLD may be considered for radiotherapy in combination with RIS, RIS +/# rituximab, or standard practice outside of PTLD. Radiotherapy is also used for rare forms of PTLD such as nasal natural killer/T-cell lymphoma, and the dose and fractionation regimen follow normal lymphoma protocols.
Antivirals and Immunoglobulins:
Limited data on effective response to antiviral agents or immunoglobulins in EBV-positive lymphoproliferative disorders.Treatment not recommended outside clinical trials.
Interferon-alpha (IFNa) Treatment: Historical use, no new developments.Not recommended outside clinical trials.
Therapy for Relapsed/Refractory PTLD:No prospective data available. R-CHOP considered a reasonable approach. Patients should be offered clinical trial enrollment.
Adoptive Immunotherapy: EBV-specific CTL immunotherapy promising for EBV-positive PTLD. Autologous/allogeneic EBV-directed CTLs should be considered.
Burkitt Lymphoma-like PTLD: Rituximab monotherapy inadequate. R-CHOP with concurrent RIS considered reasonable option. CNS prophylaxis strongly advised.
Plasmablastic and Plasma-cell Myeloma PTLD: Paucity of data, treat as plasmacytoid dyscrasia with RIS.
T-cell Lymphoma PTLD: Rare and poorly understood. Anthracycline-based chemotherapy with RIS recommended.
Hodgkin Lymphoma PTLD: Rare and data lacking.Standard chemotherapy with ABVD and RIS considered safe and effective.
Extra-nodal Marginal Zone Lymphoma PTLD: Rituximab monotherapy effective. Radiotherapy considered effective.
Post-transplant Lymphoproliferative Disease Affecting CNS: Optimal therapy not established. RIS and combination chemotherapy with rituximab considered for suitable patients. EBV-specific CTL considered where available.
Supportive Care: G-CSF as primary prophylaxis for febrile neutropenia. Antibiotic, antifungal, and antiviral prophylaxis during therapy.
This Article is is an updated guideline and details the recommendations for the front-line management of adult patients with an established diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation .
PRETREATMENT ASSESSMENT
The pretreatment evaluation of patients with PTLD both determines the extent of the disease and provides information about the individual’s comorbidities that are likely to have an impact on treatment options.
While most elements of the patient’s history are pertinent to the problem at hand, some are particularly relevant to treatment selection. These include the patient’s performance status and comorbidities, the type of transplant, the immunosuppressive regimen used, the status of the graft, the potential impact of graft failure, and the presence of graft-versus-host disease (in hematopoietic cell transplant recipient)
In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with PTLD:
●Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase (LDH), albumin, HIV, hepatitis B, Epstein-Barr virus (EBV) serology with quantitative polymerase chain reaction (PCR), and cytomegalovirus (CMV) PCR.
●Contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis should be performed in patients suspected of having PTLD. This study provides critical information on the measurement of disease prior to treatment, and aids in staging .When available, a combined positron emission tomography (PET)/CT scan as a measure of disease activity should be obtained.
●Assessment of the function of the transplanted organ.
●Unilateral bone marrow aspiration and biopsy is suggested for patients with cytopenias.
●If involvement of the central nervous system is suspected, further evaluation should include gadolinium-enhanced magnetic resonance imaging (MRI) of the head and cerebral spinal fluid (CSF) analysis.
●A study of cardiac function (eg, echocardiogram or MUGA) should be performed for patients with a history of cardiac disease (and no heart transplant) and for those who plan to undergo anthracycline-based chemotherapy (eg, R-CHOP).
●Men and women with child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures.
Treatment-
Reduction of immunosuppression -Where safe to do so, immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team. RIS aims to partially restore T-cell function. Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function. Where RIS is being considered as the sole initial treatment, response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond. If a complete remission (CR) is obtained, then no other therapy may be required in patients with low risk factors.Close monitoring for rejection of the SOT by the relevant transplant team is crucial in these patients who are in CR and maintained at RIS.Patients that achieve a PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks or further rituximab-based treatment may be considered as described in the section Rituximab +/chemotherapy.
Rituximab +/chemotherapy–All patients with PTLD should be considered for RIS and early assessment of response at 2–4 weeks needs to be undertaken. Sequential therapy with rituximab should be started in patients with CD20-positive PTLD, who fail to achieve adequate response to RIS alone. Following re-assessment after initial rituximab treatment, patients in CR should be considered for a further four cycles of rituximab and those not in CR should be treated with four cycles of R-CHOP-21.Rituximab is not effective in CD20 negative PTLD ,where reduction of immunosuppression(RIS) and Chemotherapy are main treatment.
Radiotherapy –For patients with localized disease and those with central nervous system involvement, involved-field radiation therapy, alone or in combination, may be beneficial.
Therapy for relapsed or refractory PTLD-Patients with R/R PTLD post R-CHOP have a poor longterm survival.Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD . Patients with relapsed/refractory PTLD should be offered clinical trials where available.
Post-transplant lymphoproliferative disease affecting the central nervous system-Although the risk of CNS lymphoma is elevated in SOT recipients, it remains between 10 and 20% of PTLD.The histology of CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive.Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity . Local radiotherapy +/corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD .Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
Supportive care-Prophylactic administration of G-CSF for the risk of febrile neutropenia (FN) should be considered.Prophylaxis with co-trimoxazole or equivalent should be considered in all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia (PJP).Given the degree of immunosuppression in patients with PTLD, strong consideration should be given to antibiotic, antifungal (e.g. fluconazole) and antiviral (e.g. acyclovir) prophylaxis during therapy, particularly if treatment is associated with neutropenia as per local protocols.
Re-transplantation-Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re-transplantation is low.Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed .
INTRODUCTION:
This article is an updated guideline of the British society for hematology with regards to management of a diagnosed case of Post-transplant lymphoproliferative disorder in solid organ transplant patients.
PTLD remains a considerable concern is post-transplant patients accounting for 1/5th of all post-transplant cancers. It has a bimodal peak, during first year and at 10 years post-transplant. Majority are B cell associated secondary to EBV infection. As compared to other organs, renal transplantation is associated with lower incidence of PTLD. DIAGNOSIS & STAGING:
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.
It should be staged according to the Ann Arbor or Lugano classification (based on imaging modality used). FDG-PET scan is recommended as investigation of choice for both staging as well as monitoring of disease. MULTIDISCIPLINARY APPROACH:
It is recommended to have a multidisciplinary team management for PTLD involving transplant physician, haem-oncologist, pathologist, radiologist and radiation oncologist. PROGNOSTIC SCORING:
There are many prognostic scoring systems in use, although none is universally accepted. The Ghobrial prognostic score, International Prognostic index (IPI) & PTLD prognostic index are all available and each has its own drawbacks. However the IPI has shown to predict overall survival with statistical significance. MANAGEMENT:
Due to histological subtypes and rarity of certain subtypes there is no consensus for treatment of PTLD and most evidence is based on case series, however for the most common monomorphic diffuse large B cell lymphoma there is strong evidence from phase II clinical trials.
1. REDUCTION OF IMMUNOSUPPRESSION:
If graft function allows then reduction of immunosuppression it the first step of management. This implies stopping the antimetabolite, decreasing dose of CNI by 50-75% and reducing steroids to physiological dose.
For low risk cases this alone can achieve complete remission. Response to reduction should be assessed at 2-4 weeks. Monitoring graft function for signs of rejection is necessary. If complete remission is achieved then continue at lower dose of immunosuppression, in case of partial remission either reassess at 2-4 weeks interval or start rituximab (+/- chemotherapy).
For high risk cases reduction in immunosuppression should be accompanied by rituximab followed by CHOP (cyclophosphamide + vincristine + doxorubicin + prednisolone) regime if indicated.
2. RITUXIMAB (+/- CHEMOTHERAPY)
For Monomorphic CD-20 positive and polymorphic PTLD rituximab is the first line therapy following failure to respond to modification of immunosuppression. Rituximab + CHOP vs Rituximab followed by assessment and if not in remission then CHOP (high risk) have been studied in PTLD phase II trials.
3. RADIOTHERAPY:
Limited stage disease, localized disease, orbit and CNS disease and MALT type lymphoma are indications for radiotherapy, although the evidence for this is weak.
4. ANTI-VIRAL, IV IG & IFN alfa
No strong evidence is available for use of antiviral therapy, IV immunoglobulins or interferon alfa in the treatment of PTLD.
5. RELAPSE OR REFRACTORY DISEASE:
For rituximab refractory disease CHOP chemotherapy is recommended. For R-CHOP resistant / refractory disease no recommendations are available and patient should be offered enrolment into clinical trials followed by autologous stem cell transplant if remission is achieved.
6. ADOPTIVE IMMUNOTHERAPY:
Trials using EBV specific T lymphocytes are underway and show promising results.
7. UNCOMMON SUBTYPES OF PTLD
Burkitt lymphoma like, Plasmablastic and plasma-cell myeloma, T-cell lymphoma, Hodgkin lymphoma, extra-nodal marginal zone lymphoma subtypes of PTLD have no standardized data available to guide therapy. Guidelines recommend treatment of these subtypes as per guidelines available for immunocompetent patients with the added point of reduction in immunosuppression.
8. CNS involving PTLD
Any subtype can involve CNS but most common is monomorphic EBV associated PTLD with poorer prognosis as compared to no CNS involvement. Standard reduction of immunosuppression, Rituximab and chemotherapy and additionally radiotherapy and intrathecal chemotherapy are recommended. EBV specific T cell therapy can also help. SUPPORTIVE CARE:
Treatment related mortality remains an issue. All patients should be given G-CSF prophylaxis as well as considered for prophylactic antibiotics, antifungals and antivirals. Viral infection monitoring should be done including CMV, Hepatitis B & C and HIV. RE-TRANSPLANTATION:
After achieving complete remission for 1 year patient can safely be considered for re-transplantation. What is the level of evidence provided by this article?
Level 1 as it is evidence based consensus guideline.
Shah, N., Eyre, T.A., Tucker, D., Kassam, S., Parmar, J., Featherstone, C., Andrews, P., Asgari, E., Chaganti, S., Menne, T.F., Fox, C.P., Pettit, S., Suddle, A., Bowles, K.M. and (2021), Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline. Br. J. Haematol., 193: 727-740. https://doi.org/10.1111/bjh.17421
Summary of the article:
After skin is the 2nd most common cancer occurring in about 12% of patients usually in 1st post transplantation year. Early onset PTLD, is usually of B- cell type is linked to EBV infection.
20-40 % of PTLD are EBV –ve occurring >1 year post transplantation.
Multiorgan and intestinal transplants have the highest incidence of PTLD (20%) followed by lung transplants (3–10%), heart transplants (2–8%).
Updated guideline and recommendations for front-line management of PTLD following Solid Organ Transplant (SOT) .
Diagnosis and staging : needs
1- Histopathologic diagnosis by tissue biopsy is recommended.
2- CT is recommended in all patients.
3- a PET-CT used for staging in FDG-avid lymphoma .
Multidisciplinary approach to care:
– All cases should be discussed at a haemato-oncology MDT and organ transplant physicians .
– All diagnostic material should be reviewed by a haematopathologist .
Reduction of immunosuppression:
1- Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids.
2- Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond .
Rituximab +/# chemotherapy:
1- Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy .
2- Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab .
3- Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles.
4- Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise .
5- Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
6- PET-CT should be considered for interim and end of-treatment response assessment where available.
Radiotherapy:
The role of radiotherapy as a component of treatment for PTLD is undefined.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment:
He data is limited.
Recommendations
1- Involved-field radiotherapy may be offered for selected patients with PTLD .
2- In localised disease, radiotherapy may be offered concurrently with RIS .
3- Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFN a is not recommended.
Therapy for relapsed or refractory PTLD:
There are no prospective studies and the data is limited to case reports. Adoptive immunotherapy: 1- Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved. 2- Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD. 3- Patients with relapsed/refractory PTLD should be referred to clinical trials.
Burkitt lymphoma-like PTLD:
According to the studies , R-CHOP with RIS could be considered a reasonable treatment for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immunocompetent patient. Plasmablastic and plasma-cell myeloma PTLD:
There is a paucity of data to recommend any a standardised approach T-cell lymphoma PTLD:
Is a rare form of PTLD. occur later after SOT and are often has poor outcome. Hodgkin lymphoma PTLD:
Combined chemotherapy of (doxorubicin, bleomycin, vinblastine, dacarbazine) +/- radiotherapy may represent a safe and effective treatment with RIS in HL-PTLD patients. Extra-nodal marginal zone lymphoma – PTLD :
SOT is a risk factor for extra-nodal marginal zone lymphoma by 2-3 times. Treatment algorithms are heterogeneous and poorly standardised. Post-transplant lymphoproliferative disease affecting the CNS :
1- It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management.
2- Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity .
3- Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity .
4- Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD.
5- Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD .
As asuportive care
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered
to all patients with diagnosis of PTLD.
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed .
The immunosuppression following Solid Organ Transplantation (SOT) results in lymphoid proliferation which causes a spectrum of disorders which are represented as Post-Transplant Lymphoproliferative Disorder (PTLD). This article provides an updated form of guidelines for the frontline management of adult patients with PTLD.
Discussion
All diagnostic material, clinical information along with excision biopsy is recommended for PTLD sub-classification and subsequent ancillary investigations. If PET-CT is available, it should be used for staging. If not, CT is recommended.
All parts of the diagnostic material should be considered. A multidisciplinary team (MDT) with a lymphoma doctor in the lead should agree upon a management plan for all cases.
The International Prognostic Index (IPI) is chosen as the up-front scoring based on the recent analysis of CD20-positive B-cell PTLDs where IPI was incorporated and showed to be quite significant.
For commonest monomorphic subtype, data from prospective phase II studies provide treatment algorithms while for rare sub-types, small case series and case reports are used for treatment decisions.
Under the guidance of transplant physician, the azathioprine and MMF should be stopped and CNIs should be reduced. This should be done while maintaining or reducing corticosteroids.
CD20-positive B-cell PTLDs who fail RIS should be recommended for rituximab monotherapy. If patients fail to obtain CR or CMR after 4 weekly rituximab doses, 4 cycles of R-CHOP-21 immunotherapy is recommended.
Treatment with anti-viral, IVIG and IFNα is only for clinical trials and should not be done outside of it. PTLD patients with access to clinical trials should be offered it.
Relapse patients should be considered for clinical trials and selected for second line chemotherapy and autologous stem cell transplant.
Combining RIS with anthracycline-based chemotherapy is considered as proper approach for patients with good cardiac function having Peripheral T-Cell Lymphoma (PTCL) Hodgkin lymphoma PTLD patients are often excluded from clinal trial because lack of data. For patients with extra-nodal marginal zone, treatment that may be adopted is radiotherapy provided they are immunocompetent. Any less common PTLD should be approached with RIS for initial management.
PTLD patients should be offered PJP prophylaxis and G-CSF for ones taking chemotherapy.
At least one year of consideration is necessary for Re-transplantation.
PTLD represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT.
This document is an updated guideline and the recommendations for the management of adult patients with diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT).
Excisional or incisional biopsy is recommended to establish a diagnosis.
Where available a PET-CT should be used for staging in line with the recommendation for FDG-avid lymphoma.
Prognostic scoring:
Poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypalbuminaemia.
Another we can use is International Prognostic Index (IPI) for non-Hodgkin lymphoma.
Management:
Multidisciplinary approach to care with a experienced haemato-oncology, hematopathology and organ transplant physicians.
Reduction of immunosuppression:
Rituximab +/- chemotherapy:
Front-line therapy for monomorphic CD20-positive B-cell PTLD who fail to respond adequately to RIS as initial therapy.
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles.
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
PET-CT should be considered for interim and end of-treatment response assessment where available
In localised disease, radiotherapy may be offered concurrently with RIS.
Relapse:
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD.
CNS PTLD:
Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD
Prophylaxis:
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis.
Re transplantation:
Re-transplantation is dictated by clinical need and organ type.
A minimum of one year may be considered before re-transplantation, but a longer period may be needed.
Lymphoproliferative disorders represent 21% of all cancers of SOT recipients.
Post-transplant lymphoproliferative disease occur due to lymphoid proliferations caused by immunosuppression after SOT.
PTLD commonly occurs after skin cancer with high mortality rate ,it can develop early or late after transplantation but it’s highest incidence of occurrence is with multiorgan or intestinal transplantation ,followed by lung transplant ,then heart transplant ,then liver transplant then pancreatic transplant then the smallest incidence is with renal transplant.
PTLD is derived from B lymphocyte and is associated with EBV Diagnosis and staging
PTLD is divided into 4 histopathological categories which are non destructive, poly morphic ,monomorphic and classical Hodgkin lymphoma.
Diagnosis is difficult and staging requires using the Ann Arbor classification or the Lugano classification for staging lymphomas although using PETCT for PTLD staging is less well defined in comparison to lymphoma.
In fact PETCT has beneficial role in PTLD diagnosing , staging ,detecting new involved sites and post treatment relapse to some extent.
For cases with possible CNS involvement MRI ,CT imaging and CSF analysis will be needed.
-Surgical excisional or incisional biopsy is needed for diagnosis (alternative core needle biopsy) and PET CT is needed (alternative is CT ) for staging Multidisciplinary care
(MDT) need to involve transplant physicians, haemato-oncologists, haematopathologists,
radiation-oncologists and radiologists. Prognostic scoring
There is not a standardised prognostic scoring for PTLD ,however some ominous risk factors were acknowledged involving including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH and hypoalbuminaemia. PTLD management Reduction of Immunosuppression(RIS)
Can be done if applicable under transplant team supervision, representing the only therapy for low risk early stage disease, along with follow up for 2-4 weeks because in case of failure to reach complete remission , alternative treatment can be started in addition to close monitoring of rejection.
Cases who reached partial remission with RIS can either followed and be reassessed within 2-4 weeks or rituximab based therapy can be started.
There are American, SWOG and European Renal Guidelines for RIS.
It is recommended to RIS by stopping azathioprine and MMF ,decreasing CNIs to 30–50% and maintaining or reducing corticosteroids also early disease assessment is adviced for cases on RIS onlt in order to start alternative treatment soon if RIS alone failed. Rituximab +/- chemotherapy
– Monomorphic CD20-positive B-cell PTLD which is the most common PTLD forum.
Rituximab is used for treatment of polymorphic PTLD, or monomorphic DLBCL-like PTLD, unresponsive to initial RIS.
wasnot achieved —4 cycles of CHOP21
If RIS failed —-4 weekly IV Rituximab will be given —-If CR
was achieved—4X 3weekly IV Rituximab
A trial that used sequential 4 cycles of weekly IV Rituximab, followed by four cycles of standard-dose CHOP-21 chemotherapy every 21 days with GCSF and prophylaxis against PJP demonstrated better outcomes than using Rituximab alone also TRM was less in R-CHOP21 group compared to CHOP21 group.
At the same time some patients can not tolerate the combination therapy so attenuated or less toxic regimens can be tailored for them.
Special considerations are needed to be taken in each individual case as cardiac transplant recipents with vasculopathy can experience preserved LV EF HF
– Polymorphic CD20-positive B-cell PTLD treatment algorithms similar to monomorphic due to paucity of data on polymorphic
It includes IV Rituximab of 4 weekly standard cycle as monotherapy for cases who did not respond to RIS initially followed by 4 more 3 weekly cycles for cases with CMR while cases who did not reach remission can receive 4 cycles of RCHOP21.
Along with cardiac and renal assessment for SOT recipients.
PETCT is needed for evaluation of treatment response. Radiotherapy
A study proposed that adults with early-stage disease, apart from the histological subtype, can achieve CRs after surgical resection or radiotherapy, usually with concurrent RIS.
Radiotherapy can be applied for some extra-nodal sites, as the orbit, isolated CNS relapse and for localised extra-nodal marginal zone lymphomas of the MALT.
Radiotherapy with chemotherapy regimens can be used in nasal NK/T-cell lymphoma Antivirals, IVIG and interferon-alpha treatment
are not adviced outside clinical trials Therapy for relapsed or refractory PTLD
R/R PTLD cases post R-CHOP have poor prognosis, extrapolating treatments from R/R DLBCL in
immunocompetent patients can be offered, but with little evidence in R/R PTLD. Adoptive immunotherapy
EBV positive PTLD and R/R EBV-positive PTLD can be treated by EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy without graft rejection risk and the outcomes were acceptable.
These T lymphocytes are either autologous or extracted from a bank of partially matched HLA EBV-specific CTLs.
Chimeric antigen receptor (CAR)-T cells used for B-cell malignancies suggests it’s possible
role in the treatment of PTLD. Burkitt lymphoma-like PTLD
Rituximab monotherapy cannot induce remission
R-CHOP with concurrent RIS can be used for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immunocompetent patient ,Dose-adjusted EPOCH-R with CNS prophylaxis can be suitable in selected patients. Plasmablastic and plasma-cell myeloma PTLD
No sufficient data is available therefore RIS along with plasmacytoid dyscrasia disease in the immunocompetent cases can be used T-cell lymphoma PTLD
It is a rare forum ,that occurs late post SOT , it has a poor prognosis .
RIS with anthracycline-based chemotherapy was proposed for therapy .
Immunocompetent patients with T-cell lymphoma treatment algorithm can be applied. Hodgkin lymphoma PTLD
It is rare with no much data available, it is supposed to occur late after SOT.
HL-PTLD patients with normal cardiac and pulmonary function can be treated by standard combination chemotherapy with ABVD(doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy alongside RIS .
BEACOPP , Eescalated BEACOPP or BEACOPDac is an option in patients with high-risk disease but toxicities must be considered. Extra-nodal marginal zone lymphoma – PTLD
It’s risk increase with SOT.
Stomach is the most common site to be affected in MALT lymphoma, also colonic and small bowel involvement were dteceted.
EBV-positive MALT lymphoma occurs in the skin and can respond to RIS.
Rituximab monotherapy or Radiotherapy in certain cases are other options. CNS involvement in PTLD
CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive.
It is multifocal as detected by MRI and tissue biopsy can be needed.
Median OS is 33–47 months.
RIS with intrathecal chemo and whole brain radiotherapy ,outcomes were acceptable.
Systemic chemotherapy with CNS penetration is the standard for primary CNS lymphoma in immunocompetent.
Rituximab with RIS can be used in patients unfit for chemotherapy.
EBV-specific CTLs can be used in patients with EBV-positive CNS-PTLD post HSCT or SOT Supportive care
G-CSF as primary prophylaxis can be useful in patients with PTLD having high TRM.
Antibiotic ,antiviral and antifungal treatment can be considered for cases with neutropenia
PJP prophylaxis in all PTLD cases
CMV surveillance is adviced, patients with HBV ,HCV or HIV need to be treated . Retransplant
Can be considered after PTLD control as it’s recurrence rate is low post transplant.
One year gap is considered as a minimum period before re-transplantation varing according to the organ and clinical need.
Introduction :
PTLD is not uncommon complication post SOT , its the 2nd most common malignancy after skin malignancy post transplant ( 21 % of all cancers ) , the incidence depends on the age , which organ is transplanted and type of immunosupression .
the majarty of cases occurs in the 1st year Post transplantation and associated with EBV infection , about 20-40 are EBV negative and occurs usually after the 1st year of transplantation .
there is four types of PTLD Non-destructive , Polymorphic , Monomorphic and Classical Hodgkin Lymphoma .
Diagnosis and staging :
comprehensive clinical information including the date of transplant, immune suppression regimen and organ type should be obtained .
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative .
Staging with a CT is recommended in all patients where PET-CT is not available
Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma .
MDT team should be involved in the management PTLD including : transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists
Prognostic scoring :
There is no universally accepted prognostic scoring system specific for PTLD till now , there is mang ongoing studied and trial to achieve that , but in general there is many adverse risk factors including : poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH , and hypoalbuminaemia .
Management :
1) Reduction of immunosupression .
The 1st line mangment for PTLD is reduction of immunosupression , in low risk patient and early disases this strategy could be the only treatment required for cure ,
there is many protocols for RIS according to the staging of diseaes
Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function . “
Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond
2) Rituximab +/- chemotherapy
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy .
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 .
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles .
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise .
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
3) Radiotherapy and Antivirals treatment
In localised disease, radiotherapy may be offered concurrently with RIS .
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials .
Therapy for relapsed or refractory PTLD
No prospective data to guide therapy.
Evidence base is limited to case reports.
R-CHOP is a logical approach if no responsive to rituximab.
R/R PTLD post R-CHOP have a poor prognosis.
Patients offered enrolment in a clinical trial.
Adoptive immunotherapy:
Intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved .
EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD .
Patients with R/R PTLD offered clinical trials .
Extra-nodal marginal zone lymphoma – PTLD
Extra-nodal marginal zone lymphoma – PTLD SOT is estimated to increase the risk of developing MALT lym- phoma by two- to threefold.
The predominant site of involvement of MALT lymphoma is gastric, although there are isolated cases of colonic and small-bowel involvement.
Is a disease of the central nervous system that affects between 10 and 20% of patients who have received a stem cell transplant.
The risk of CNS lymphoma is elevated in SOT recipients, but it remains within the range of 10 to 20% in PTLD.
RIS is routinely performed, usually alongside radio- therapy resulting in an ORR of 75% in one series 111.
Chemotherapy with rituximab and high-dose methotrexate (HD-MTX) is the standard for immunocompetent primary CNS lymphoma , but may be challenging to administer safely in patients with a compromised central nervous system (CNS-PTLD).
Extrapolating regimens from immunocom- petent can be considered on a case-by-case basis
Patients with less common forms of post-transluminal polycystic ovary syndrome (PTLD) should be considered for treatment with radiotherapy with ris as part of their initial management , the World Health Organization (WHO) has advised.
Supportive care
Patients with a history of CMV infection or hepatitis B or C infection should be monitored by a hepatologist.
G-CSF should be offered to all patients with diagnosis of PTLD (1B) and PJP prophylaxis is recommended for those receiving chemotherapy and radiotherapy, according to the World Health Organization (WHO) Guidelines for Treatment of Post-Chemotherapy Liver Disease (PCLD) have been published by the WHO.
Re-transplantation
May be considered after successful control of PTLD as the risk of recurrence of PTLD after re-trans- plantation is low.
A period of one year should be considered as a minimum before re-plantation depending on the organ and clinical need.
Summary of the article:
PTLD is the second most common malignancy after skin cancer (21%) in transplant recipients; occur mostly in the first-year post-transplant, a second peak after around 10years have been noted.
Early onset PTLD, derived from B lymphocytes, are associated with EBV infection.
EBV-negative cases account for 20–40% of PTLD, occur >1 year after transplantation, with a second peak occurring about 10 years post-transplant.
Multiorgan and intestinal transplants have the highest incidence of PTLD (20%) followed by lung transplants (3–10%), heart transplants (2–8%).
This article composed of Updated guideline and recommendations for front-line management of PTLD following Solid Organ Transplant (SOT).
Diagnosis and Staging:
Clinical info, basic tests and viral assay; Bone marrow biopsy (selected cases) Surgical excision / incisional / core needle biopsy is diagnostic – ancillary tests, markers, IHC Staging with CT scan neck, chest abdomen and pelvis – for treatment plan, and as baseline to compare response to treatment. (Fdg18) PET-CT scan is preferred over CT, in line with the recommendation for FDG-avid lymphoma (1B) – detected additional sites of disease in 28% of cases, upstaging in 15% compared to CT.
Special cases: Echocardiography (cardiotoxic drugs); Sperm cryopreservation CNS or craniofacial involvement – MRI / CT imaging of brain, orbits and sinuses; CSF Flow-cytometry Types of PTLD: 1. Non-destructive – florid follicular hyperplasia, early PTLD 2. Polymorphic – B-cell in stages of maturation, mixed with T cells; >90% EBV-associated 3. Monomorphic – 60–80% of PTLD; resemble diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma; 70% have cytogenetic abnormalities (Trisomy 9, 11; loss of 17p; rearrangement of 8q24 (MYC) 4. Classical HL – 90% associated with EBV Prognostic scoring systems devised from adverse risk factors: poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH and hypo-albuminemia.
v International Prognostic Index (IPI) for non-Hodgkin lymphoma: is pragmatic choice
v Ghobrial prognostic score – has limited utility
v PTLD Prognostic Index: (variation of IPI) – Age, ECOG performance status, LDH
Management: No RCT data available; Limited knowledge from case reports / case series
Multidisciplinary (MDT) meeting involving haemato-oncologist, haemato-pathologist experienced in PTLD management, organ transplant physicians. 1. Reduction of immunosuppression (RIS) Stopping Azathioprine and MMF, and reduction of CNI by 25–50%; maintaining Prednisone 7.5-10mg; Frequent monitoring to look for rejection
– RIS aims to partially restore T-cell function.
– may suffice in patients with low-risk early lesions, low-stage, non-bulky disease Assess response at 2-4 weeks – if no response à Retuxi +/- Chemo 2. Rituximab +/- chemotherapy: Front-line treatment for monomorphic CD20-positive B-cell PTLD, who fail to respond adequately to RIS. Evidence from International phase II PTLD-1 trial: sequential therapy of 4 cycles of weekly IV Rituximab (375 mg/m2) followed by 4cycles of CHOP-21 chemotherapy every 21 days, with GCSF support – median OS of 6.6 years and plateau on PFS curve, is better than Rituximab monotherapy alone (median OS 1.2–3.5 years).
Ø 2.A Rituximab monotherapy – recommended for CD20-positive PTLD, who fail to respond adequately to RIS initial therapy (1B). Complete Response (CR) or complete metabolic remission (CMR) after 4 cycles of weekly Rituximab à 4 further three-weekly cycles of rituximab are recommended (1B). Ø 2.B Failure to obtain Complete Response or CMR after 4 cycles of weekly Rituximab, or clinical progression during Rituximab monotherapy à 4 cycles of R-CHOP-21 chemotherapy recommended 3. Rituximab + Anthracycline therapy(R-CHOP-21) with RIS is directly recommended for patients diagnosed with clinically aggressive lymphoma with critical organ compromise (1B).
4. Local Radiation + RIS +/- Retuximab – may be offered in localised disease Cardiac (2D Echo) and renal function assessment should be done in all SOT recipients or patients with renal or cardiac impairment (1B) Interim or end of-treatment response assessment – by PET-CT (if available). Relapse / Refractory cases: Late Relapse post-Retuximab-monotherapy: sequential R-CHOP like front-line therapy R/R PTLD post R-CHOP: poor long-term survival (OS < 20%) — patients should be carefully selected for salvage chemotherapy followed by consolidation autologous stem cell transplantation (ASCT). Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD CNS PTLD: 10 and 20% of PTLD; high grade B cell lymphoma, mostly EBV positive (30-40% are EBV negative) RIS à combination Retuxi + Chemotherapy – in suitable patients (adequate organ function and comorbidity) Local Radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors EBV-specific CTL can be considered for EBV-positive CNS-PTLD Hodgkin lymphoma PTLD (HL-PTLD) HL-PTLD had a five-year OS of 57% compared to 80% for HL-immunocompetent patients. RIS + Combination Chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) +/- Radiation may represent a safe and efficacious option Supportive care and Prophylaxis – G-CSF for patients receiving chemotherapy and PJP prophylaxis for all patients Re-Transplantation After successful control of PTLD, risk of recurrence of PTLD after re-transplantation is low. Can plan depending on clinical need, organ type and availability. Minimum waiting period – at least 1 year relapse free period may be considered, although longer period may be needed.
Summary
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT.This document is an updated guideline and the recommendations for the management of adult patients with diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT). PTLD type Non-distructive Monomorphic Polymorpjic Classical HL Diagnosis and staging
surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Where available a PET-CT should be used for staging in line with the recommendation for FDG-avid lymphoma Prognostic scoring
Poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia. Another we can use is International Prognostic Index (IPI) for non-Hodgkin lymphoma
Management
Multidisciplinary approach to care with a expirenced haemato-oncology, haematopathologist and organ transplant physicians.
Reduction of immunosuppression
Rituximab +/- chemotherapy Front-line therapy for monomorphic CD20-positive B-cell PTLD who fail to respond adequately to RIS as initial therapy
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
PET-CT should be considered for interim and end of-treatment response assessment where available
In localised disease, radiotherapy may be offered concurrently with RIS .
Relapse
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD
CNS PTLD
Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD
Prophylaxis
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis
Re transplantation
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed.
PTLD AFTER SOLID ORGAN TRANSPLKANT – BRITISH SOCIETY FOR HEMATOLOGY
21 % OF ALL CANCER ARE PTLD
SECOND MOST COMMON AFTET SKIN ACNCER
ASSOCIATED WITH MORTALITY
SAME INCIDENCE EVEN AFTER 1 YEAR ( CONTRARY TO EARLIER BELIEF)
COMMON AFTER MULTI ORGAN AND INTESTINAL , LUNG , HEART, LIVER, PANCREAS AND LEAST IN KIDNEY ( DECREASING ORDER)
TYPES OF PTLD
– NON DESTRUCTIVE LIEK INFECTIOUS MONONUCLEOSIS
POLYMORPHIC – WITH T CELLS
MONOMORPHIC – B CELLS – MOST OF THE LESIONS ARE INCLUDED , BURKIT , MALT LYMPHOMA
CLASSIC HODGKINS LYMPHOMA
STAGING
APART FROM ROUTINE BLOOD LABS, EXCISION OR INCISIONAL BIOPSY IF POSSIBE TO SUBTYPE THE PTLD LESION
CT SCAN OF NECK , THORAX AND ABDOMEN
PET SCAN IS ADVISABLE
MRI FOR CNS INVOLVEMET
CSF EXAM
MDT APPROACH
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management,
with input from the organ transplant physicians
” All diagnostic material should be reviewed by a haematopathologist
POOR PROGNOSIS
poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or
bone marrow involvement, raised lactate dehydrogenase
(LDH) and hypoalbuminaemia.
MANAGEMENT
NO RCT AVAILABLE
REDUCTION OF IMMUNOSUPPRESSION (IS) TO RESTORE T CELL FUNCTION
STOPP AZATHIPRINE AND MMF
CNI REDUCTION 50% OR 75 % ON CLINICAL URGENCY
STERIOD REDUCTION TILL PHYSIOLOGICAL LEVEL OF 7.5 MG /DAY ON CLINICAL UREGENCY BASIS
IN CASE OF KIDNEY , REDUCTION IN IMMUNOSUPPRESSION IS MORE FEASIBLE AS ALTERNATIVE THERAPY FOR REJECTION IS AVAILABE
ASSES THE RESPONSE TO IS BY 2-4 WEEKS
IN CASE OF COMPLETE RESPONSE- REASSESSMENT AT 4-6 WEEKS IS ONLY REQUIRED
IN CASE OF PARTIAL RESPONSE , RETUXIMAB +/- CHOP
IN CASE OF FAILURE , RETUXIMAB AND THEN CHOP AS SEQUENTIAL THERAPY
MONOMORPHIC B CELL PTLD – WELL STUDIED EVIDENCE BASED THERAPY IS AVAILABE
4 WEEKLY DOSE OF RETUXIMAB 375 MG PER METER SQ FOLLOWED BY RESPONSE ASSESSMNET BY CT
IF COMPLETE RESPONSE – CONSIDR THE CASE AS LOW RISK
IF PARTIAL RESPONSE ON CT SCAN – CONSIDER CHOP CHEMO
ONE MORE CONCEPT IS RESPONSE ADAPTED TREATMENT WHEREIN RESPONSE TO RETUXIMAB IS TAKEN AS GOOD PROGNOSTIC FACTOR AND DISEASES IS LABELLED AS LOW RISK . THIS MINIMISES TREATMENT RELATED MORTALITY
POLYMORPHIC PTLD
ABOVE PRINCIPLES STILL APPLIES HERE
IN ADDITION , Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at
any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
RADIOTHERAAPY
UNDEFINED ROLE
LIMITED DISEASE CAN BE TREATED WITH RESECTION AND RT PLUS RDUCTION IN IS
LYMPHOMA PROTOCOL TO BE FOLLOWED
RELPASED OR REFRACTORY DISEASE
R-CHOP CAN BE USED
ADAPTIVE IMMUNOTEHRAPY WITH EBV POSITIVE CYTOTOXIC T CELL IS UNDER TRAIL AND IS PROMISING
BURKITT LYMPHOMA LIKE PTLD
RETUXIMAB IS NOT FOUND TO BE USEFULL
R- CHOPP WITH REDUCTION OF IS IS THE CHOCE
T CELL LYMPHOMAA LIKE PTLD
LESS ROLE OF RETUXIMAB
R- CHOPP WITH REDUCTION OF IS IS THE CHOCE
HODGKIN LYMPHOMA PTLC
RETUXIMAB HAS LESS ROLE
CHEMOTHERAPY IS TEH CHOIC ALONG WITH REDUCTION OF IS
CNS LESION AS PTLD
The histology of CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive
CASE TO CASE BASIS
REDUCTION IN IS AND RAADIOTEHRAPY IS TEH CHOICE
MRI FOR ASSESSMENT
MANAEMENT OF TRM ( TREATMENT RELATED MORBIDITY )
LIBERAL USE OF G-CSF IN NEUTROPENIA WITH FEVER
COTRIAMAXAZOLE FOR PIP PROPHYLAXIS
FLUCONAZOLE FOR FUNGAL PREVENTION
RETRANSPLANTATION
SO FAR 27 KIDNEYS WERE RETRANSPLANTED WITH GAP OF 20-100 MONTHS POST TREATMENT
RECURRENCE OF PTLD IS RARE
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following solid organ transplant.
Lymphoproliferative disorders account for 21% of all cancers of solid organ transplant recipients, as compared with 4–5% within the immunocompetent population. PTLD is a common malignancy after skin cancer.
EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation more severe than EBV positive patients. Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Reduction of Immunosuppression:
– It is the mainstay of therapy
– the EBV negative cases are less responsive.
– RI can reverse 20% – 80% of patients with PTLD.
– RI includes: CNI reduction by 50% , along with withdrawal of the
antimetabolites and maintain Steroids.
– In critically ill cases should consider withdrawal of all IS medications except
Steroids.
– Switch to mTORi.
– Monitoring allograft function for rejection.
– Assess disease response assessment early (at 2–4 weeks) by CT.
– If PR achieved or in those that fail to respond; can consider sequential therapy Rituximab +/- chemotherapy RCHOP- 21 used in addition to RI.
Rituximab therapy:
– CD20 +ve B-cell PTLD approached 75% of TR.
– The overall response to RTx monotherapy approached 44%-79%.
Chemotherapy R-CHOP- 21
– 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
· Post-transplant lymphoproliferative disease results from lymphoid proliferations that occurs due to immunosuppression following SOT.
· Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population
· PTLD is a common malignancy after skin cancer with different incidence according to patient age, transplant type and the degree of immunosuppression.
· The majority of cases in the western world are derived from B lymphocytes and are EBV-associated, particularly in the first-year post SOT.
· EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years
Diagnosis and staging
· Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
· Staging with a CT is recommended in all patients where PET-CT is not available (1A).
· Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
· Categories of PTLD: Non-destructive, Polymorphic, Monomorphic, and Classical Hodgkin Lymphoma
Multidisciplinary approach to care
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
· All diagnostic material should be reviewed by a haematopathologist (1A).
Management of PTLD
Reduction of immunosuppression:
· This may be the only treatment required for a select group of patients with low-risk patients which have early lesions, low-stage disease and non-bulky disease.
· After 2–4 weeks, if a complete remission (CR) is obtained, then no other therapy may be required in patients with low risk factors
· Patients that achieve a PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks or further rituximab-based treatment may be considered as described in the section Rituximab +/- chemotherapy Recommendations
· Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
· Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab +/- chemotherapy
· Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
· 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 (1B).
· Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
· Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
· Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
· PET-CT should be considered for interim and endof-treatment response assessment where available (1C).
Radiotherapy
· Localised monomorphic type DLBCL and Hodgkin lymphoma (HL) PTLD could be considered for treatment with RIS and combined modality treatment in line with standard practice outside the setting of PTLD, or in combination with RIS +/- rituximab in DLBCL if the patient is not eligible for intensive chemotherapy.
· Radiotherapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localised extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
· Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
· In localised disease, radiotherapy may be offered concurrently with RIS (2C).
· Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Adoptive immunotherapy
· Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
· Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
· Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Burkitt lymphoma-like PTLD
· R-CHOP with concurrent RIS could be considered a reasonable option for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immunocompetent patient.
· However, dose-adjusted EPOCH-R with appropriate CNS prophylaxis may also represent a clinically appropriate option in selected patients aiming to achieve curative therapy, given clear data for efficacy and tolerability outside the PTLD setting.
T-cell lymphoma PTLD
· Combined RIS with anthracycline-based chemotherapy if good cardiac function.
Hodgkin lymphoma PTLD
· standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function.
Extra-nodal marginal zone lymphoma – PTLD
· SOT is estimated to increase the risk of extra-nodal marginal zone lymphoma by 2-3 folds.
· The predominant site of involvement of MALT lymphoma is gastric, although isolated cases of colonic and small-bowel involvement are described
· Occasionally EBV-positive MALT lymphoma occurs in the skin and may respond well to RIS in the first instance.
· Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option.
Post-transplant lymphoproliferative disease affecting the central nervous system
· Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
· Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
· Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C). Supportive care
· G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation
· Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Introduction
The term “post-transplant lymphoproliferative disease” refers to a variety of illnesses brought on by lymphoid proliferations as a result of immunosuppression after SOT.
PTLD is a common malignancy in SOT recipients, associated with significant cancer-related mortality.
PTLD is most common in the first year post-transplantation, with EBV-associated cases being the most common.
EBV-negative cases account for 20-40% of PTLD, with peak incidence at 10 years.
Diagnosis and staging
Excision biopsy samples should be utilized to permit precise sub-classification, and staging and response evaluations are crucial for proper PTLD diagnosis and therapy.
For PTLD management, staging and response assessments are crucial, and they should be documented using the Ann Arbor or Lugano categorization.
A multidisciplinary approach to care
A management plan should be agreed upon by a core multidisciplinary team (MDT) which should include
Transplant physicians,Haemato-oncologists,Hematopathologist,Radiation-oncologists and radiologists.Prognostic scoring
Although there is no widely used prognostic grading system for PTLD, detrimental risk factors such
· Low-performance status,
· EBV-negative tumor,
· Graft involvement,
· Monomorphic histology, Advanced age,
· CNS or bone marrow involvement,
· Elevated LDH,
· Hypoalbuminemia.
Management of PTLDReduction of immunosuppressionReduction in immunosuppression should be used to restore T-cell function in low-risk patients with early lesions, low-stage disease,
and non-bulky disease.
Rituximab +/− chemotherapy Front-line therapy for monomorphic CD20-positive B-cell PTLD
PTLD has a CD20-positive, B-cell monomorphic histology similar to DLBCL. Patients with polymorphic PTLD who are not responding to first RIS are often treated with rituximab as standard care. Polymorphic CD20-positive B-cell PTLD
Management of polymorphic CD20-positive B-cell PTLD is the same as monomorphic PTLD, with an overlap with Hodgkin Lymphoma PTLD.
RadiotherapyCurrently available analysis suggested that adults with the limited-stage disease, regardless of the histological subtype, can obtain durable complete remission after surgical resection or radiotherapy, usually with a concurrent reduction in immunosuppression.
Antivirals, intravenous immunoglobulin, and interferon-alpha treatment: Data is lacking to demonstrate effective EBV-positive lymphoproliferative disorders with antiviral agents or immunoglobulins. IFNα is not recommended for EBV-positive lymphoproliferative disorders due to a lack of data.
Therapy for relapsed or refractory PTLDIn patients who are unresponsive to rituximab, R-CHOP is a reasonable and logical approach for R/R PTLD, with a sequential approach if relapse occurs late. R/R PTLD post-R-CHOP has poor long-term survival with OS <20%.
Adoptive immunotherapy CTL immunotherapy offers an alternative to graft rejection in EBV-positive PTLD.
EBV-specific CTLs either use a bank of partly HLA-matched EBV-specific CTLs to produce autologous EBV-directed CTLs from the recipient’s own cells or use their own cells to produce T-cell immune-mediated responses against these aberrant B cells.
Supportive care
Prophylactic administration of G-CSF if the risk of febrile.
Antibiotic, antifungal (e.g. fluconazole), and antiviral (e.g. acyclovir) prophylaxis during therapy,
The advent of highly active antiretroviral therapy (HAART) has made chemotherapy much more tolerable in the HIV-infected non-transplant population with lymphoma.
Summary
Post-transplant lymphoproliferative disease occur as a result of immunosuppression post solid organ transplant- SOT .
Lymphoproliferative disorders account for 21% of all cancers of SOT recipients and it is a common malignancy after skin cancer. it depends upon age, transplant type and the degree of immunosuppression. Most cases are Epstein–Barr virus (EBV)-associated.
Accurate diagnosis and staging are important in planning treatment.if feasible excision biopsy should be done. Staging used are Ann Arbour classification.
also bood test i,e. full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH), HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres should be done
for Imaging CT is recommended in these patients. when available a PET-CT should also be done. with Multidisciplinary approach is needed. Categories of PTLD
non-distructive
monomorphic
polymorpjic
classical HL treatment includes Reduction in IS, chemotherapy, Ritux, Radiation, IVIG, adoptive therapy and even retransplantation.
For early stage and low risk cases MMF/AZA can be stopped, and CNI should be reduced by 50% with close monioring for rejection. Rituximab has become a standard of care in patients with polymorphic PTLD, or monomorphic DLBCL-like PTLD, who are unresponsive to initial therapy and CD20+.
If remission is not achieved with Rituximab alone or if disease progressive in nature then R -CHOP should be given
Radiotherapy may be considered for some extra-nodal sites, Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes.
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa are tried in cinical trials only and not recommended yet. 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. Intrathecal chemotherapy or radiotherapy can be considered if CNS involment is there. Retransplant
This can consider but a waiting time of at least 2 years post complete remission.
Post-transplantation lyphoproliferative disorder is complication of immunosuppression drugs. 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%.
Diagnosis and staging; For accurate diagnosis the lesion needs excision biopsy and histology. Baseline investigation, LDH, Urate, Lactate, Viral serology, HIV, HCV, HBV, EBV, CMV/EBV titers, Bone marrow biopsy, Echocardiography, CT chest, abdomen, and pelvis, MRI brain, Other special measures like cryopreservation for male and female sperm banking, For further staging need PET-Scan to apply Lugano Classification.
Prognostic scoring; Different prognostic scores are being utilized but no agreement yet, so till date there is no specific prognostic scoring system. Because not applicable, majority of patient up-to 96% have monomorphic disease. However, IPI has edge compared to others. 1. Ghobrial prognostic score, 2. International prognostic score, 3. PTLD prognostic index, However, the risk factor can guide the prognosis like older age, EBV negative PTLD, CNS bone marrow involvement, monomorphic histology, elevated LDH and low albumin level serum.
Management; The recipient developed PTLD will need multidisciplinary approach like dermatologist, surgeon, oncologist, hematologist, and radiologist. Till for EBV-associated disease there is management consensus, but for rarer sub types and refractory disease there is no such randomized trails and guidelines. Usually decision of therapy is made after according to extent of disease and clinical picture. The European and American guidelines says to reduction of immunosuppression, usually is this done for low grade and low risk patients to restore T-cell function, usually respond. If no response then second line treatment with rituximab +/- chemotherapy (CHOP). If extensive disease stop agents except for maintaining prednisolone. According to SWAG protocol stop antimetabolite agents, decrease cyclosporine by 75%, continue prednisolone. Rituximab is indicated for monomarphic and polymorphic disease like DLBCL-like PTLD, total of four doses weekly bases, followed by four cycles of standard doses of CHOP-21 chemotherapy. In aggressive disease with compromised organs rituximab plus anthracycline based regimen is recommended. Patient with refractory disease post R-CHOP should be selected for second line chemotherapy followed by stem cell transplant. Radiotherapy, its role is undefined, but can be used in specific histological and localized cases.
Adaptive immunotherapy; For EBV positive PTLD there is another approach that is cytotoxic T-cell lymphocyte immunotherapy while avoiding the risk of rejection. If available should be considered. In trail of total 33 patients who have failed initial therapy the overall response rate was 52%. In addition another small trail shows promising result who were refractory to rituximab.
Post –transplant lymphoproliferative disease remains between 10 to 20% of PTLD. They should be treated initially by RIS and wait for response, if no response then should be considered for combination of chemotherapy.
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, Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT.
PTLD is a common malignancy after skin cancer and is associated with a significant cancer-related mortality.
PTLD has been reported to occur most frequently in the first year following transplantation.
The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, particularly in the first year post SOT. EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.
renal transplant recipients having the lowest incidence of PTLD ( 0.8–2.5 %).
Diagnosis and staging
Hx date of transplant, immune suppression regimen and organ type
PET-CT detected additional sites of disease in 28% of cases, resulting in upstaging in 15% when compared to CT alone.
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative
• Staging with a CT is recommended in all patients where PET-CT is not available
• Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma
Multidisciplinary approach to care
management plan should be agreed by a core multidisciplinary team (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists
cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians .
• All diagnostic material should be reviewed by a haematopathologist
Management of PTLD
Reduction of immunosuppression
immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team.
This may be the only treatment required for a select group of patients with low-risk patients which have early lesions, low-stage disease and non-bulky disease. response should be assessed within 2–4 weeks
some guidelines suggest stopping all immune suppression in certain clinical scenarios. However, this should only be done with guidance from the transplant team and only if absolutely necessary.
Reduction of CNIs by 50% Consider stopping azathioprine/MMF Maintain prednisolone 7.5/10 mg/day
Rituximab +/chemotherapy
Front-line therapy for monomorphic CD20-positive B-cell PTLD
The commonest form of PTLD has a CD20-positive, B-cell monomorphic histology similar to DLBCL
The response to RIS was assessed early between two and four weeks and failure of RIS was followed by sequential treatment with rituximab and subsequently by CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy in adult B-cell PTLD.
Radiotherapy
retrospective analysis suggested that adults with limited-stage disease, regardless of the histological subtype, can obtain durable CRs after surgical resection or radiotherapy, usually with concurrent RIS.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
use of interferon alfa (IFNa) remains historical and there are no new developments to recommend its use outside of clinical trials.
Recommendations
• Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes
• In localised disease, radiotherapy may be offered concurrently with RIS
• Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials
Therapy for relapsed or refractory PTLD
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD. The evidence base is limited to case reports across various histological subtypes.
Adoptive immunotherapy
autologous or allogeneic EBV-directed CTLs should be considered in patients with R/R EBV-positive PTLD.
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD
• Patients with relapsed/refractory PTLD should be offered clinical trials where available
Burkitt lymphoma-like PTLD
Burkitt-like PTLD has many features in common with sporadic Burkitt lymphoma, but some differences can be observed. A strong association with EBV is described, along with an association with 11q aberrations in patients presenting with typical histopathological features but without a demonstrable MYC rearrangement.
Supportive care
Recommendation
• G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD
Re-transplantation
Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re-transplantation is low.
A period of one year should be considered as a minimum before re-transplantation depending on the organ and clinical need.
This article is about one of the important malignency that appear in post transpla peroid which is PTLD .THis type of malignancy the second common type of cancer after skin cancer in SOT.
PTLD is account foe 21% of malignancy in post TRX while it is only 4% in general populations .
PTLD is related to EBV + virus which is common in the first year post transplant while the EBV – IS associated with late onset .
How to diagnose PTLD we need rutine work up including CBC,CMP,LFT,LDH CSF in case of CNS involvment .Echo as base line is mandatory as one of the chemotherapy traetmen t is cytotoxic to the heart .
staging of the PTLD IS Need to do excisional bviopsy as main corner and PET scan for staging purposes. Ct scan in case PET not available .
Reduction of IS is the main treatmen t for the low grade and non bulking disease , alomg with stop of antimetabolites medications . This group of patient need close follow up every 2 to 4 weeks for possible relaps .
Rituximab îs for treatment for EBV + PTLD and monomorphic disease with CD20+.Need to start by RIS and RTX every 4 weeks if CR occure that it other wise the patient may need to go for other type of chemotherapy like CHOP regime .
still the chemotherapy is depends on the type of lymphoma
Front-line management of PTLD in adult SOT— A British Society for Haematology Guidelines
Lymphoproliferative disorders (PTLD) is the second most prevalent malignancy in adult recipients of solid organ transplants, behind skin cancer, and poses a significant mortality risk.
The risk is increased when an EBV-negative recipient receives a transplant from an EBV-positive donor, when there is strong immunosuppression such as ATG induction and tacrolimus-based maintenance therapy, when immunosuppression is at its peak in the first year after transplantation, and when transplanted organs such as the small bowel and heart-lung.
90% of PTLD are EBV-positive and derived from B cells, with the remaining 10% deriving from T cells.
Lymphoproliferative disorders account for up to 21% of all Cancer post transplant in comparison to approx. 4.5% in the healthy non transplant group.
PTLD is common in 1st 1 yr post transplant ,commonly EBV +VE PTLD while EBV -VE that comprises 20-40% of all PTLD occurs after 1 yr with a second peak at 10 years.
Histomorphological description categorizes PTLD into four groups.
1-Non-destructive; includes plasmacytic hyperplasia, infectious mononucleosis-like cells, and florid follicular hyperplasia. Most EBV-associated cases are early PTLD.
2-Polymorphic; B-cell maturation stages with T cells, EBV-associated in >90% instances.
3-Monomorphic; 60–80% of PTLD are DLBCL, Burkitt lymphoma, plasma cell myeloma, or plasmacytoma. Indolent B-cell lymphomas and T-cell neoplasms are diagnosed less often. EBV-negative monomorphic PTLD.
4-Classical Hodgkin Lymphoma: This is classical Hodgkin lymphoma and usually (>90%) associated with EBV.
Diagnosis and staging:
1-Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
2-Staging with a CT is recommended in all patients where PET-CT is not available (1A).
3-Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Essential pre-treatment baseline evaluation for all patients diagnosed with PTLD:
2-Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres .
3-Bone marrow biopsy is indicated and some selected patients it may not be clinically needed or appropriate .
4-Echocardiography where appropriate and potentially when cardiotoxic agents are being used .
5-Fertility-preserving treatments, such as sperm cryopreservation for male and referral to a fertility specialist in female patients, should be considered for eligible patients .
6-Details should include; date of transplant, organ type and immunosuppresion regimen .
7-all patients require assessment of the function of the transplanted organ, ideally directed by the transplant physician .
8-All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response .
9-Where available, PET-CT scan should be utilised for staging over CT scan .
Multidisciplinary approach to care:
1-All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
2-All diagnostic material should be reviewed by a haematopathologist (1A).
Treatment of PTLD
1- Immunosuppression reduction:
Withdrawal of azathioprine and MMF and reducing CNIs by 30–50% while maintaining or reducing corticosteroids in all patients whenever possible under the advice of the transplant physician with graft function monitoring (1B).
Patients receiving RIS alone should be assessed for disease response at 2–4 weeks to see if they need additional treatment (1B).
2- Rituximab +/- chemotherapy:
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
-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 (1B).
-Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
-Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
-Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
3- Radiotherapy: Used incorporation with chemotherapy in some sort of PTLDs.
may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse, and localised extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
4- Antivirals, intravenous immunoglobulin and interferon-alpha treatment:
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
5- Therapy for relapsed or refractory PTLD:
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Adoptive immunotherapy is a permissive modality of treatment in some R/R PTLD.
Extra-nodal marginal zone lymphoma – PTLD:
EBV-positive MALT lymphoma may respond well to RIS, Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option.
Radiotherapy is an effective treatment.
Post-transplant lymphoproliferative disease affecting the central nervous system:
Intrathecal chemotherapy and whole-brain radiotherapy.
Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate with rituximab.
Supportive care:
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Recommendations:
All patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Re-transplantation: Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
but as by Prof. Dr Ahmed Halwa better to wait a 2 year for Re-Transplant
FRONTLINE MGT OF PTLD IN ADULT SOT RECIPIENTS -BSC GUIDELINES.
Lymphoproliferative disorders account for up to 21% of all Ca post transplant in comparison to approx. 4.5% in the healthy non transplant group.
PTLD is common in 1st 1 yr post transplant ,this is mostly EBV +VE PTLD while EBV -VE that comprises 20-40% of all PTLD occurs after 1 yr with a second peak at 10 years.
PTLD is classified as; Non destructive, Polymorphic, Monomorphic and Classical Hodgkin’s Lymphoma.
DIAGNOSIS & STAGING.
An excision biopsy is recommended to get a histological diagnosis.
Where available, a PET Scan is used for staging it into the various Ann Arbor categories. In absence of a PET scan, a CT scan can be used for staging prior to treatment.
Baseline pre treatment workups need to be done ; FHG,UECS,LFTS,HIV,HEP B,HEP C serologies, LDH,CMV/EBV DNA etc A csf analysis is indicated in those with CNS symptoms. ECHO should be done in those at risk of cardiovascular dx prior to initiating Chemo.
MANAGEMENT
An MDT approach with a transplant physician,hematologost,oncologist,pathologist,radiologist,psychiatrist and nutritionist should be involved in discussing the individual pt prior to starting treatment.
Reduction of Immunosuppressive Medication.
For those with low risk, non bulky disease, RIS should be done and response gauged in2-4 weeks, if CR, no other therapy indicated, we monitor the patient for any rejection, while for those with PR, we either monitor for a further 2-4 weeks or consider adding Rituximab.
Recommendation is to stop antimetabolites and decrease CNIs by 30-50% and maintain/reduce steroids when possible and again monitor for rejection.
RTX +/- Chemo.
This is 1st line for monomorphic CD20+VE B cell PTLD.
After RIS ,if in remission, maintain, if RIS failed, consider 4 weekly 375 mg/m2 or IV RTX, if CR proceed to 4×3 weekly 375mg/m2 IV RTX, if no CR, give CHOP-21.PCP prophylaxis should be considered while on chemo and infection monitored.
For patients unable to tolerate the above, single agent RTX, steroids, oral etoposide and alkylating agents can be considered.
Polymorphic CD20+VE B Cell PTLD.
This is treated as monomorphic or Hodgkin’s lymphoma if an over lap occurs.
NB – Response to treatment should be assessed by a CT Scan if symptoms progress and at the end of treatment.
Radiotherapy.
Candidates include;
a. Pt with limited dx in combination with SX/RIS.
b. Pts with extra nodal dx ;orbit, CNS etc not eligible for chemo.
c. Rare PTLD; nasal NK/T cell lymphoma.
.Antivirals/IVIG and interferon alpha.
Use recommended within a clinical trial.
Refractory PTLD.
Salvage therapy with autologous stem cell transplant or enrollment into a clinical trial should be discussed with the patient. Refractory carries a poor prognosis.
Adoptive immunotherapy.
Autologous /allogenic CTL to be considered in those with EBV +VE PTLD.
Burkitt lymphoma like PTLD.
R CHOP +RIS to be considered.
Dose adjusted EPOCH R with CNS prophylaxis is another option in specific patients.
Plasmablastic and plasma cell myeloma PTLD.
Treated as plasmacytoid dyscrasia in healthy population.
T Cell lymphoma PTLD.
This is treated using the same algorithm as those in the general population.
HL PTLD
ABVD +/- DXT +RIS in those with normal cardiac and lung function.
BEACOPP/Escalated BEACOPP or BEACOPDac to be considered in those with high risk disease.
Extra nodal marginal zone lymphoma PTLD
Main site is gastric for MALT lymphoma.
EBV+VE MALT -RIS +/- RTX.
DXT to be adopted as per healthy pts guidelines with extra nodal marginal zone lymphoma.
PTLD affecting the CNS.
Estimated to affect 10-20% of PTLD. Typically monomorphic,high grade B cell Lymphoma that are EBV +VE.
Treatment options;
-RIS
-DXT
-Chemo with CNS penetration -high dose methotrexate. RTX may be added to chemo.
Supportive care.
G-CSF to prevent infection in those with high risk of febrile neutropenia.
Antibiotics, antivirals and antifungals prophylaxis esp if treatment associate d with a low white cell count.
Septrin to be considered in those with a hx of PCP.
A hepatologist should be involved in managing those with Hep B and C infection.
Re transplantation.
This can be evaluated after 1 yr control of PTLD. A minimum of 1 yr should lapse before evaluation.
II. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline
Summarise this article
Introduction
Post-transplant lymphoproliferative disease (PTLD) is a common malignancy following solid organ transplantation (SOT) and is associate with a significant cancer-related mortality.
The incidence of PTLD varies with the level of immunosuppression, type of transplant and patient’s age. Lymphoproliferative disorders are more common in SOT recipients compared to immunocompetent people (21% vs 5%).
Most PTLD cases are EBV-positive and occur within the first-year post-transplant. On the other hand, EBV-negative PTLD accounts for 20-40% of the cases and mostly occur after the first-year post-transplant with a second peak after ten years.
PTLD is most common among multiorgan and intestinal transplants (20%) while the lowest incidence is reported among kidney transplants (0.8-2.5%).
Four histopathological categories have been described i.e., Non-destructive, Polymorhic, Monomorphic and Classical Hodgkin lymphoma type
Diagnosis and staging
Patients with PTLD require baseline investigations as indicated, these include: – CBC, UEC, LFT, LDH, uric acid, viral screen (HIV, HBV, HCV, EBV, CMV), bone marrow biopsy.
For staging purposes, staging CT scans (neck, chest, abdomen, pelvis) or a PET-CT scan can be done.
Additional investigations in patients with CNS involvement include: – brain MRI or CT scan and a diagnostic lumbar puncture.
A biopsy (surgical excisional or incisional or core needle biopsy) is essential to establish the diagnosis.
Multidisciplinary approach to care
A multidisciplinary team composed of the transplant physicians, radiologists, hematopathologists, hemato- and radio- oncologists should all be engaged in patient care.
Prognostic scoring
Currently there is no universally approved prognostic scoring system for PTLD. However, a number of adverse risk factors have been recognized i.e., older age, EBV-negative status, graft involvement, monomorphic histologic type, elevated LDH, low serum albumin, CNS or bone marrow involvement, poor performance status.
Management of PTLD
Unfortunately, there are no RCTs to guide on management of PTLD.
Reduction of immunosuppression
Reduction in immunosuppression (RIS) helps to partially restore the patient’s T-cell function. This approach is adequate for low-risk patients i.e., patients with early lesions, low-stage and non-bulky disease.
Following RIS, response to treatment should be reassessed in 2-4weeks.
· Patients who achieve complete remission following RIS should be closely monitored for rejection given the reduction in immunosuppression.
· Patients who achieve partial remission, can be monitored and assessed again in another 2-4weeks or can be considered for rituximab ± chemotherapy
There is no specific guidance on RIS but there are recommendations i.e., stop MMF and azathioprine, reduce CNI dose by 30-50% but maintain or reduce the corticosteroid dose while monitoring the graft function.
Rituximab ± chemotherapy
o CD20+ PTLD patients who do not respond to RIS should be offered rituximab monotherapy i.e., 4 cycles of weekly standard-dose rituximab.
o If they achieve complete remission (CR) or complete metabolic remission (CMR), they should be offered four further 3-weekly cycles of rituximab.
o Patients who fail to achieve CR after 4 cycles of weekly standard-dose rituximab or patients who deteriorate clinically during these 4 cycles should be offered 4 cycles of R-CHOP-21.
o Patients with clinically aggressive lymphoma with compromise of critical organs should receive R-CHOP-21 automatically.
o A cardiac and renal function assessment should be done for all SOT patients.
o PET-CT scan should be done to assess response to treatment where available.
Radiotherapy
The role of radiotherapy in treatment of PTLD is not well defined.
Radiotherapy can be considered in the following instances: –
o Limited-stage disease with concurrent RIS
o Extra-nodal sites e.g., orbit
o Isolated CNS relapse
o Localized extra-nodal marginal zone lymphomas of the MALT type
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
These agents are not recommended outside clinical trials.
Therapy for relapsed or refractory PTLD
There is no data to guide treatment.
R-CHOP can be considered in patients who do not respond to rituximab.
Patients who do not respond to R-CHOP or who relapse post R-CHOP have poor outcomes since autologous stem cell transplantation (ASCT) remains a challenge among SOT patients. In such cases, intensive second-line chemotherapy should be considered followed by ASCT if the patient achieves a good remission.
Adoptive immunotherapy
In this therapy, EBV-specific cytotoxic T-lymphocytes (CTLs) use either the patients’s own cells are used to generate autologous EBV-directed CTLs or a bank of partially HLA-matched EBV specific CTLs to generate a T-cell immune-mediated response to the abnormal B cells.
EBV-directed CTLs (autologous or allogeneic) should be offered to patients with relapsed or refractory EBV-positive PTLD.
Burkitt lymphoma-like PTLD
Rituximab monotherapy has been found to be inadequate.
R-CHOP in addition to RIS is a viable option.
Assessment for CNS involvement should be done at baseline and CNS prophylaxis considered.
Plasmablastic and plasma-cell myeloma PTLD
There is no data to guide treatment. However, Treatment offered is similar to that for plasmacytoid dyscrasia disease in addition to RIS.
T-cell lymphoma PTLD
This form of PTLD is rare, occurs later after SOT and is associated with poor outcomes.
There is paucity of data to guide treatment, but RIS and anthracycline based chemotherapy can be considered in patients with adequate cardiac function.
Hodgkin lymphoma PTLD (HL-PTLD)
Classical HL-PTLD is rare, occurs late post-SOT, unfortunately there is no data to guide treatment.
RIS in addition to standard combination chemotherapy i.e., ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) ± radiotherapy is considered a safe and efficacious option in HL-PTLD patients with normal pulmonary and cardiac function.
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,
procarbazine, prednisolone) can be used with caution in high-risk patients due to the hematological and infection-related toxicities associated with this regimen.
Extra-nodal marginal zone lymphoma PTLD
SOT increases the risk of extra-nodal marginal zone lymphoma. The most predominant site of MALT lymphoma is gastric. There are no specific treatment guidelines but RIS, rituximab monotherapy and radiotherapy have been found to be effective in selected cases.
Post-transplant lymphoproliferative disease affecting the central nervous system
CNS-PTLD accounts for 10-20% of PTLD cases and is associated with a poor prognosis.
Tissue biopsy provides the definitive diagnosis, it helps rule out opportunistic infections which present with similar findings on MRI.
Optimal therapy for CNS-PTLD remains unknown, but the possible treatment options include: –
o RIS alongside radiotherapy
o RIS, whole-brain radiotherapy and intrathecal chemotherapy
o RIS with concurrent chemotherapy in patients not fit for radiotherapy
o Systemic chemotherapy with CNS penetration i.e., high-dose methotrexate in selected cases
o EBV-specific CTLs in EBV-positive CNS-PTLD patients where available
Supportive care
Primary prophylaxis with G-CSF is recommended in PTLD patients treated with combination immunochemotherapy since this treatment is associated with significant treatment related mortality.
Prophylaxis with antibiotics, antivirals (e.g., acyclovir), antifungals (e.g., fluconazole) and G-CSF should be considered in PTLD patients at risk of febrile neutropenia.
Co-trimoxazole should be offered in all PTLD patients.
Surveillance for CMV should continue.
Liver function tests should be monitored in patients with past hepatitis B or hepatitis C infection. Hepatitis B viral load should be considered as well.
Initiation of HAART in HIV patients has been shown to make chemotherapy more tolerable.
Re-transplantation
Risk of PTLD recurrence after re-transplantation is low. The timing of re-transplantation depends on the organ and the clinical need. A minimum of one year is acceptable before re-transplantation can be considered. However, a longer period might be needed i.e., at least 2 to 5 years after PTLD clearance. This gives the immune system adequate time to recover to increases the probability of a successful re-transplant.
PTLD:
Is a common post-transplant malignancy second to skin cancer
Result from lymphoid proliferation associated with immunosuppression most are EBV
Positive, 20_40percent EBV negatives .lung multi organ transplant more associated with PTLD. , renal
Transplant is least affected other organ like pancreases, heart liver Transplantation also affected with PTLD. Diagnosis:
Staging should be recorded using the Ann Arbor classification or the Lugano classification which is the recommended classification for staging following Positron Emission Tomography–Computed Tomography (PET-CT) in 18F-fluorodeoxyglucose -avid (FDG-avid) nodal lymphomas.
Complete hematology, chemistry panel, virology screening, echocardiogram, plus minus BM biopsy. Fertility-preserving treatment. Classification:
Non-destructive, Polymorphic, Monomorphic and Classical Hodgkin Lymphoma.
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haematopathologist. Prognostic scoring:
International Prognostic Index the IPI was statistically significant, with low IPI risk (0–2 points) exhibiting a superior, OS compared to high IPI risk (≥3 points) at three years (OS 78% vs 54%, respectively, P = 0.0003).27 Thus, the IPI is a pragmatic choice of up-front score to use. Management of PTLD: Reduction of immunosuppression: Low-risk patients which have early lesions, low-stage disease and non-bulky disease.
Response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond.
If a complete remission (CR) is obtained, then no other therapy may be required in patients with low risk factors.
Close monitoring for rejection of the SOT.
Patients that achieve a PR by RIS alone can either be monitored or reassessed within a further 2–4 weeks or further rituximab-based treatment.
Recommendations
Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function. Rituximab +/# chemotherapy:
A standard of care in patients with polymorphic PTLD, or monomorphic DLBCL-like PTLD, who are unresponsive to initial RIS.
Sequential therapy:
of four cycles of weekly intravenous rituximab at standard dose (375 mg/m2 ) followed by four cycles of standard-dose CHOP-21 chemotherapy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF). This approach resulted in a median OS of 6.6 years and a clear plateau on the PFS curve.
Patients with a low risk of disease progression are ALSO defined as those who achieve a CR after the first four courses of rituximab monotherapy and those with an IPI of 0–2 who achieve a g. This strategy increases the number of PTLD patients who only require rituximab monotherapy and is likely to reduce grade 3–4 leucopenia, infection and subsequently the TRM, but retaining a similar OS.
In case of clinical signs of disease progression at any time during rituximab monotherapy or before interim staging, restaging should be performed prematurely, and RCHOP-21 should be considered to commence immediately if disease progression is confirmed.43–45 Response to treatment can be assessed by CT; however, even though the role of interim PET-CT is not yet established it can be considered a more sensitive tool for interim response assess. Radiotherapy:
The role of radiotherapy as a component of treatment for PTLD is undefined.
Radiotherapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localized extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
In rare forms of PTLD, radiotherapy tends to be incorporated with the chemotherapy regimens such as in nasal natural killer/T-cell lymphoma.
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials. Therapy for relapsed or refractory PTLD:
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD. Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C). Adoptive immunotherapy:
EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV positive PTLD whilst avoiding the risk of graft rejection. Burkitt lymphoma-like PTLD
R-CHOP with concurrent RIS could be considered a reasonable option for Burkitt-like PTLD.
Dose-adjusted EPOCH-R with appropriate CNS prophylaxis may also represent a clinically appropriate option in selected patients. Plasmablastic and plasma-cell myeloma PTLD:
Recommend a standardized approach and therefore it is reasonable to treat as for the plasmacytoid dyscrasia disease. T-cell lymphoma PTLD:
Combine RIS with anthracycline-based chemotherapy. Hodgkin lymphoma PTLD:
Rare PTLD.
Treatment standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function Extra-nodal marginal zone lymphoma – PTLD
Site of involvement of MALT lymphoma is gastric, although isolated cases of colonic and small-bowel involvement are described.
Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option. Post-transplant lymphoproliferative disease affecting the central nervous system:
Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with.
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD. Supportive care:
Use G-CSF as primary prophylaxis.
Antibiotic, antifungal (e.g. fluconazole) and antiviral (e.g. acyclovir) prophylaxis during therapy.
Prophylaxis with co-trimoxazole for all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia. Re-transplantation:
A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Post-transplant lymphoproliferative disease represents spectrum of disorders resulting from lymphoid proliferationsthat 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
Diagnosis and staging:
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
· Staging with a CT is recommended in all patients where PET-CT is not available (1A).
Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Multidisciplinary approach to care:
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
· All diagnostic material should be reviewed by a haematopathologist (1A).
Management of PTLD:’
· Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) isrecommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab +/- chemotherapy:
· Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
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 (1B).
Four cycles of R-CHOP-21 immuno chemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ! 3) after four cycles of weekly standard-dose Rituximab or who clinically progress during these four cycles (1B).
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
· Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
· PET-CT should be considered for interim and endof- treatment response assessment where available (1C).
· Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
· In localised disease, radiotherapy may be offered concurrently with RIS (2C).
· Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD:
· Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
· Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Plasmablastic and plasma-cell myeloma PTLD:
·It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
· Treatment of less common forms of PTLD with standard- of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
· Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
·Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care:
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation:
· Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period
Post-transplant lymphoproliferative disease results from lymphoid proliferations that occur as a result of immunosuppression post solid organ transplant- SOT . Lymphoproliferative disorders account for 21% of all cancers of SOT recipients. PTLD is a common malignancy after skin cancer. Incidence depends upon to patient age, transplant type and the degree of immunosuppression. Most cases are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated.
Diagnosis and stagin
Accurate diagnosis and staging are important in planning treatment.
Where possible excision biopsy should be done. Staging uses Ann Arbour classification.
Blood tests– These include Full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH), HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres. In some situation a bone marrow may be required.
Imaging Staging CT is recommended in all patients. when available a PET-CT should be done.
MDT Approach
All cases should be discussed at a haemato-oncology MDT
there should be an input from the organ transplant physicians
All investigations must be reviewed by haematologist
Categories of PTLD
These include-
Non destructive
Mono Morphic
Polymorphic
Classical Hodgkin lymphoma
Management
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.
Radiotherapy
Radiotherapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localised extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type. Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials
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
CNS PTLD
Intrathecal chemotherapy or radiotherapy can be considered.
Retransplant
This can considered 2 years post complete remission.
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT. PTLD subtypes: Non-destructive, Polymorphic, monomorphic, Hodgkin Lymphoma Baseline invest: – FBC, U&E, LFT, LDH, urate, BM, HIV, HCV, HBV, EBV, CMV +/- Bone marrow – ECHO – Staging PET scan (better) or CT CAP – Fertility-preserving treatments for eligible patients Diagnosis and staging
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A)
Staging with a CT is recommended in all patients where PET-CT is not available (1A).
Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B)
MDT:
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haematopathologist (1A)
Management of PTLD 1- Reduction of immunosuppression
Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
2- Rituximab +/- chemotherapy
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
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 (1B).
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B)
3- Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
In localised disease, radiotherapy may be offered concurrently with RIS (2C).
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C)
Therapy for relapsed or refractory PTLD
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Post-transplant lymphoproliferative disease affecting the central nervous system
It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C)
Supportive care: G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B). Re-transplantation: Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Management-of-PTLD-A-British-Society-for-Haematology-Guideline: PTLD is second most common cause of solid organ transplant after skin cancer.
It’s account 21% of all solid organ transplant.
Incidence of PTLD depend on age and type of transplant and degree of immunosuppressive therapy.
PTLD is associated with EBV and mainly B lymphocytes.
Diagnosis and staging of PTLD:
It’s mainly by PET-CT which are important for staging of PTLD.
MRI and CT brain, orbits and sinus is recommended in patients with CNS lymphoma.
Lumper puncture and CSF analysis is important for cytology and flow cytometry.
Multidisciplinary approach to care:
It’s need care and discussion regarding policy of treatment by transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
Prognostic scoring:
There’s no specific prognostic factors in PTLD. However prognostic factors associated with risk factors as fallowing
Poor performance status
EBV-negative tumour
Graft involvement
Monomorphic histology
Older age
CNS or bone marrow involvement
Raised lactate dehydrogenase (LDH)
Hypoalbuminemia.
Management of PTLD:
Reduction of immunosuppression:
Reduce calcinurine inhibitors to 30-50%, and continue steroid dose but stop azathioprine and MMF.
Start Rituximab and chemotherapy
Rituximab is a monoclonal anti-CD20 antibody against B cell .
Radiotherapy in case of CNS lymphoma.
Antivirals, intravenous immunoglobulin in case of EBV associated with PTLD.
interferon-alpha treatment is not recommended.
R-CHOP used in case of relapse PTLD.
Patients with relapse and refractory PTLD post R-CHOP have a poor long term survival.
So can treat with autologous stem cell transplant.
EBV positive can treat by adoptive immunotherapy ( EBV-specific cytotoxic T-lymphocyte immunotherapy);
Burkitt lymphoma-like PTLD treatment with R-CHOP-like regimen and EPOCH-R.
T-cell lymphoma PTLD:
It’s occur later after solid organ transplant and carry poor outcome.
Hodgkin lymphoma PTLD:
It’s rare and can treat with complications chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy.
Extra-nodal marginal zone lymphoma – PTLD:
treatment with rituximab and radiotherapy .
Post-transplant lymphoproliferative disease affecting the central nervous system: CNS lymphoma
It’s account 10% from PTLD post solid organ transplant .
It’s carrying poor prognosis
It’s treatment with systemic chemotherapy like high-dose methotrexate with rituximab.
Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re- transplantation is low.
Time of re transplant is depend on organ and clinical situations.
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.
The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, particularly in the first year post SOT. EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.
PTLDs are sub-classified into four histopathological categories as follows:
· Non-destructive: Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia. Most cases are EBV-associated and usually present as early PTLD
· Polymorphic: A spectrum of B-cell maturation stages with admixture of T cells, EBV-associated in >90% cases
· Monomorphic: Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma. Much less commonly indolent B-cell lymphomas, usually mucosa-associated lymphoid tissue lymphoma5,11,12 and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative. Approximately 70% of these lesions are reported to have cytogenetic abnormalities, including trisomy 9 and 11 or both, loss of 17p and rearrangement of 8q24 (MYC)
· Classical Hodgkin Lymphoma: Morphologically this fulfils the conventional criteria for the diagnosis of classical Hodgkin lymphoma and is generally (>90%) associated with EBV
Diagnosis and staging:
Recommendations:
· Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
· Staging with a CT is recommended in all patients where PET-CT is not available (1A).
· Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Multidisciplinary approach to care:
Recommendations:
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
· All diagnostic material should be reviewed by a haematopathologist (1A).
Prognostic scoring:
There is no universally accepted prognostic scoring system specific for PTLD. This is a result of most prognostic scores included varying risk factors, heterogeneous patients or treatments and often being retrospective or single-institution series. However, a number of adverse risk factors have been identified in various prognostic scoring systems including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia.
Management of PTLD: Reduction of immunosuppression:
Recommendations:
· Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
· Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab +/# chemotherapy:
Recommendations:
· Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
· 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 (1B).
· Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
· Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
· Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
· PET-CT should be considered for interim and endof-treatment response assessment where available (1C).
Radiotherapy:
The role of radiotherapy as a component of treatment for PTLD is undefined. Retrospective, non-randomised heterogeneous case series include patients treated predominantly with RIS and/or chemotherapy, with 7–25% of cases having radiotherapy included in their initial management.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment:
Recommendations:
· Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
· In localised disease, radiotherapy may be offered concurrently with RIS (2C).
· Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD:
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD.
Adoptive immunotherapy:
Recommendations:
· Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
· Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
· Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Burkitt lymphoma-like PTLD:
The largest series of 20 patients with Burkitt-like monomorphic PTLD demonstrated that rituximab monotherapy was inadequate at inducing sustained remission (n = 3). Seventy-three per cent (8/11) of patients receiving an R-CHOP-like regimen [R-CHOP, n = 9; EPOCH-R (EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and rituximab), n = 1; CHOP n = 1] with concurrent RIS attained a CR, which was similar to results obtained with more dose-intensive chemotherapy and concurrent RIS [LLA/LB97 protocol n = 2; CODOX-M/IVAC n = 1; Burkimab regimen n = 3 (5/6) 83% CR].95 These results are supported by a small sub-analysis of seven patients pooled from the PTLD-1 trial and a German PTLD registry.
Plasmablastic and plasma-cell myeloma PTLD:
There is a paucity of data on these subtypes to recommend a standardised approach and therefore it is reasonable to treat as for the plasmacytoid dyscrasia disease in the immunocompetent. RIS should be incorporated in the management algorithm.
T-cell lymphoma PTLD:
Patients with adequate cardiac function is to combine RIS with anthracycline-based chemotherapy. Treatment algorithms used in immunocompetent patients with T-cell lymphoma can be reasonably adopted on T-cell lymphoma PTLD patients.100 There are no published cases describing the use of ASCT in first remission in the setting of PTCLNOS (not otherwise specified) PTLD.
Hodgkin lymphoma PTLD:
Standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function.
Extra-nodal marginal zone lymphoma – PTLD:
The predominant site of involvement of MALT lymphoma is gastric, although isolated cases of colonic and small-bowel involvement are described. Treatment algorithms are heterogeneous and poorly standardised. Occasionally EBV-positive MALT lymphoma occurs in the skin and may respond well to RIS in the first instance. Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option. Radiotherapy is an effective treatment in this setting.
Post-transplant lymphoproliferative disease affecting the central nervous system:
Recommendations:
· It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
· Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
· Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
· Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
· Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care:
Recommendation:
· Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C)
Please summarise this article
-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 theimmunocompetent population.
– In adult SOT recipients,mPTLD is a common malignancy after skin cancer and is associated with a significant cancer-related mortality.
– The reported incidence varies according to patient age, transplant type and the degree of immunosuppression.
-The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, particularly in the first year post SOT. EBV-negative cases account for approximately 20–40% of PTLD and usually
occur after the first year of transplantation.
-In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%). Diagnosis and staging
-Where possible, excision biopsy samples are recommended to enable accurate PTLD sub-classification and to provide sufficient material for subsequent ancillary investigations. Where this is not possible, a core needle biopsy is an
alternative .
-Staging with a CT is recommended in all patients where PET-CT is not available .
-Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma . Multidisciplinary approach to care
-Patients with PTLD present a multifaceted clinical challenge.
-All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians.
– All diagnostic material should be reviewed by a haematopathologist . Prognostic scoring
-A number of adverse risk factors have been identified in various prognostic scoring systems including poor performance status, EBV-negative tumour, graft
involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia. Management of PTLD Reduction of immunosuppression
Where safe to do so, immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team. RIS aims to partially restore T-cell function.
-Where RIS is being considered as the sole initial treatment, response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond. Rituximab +/_ chemotherapy
-The commonest form of PTLD has a CD20-positive, B-cell monomorphic histology -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) after four cycles of weekly standard-dose rituximab .
– Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles .
– Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise .
-Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected
-PET-CT should be considered for interim and end of- treatment response assessment where available. Radiotherapy
-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes .
– In localised disease, radiotherapy may be offered concurrently with RIS .
-Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials . Therapy for relapsed or refractory PTLD
-Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good
remission is achieved .
-Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD .
-Patients with relapsed/refractory PTLD should be offered clinical trials where available . PTLD affecting the central nervous system
-The histology of CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive.
-The overall prognosis is generally considered poor.
– It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management .
-Treatment of less common forms of PTLD with standard- of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to
potential toxicity and patient comorbidity .
– Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity .
-Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD .
-Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD . Supportive care
-G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD . Re-transplantation
-Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period
may be needed .
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline Please summarise this article
# Introduction:
*This study is an updated guideline and details the recommendations for the front-line management of adult patients with an established diagnosis of (PTLD) after (SOT).
*PTLD describe a range of disorders following lymphoid proliferations that develop as a consequence of immunosuppression post- SOT.
*It is estimates as 21% of all malignancies of SOT, as compared with 4–5% within the immunocompetent community.
* In adult it is a common cancer after skin cancer and is associated with high incidence of death.
*Many cases are arise from B lymphocytes and are (EBV)-associated, especially in the first year post SOT, however the incidence of EBV-negative is 20–40% and develop after the first year of transplantation, with a second peak of incidence occurring at 10 years.
# Diagnosis and staging:
*All diagnostic material should be accompanied by relevant clinical information (date of transplant, IS regimen and organ type.
*Excision biopsy is recommended to enable accurate PTLD sub-classification and to provide sufficient material for subsequent ancillary investigations.
*Staging should be recorded using the Ann Arbor classification or the Lugano classification.
(Where possible a surgical excisional or incisional
Biopsy if not possible, a core needle biopsy is an
alternative).
*Staging with a CT is recommended in all patients where PET-CT is not available.
(Where available a PET-CT should be utilised for staging
in line with the recommendation for FDG-avid lymphoma).
*A management plan should be agreed by (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
*There is no universally accepted prognostic scoring system specific for PTLD but the international
Prognostic Index (IPI) for non-Hodgkin lymphoma can be recommended.
* IPI is based on the baseline parameters age, stage of disease, EGOG performance status, extra-nodal site involvement and LDH.
#Management of PTLD
# Reduction of immunosuppression (RIS)
*RIS aims to partially restore T-cell function.
*The only treatment required for a select group of patients with low-risk patients which have early lesions, low-stage disease and non-bulky disease.
*Evaluate the patients within 2–4 weeks and alternative protocol can be promptly initiated in those patients that fail to respond.
*If a complete remission (CR) is obtained, then no other therapy may be required in patients with low risk factors.
*Close monitoring for rejection.
*Patients that achieve a PR by RIS alone can either be reassessed within a further 2–4 weeks or recommended rituximab-based treatment.
***Reduction of IS by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function.
# Rituximab +/chemotherapy:
*Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
*4 further 3-weekly cycles of rituximab are recommended
in patients who obtain CR or complete metabolic remission (CMR) after 4 cycles of weekly standard-dose rituximab.
*4 cycles of R-CHOP-21 immunochemotherapy are
recommended in patients who fail to obtain CR or
CMR after 4 cycles of weekly standard-dose rituximab or who clinically progress during these four cycles.
*Rituximab plus anthracycline-based therapy is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise.
*Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
* PET-CT should be considered for interim and endof- treatment response assessment where available.
# Radiotherapy Antivirals, intravenous immunoglobulin and interferon-alpha treatment
*Involved-field radiotherapy may be offered for selected
patients with PTLD in line with standard protocols
for specific histological subtypes.
* In localised disease, radiotherapy may be offered concurrently with RIS.
*Treatment with anti-viral agents and/or arginine butyrate,
IVIG and IFNa is not recommended outside clinical trials.
# Therapy for relapsed or refractory PTLD / Adoptive immunotherapy
*Patients that relapse post-R-CHOP should be carefully
selected for intensive second-line chemotherapy followed
by autologous stem cell transplant if a good remission is achieved.
*Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD.
*Patients with relapsed/refractory PTLD should be offered clinical trials where available.
# Post-transplant lymphoproliferative disease affecting the central nervous system
*All patients with the less common forms of PTLD be considered for RIS as part of their initial management .
*Treatment of less common forms of PTLD with standard- of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity.
* Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity.
* Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be
offered in CNS-PTLD.
* Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
# Supportive care :
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD.
# Re-transplantation:
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed .
(In the UK they usually they wait for 2 years after completing clearance before re-transplantation).
This article entails an updated guideline and recommendations for the front-line management of adult patients with an established diagnosis of PTLD following SOT.
Diagnosis:
Surgical excisional or incisional biopsy is recommended.
A core needle biopsy is an alternative (1A).
Staging:
CT where PET-CT is not available (1A).
Multidisciplinary approach to care:
Cases discussed at a haemato-oncology MDT meeting, with input from the transplant physicians (1A).
Diagnostic material reviewed by a haematopathologist (1A).
Prognostic scoring
No universally accepted system specific for PTLD.
Adverse risk factors identified in different prognostic scoring systems including: poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH and hypoalbuminaemia.
Prognostic scoring system utilised in PTLD include:
Ghobrial prognostic score
International Prognostic Index (IPI) for non-Hodgkin lymphoma is a pragmatic choice of up-front score to use.
PTLD Prognostic Index
Management of PTLD
No data available from RCTs due to rarity of the disease.
Robust data from prospective phase II are available for the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL).
Reduction of immunosuppression:
RIS (stop azathioprine & MMF & reduce CNIs by 30–50%, & maintain or reduce steroids) in all patients whenever possible (1B).
Early disease response assessment (at 2–4 weeks) following RIS so that further treatment can be used in non-responders (1B).
Rituximab +/- chemotherapy:
Rituximab monotherapy for patients with CD20-positive PTLD who fail to respond to RIS (1B).
4 further 3-weekly cycles of rituximab in those who obtain CR or CMR) after 4 cycles of weekly standard-dose rituximab (1B).
4 cycles of R-CHOP-21 in those who fail to obtain CR or CMR after 4 cycles of weekly standard-dose rituximab or who clinically progress during these 4 cycles (1B).
Introduction
Lymphoproliferative disorders are approximately 21% of all cancers among solid organ transplantation recipients, and 4-5% within the immunocompetent population. Post-transplantation lymphoproliferative disorders (PTLD) is a common malignancy and is associated with a significant cancer-related mortality. The incidence is dependent on patient age, type of transplant, and the level of immunosuppression.
Diagnosis and staging
To establish a diagnosis, it is recommended to perform a biopsy – either an excisional or incisional, if not possible then a core biopsy may be an alternative. The diagnostic material should accompany a thorough clinical history. The evaluation should allow for staging with a PET-CT or a CT scan. For patients with suspected CNS involvement, it is recommended to perform a MRI and a lumbar puncture for CSF analysis.
A multidisciplinary team that includes transplant physicians, hemato-oncologists, hematopathologists, radiation-oncologists and radiologists should handle all cases, as the patients require a multifaceted approach to their management.
Some of the risk factors that have been identified include poor performance status, EBV-negative tumor, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase and hypoalbuminemia.
Management of PTLD Reduction of immunosuppression (RIS)
Where safe to do so, the immunosuppression should be reduced immediately, which is appropriate treatment for low-risk patients who have early lesions, low-stage disease and non-bulky disease.
If patients fail to respond to RIS after 2-4 weeks, alternative treatment should be initiated. Therefore, close monitoring for rejection and PTLD is required.
RIS should also be considered as an adjunctive therapy in patients with more advanced disease.
RIS involves stopping azathioprine and MMF and reducing the dose of CNIs.
Rituximab and chemotherapy
Rituximab can be used as monotherapy, and is recommended for patients who fail to respond to RIS that was used as initial therapy.
Rituximab can be used in conjunction with CHOP-21 immunochemotherapy for patients who fail to respond to the standard 4 cycles of weekly rituximab. This treatment can also be initiated for patients with clinically aggressive lymphoma.
It is important to monitor cardiac and renal function during the treatment.
Radiotherapy
Radiotherapy can be considered for patients in conjunction with other treatment modalities, for localized disease and in rare forms of PTLD.
The dose and fractionation regimen follows normal lymphoma protocols.
Antivirals, IVIG and interferon-alpha treatment
They are not recommended to be used outside clinical trials.
Therapy for relapsed or refractory PTLD
Patients who have relapsed and refractory PTLD should be selected for second line chemotherapy, and followed by autologous stem cell transplant if a good remission is achieved. The patients should also be offered clinical trials where available.
Burkitt lymphoma-like PTLD
Studies have shown that RIS with R-CHOP should be considered for Burkitt-like lymphoma. CNC examination should be done prior to initiation of treatment, and carefully monitored during treatment. CNS prophylaxis should be considered.
Plasmablastic and plasma-cell myeloma PTLD
There is limited data on the subject and therefore a standardized treatment approach is not available. The disease may be treated as done in immunocompetent patients. RIS should also be incorporated in the management.
T-cell lymphoma PTLD
It is a rare form of PTLD, and is associated with poor outcomes. It is suggested to combine RIS with an anthracycline-based chemotherapy.
Hodgkin lymphoma PTLD
Standard chemotherapy of ABVD, with RIS should be considered for treatment, for patients with normal cardiac and pulmonary function.
Extra-nodal marginal zone lymphoma – PTLD
Rituximab as a monotherapy has been shown to be effective. Radiotherapy can also be added to the management protocol.
PTLD affecting the CNS
Patients with PTLD affecting the CNS should be initiated on RIS, and a combination chemotherapy with rituximab. Local radiotherapy and corticosteroids have also shown to be useful.
Supportive care and re-transplantation
Patients should be carefully monitored for concomitant infections. Antibiotic, antifungal and antiviral prophylactic treatment should be considered. Re-transplantation should be considered in patients after careful clinical assessment, and is dictated by organ type.
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
PTLD:Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT.
· Account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.
· PTLD has been reported to occur most frequently in the first year following transplantation.
· The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated.
· EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation with a second peak of incidence occurring at 10 years.
· Incidence of PTLD in SOT: recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%) followed by lung transplants (3.0–10%), heart transplants (2.0–8.0%), liver transplants (1.0–5.5%), pancreatic trans- plants (0.5–5.0%) and renal transplant recipients having the lowest incidence of PTLD (0.8–2.5%).
· PTLDs are sub-classified into four histopathological categories: Non-destructive, Polymorphic, Monomorphic and Classical Hodgkin Lymphoma.
PTLD; Diagnosis and staging
1. Relevant clinical information; date of transplant, immune suppression regimen and organ type.
2. CBC, KFT, LFT, LDH and blood sugar.
3. Virology: HIV 1 &2, HBV &HCV, EBV serology, CMV/EBV DNA titres.
4. Bone marrow biopsy may be clinically indicated in some cases.
5. Excision biopsy samples to enable accurate PTLD sub-classification.
6. Staging should be recorded using the Ann Arbor classification or the Lugano classification following Positron Emission Tomography–Computed Tomography (PET-CT).
7. MRI or CT imaging of the brain, orbits and sinuses is recommended for patients with suspected central nervous system (CNS) or craniofacial disease.
8. Diagnostic lumbar puncture for cerebrospinal fluid (CSF) analysis, including cytology and flow cytometry, is recommended for patients with suspected CNS involvement. PTLD;Multidisciplinary approach to care
· A management plan should be agreed by a core multidisciplinary team (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD managemen with input from the organ transplant physicians (1A).
· All diagnostic material should be reviewed by a haematopathologist(1A). PTLD; Prognostic scoring
· No universally accepted prognostic scoring system specific for PTLD.
· Adverse risk factors: poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia. PTLD; Management 1. Reduction of immunosuppression
· immediate reduction in immunosuppression (RIS) by 25% in limited diseases and up to 50% in extensive disease. Response should be assessed within 2–4 weeks, If a complete remission (CR) is obtained, then no other therapy may be required.
· Patients that achieve a PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks or further rituximab-based treatment.
· Consider stopping AZA/MMF. Maintain prednisolone 7.5/10 mg/day.
· Failure of RIS to be followed by sequential treatment with rituximab and subsequently by CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy in adult B-cell PTLD. 2. Rituximab +/- chemotherapy
· RTX is the front-line therapy for monomorphic CD20-positive B-cell PTLD. Rituximab at standard dose (375 mg/m2) followed by four cycles of standard-dose CHOP-21 chemotherapy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF).
· Based on data from PTLD-1and PTLD-1/3, patients with a low risk of disease progression achieved a CR after the first four courses of rituximab monotherapy.
· Dose-attenuated treatment or alternative less toxic treatment regimens (such as single-agent rituximab, corticosteroids, oral etoposide and alkylating agents) can be considered in selected patients.
· Polymorphic CD20-positive B-cell PTLD, to be treated with the same algorithm as monomorphic CD20-positive B-cell PTLD as described above. Rarely, polymorphic PTLD can have an overlap with Hodgkin Lymphoma PTLD and thus the management would be as in Hodgkin Lymphoma PTLD.
· Recommendations:
a) Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
b) 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 (1B).
c) Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville £ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
d) Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
e) Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B). PET-CT should be considered for interim and end- of-treatment response assessment where available (1C).
3. Radiotherapy:
· Radio- therapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localized extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
· Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
· In localised disease, radiotherapy may be offered con- currently with RIS (2C). 4. Antivirals, intravenous immunoglobulin and interferon-alpha treatment.
· Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
5. Therapy for relapsed or refractory PTLD (R/R PTLD)
· Patients with R/R PTLD post R-CHOP have a poor long- term survival.
· conventional salvage approaches with consolidation autologous stem cell transplantation (ASCT) are challenging to deliver in SOT patients.
· Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B). 6. Adoptive immunotherapy
· EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV- positive PTLD whilst avoiding the risk of graft rejection.
· Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD(1C)
· Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C). Burkitt lymphoma-like PTLD
· Rituximab monotherapy was inadequate at inducing sustained remission.
· R-CHOP with concurrent RIS could be considered a reasonable option for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immune-competent patient.
· Dose-adjusted EPOCH-R with appropriate CNS prophylaxis may also represent a clinically appropriate option in selected patients aiming to achieve curative therapy. Plasmablastic and plasma-cell myeloma PTLD
· There is a paucity of data on these subtypes.
· it is reasonable to treat as for the plasmacytoid dyscrasia disease in the immunocompetent.
· RIS should be incorporated in the management algorithm. T-cell lymphoma PTLD
· Peripheral T-cell lymphomas (PTCL) are a rare form of PTLD.
· A reasonable approach in patients with adequate cardiac function is to combine RIS with anthracycline-based chemotherapy. Hodgkin lymphoma PTLD
· Classical Hodgkin lymphoma-type PTLD (HL-PTLD) is rare.
· A standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function.
· BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone), Escalated BEACOPP or BEA- COPDac (dacarbazine substituted for procarbazine) should only be considered and used with caution in patients with particularly high-risk disease given the known associated haematological and infection-related toxicities with these regimen(s). Extra-nodal marginal zone lymphoma – PTLD
· Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option.
· Radiotherapy is an effective treatment in this setting. PTLD affecting the CNS:
· Overall prognosis is poor.
· No optimal therapy for CNS-PTLD has been established.
· Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
· RIS is routinely performed, usually alongside radiotherapy (ORR of 75%).
· RIS, intrathecal chemotherapy and whole-brain radiotherapy yielded an ORR of 75% and OS of 62% at five years.
· Intensive, systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate (HD- MTX) with rituximab, is the standard for immunocompetent primary CNS lymphoma.
· Prockop et al. demonstrated responses with donor and ‘third-party’ (Tabelecluecel) EBV-specific CTLs in patients with EBV-positive CNS-PTLD in patients following haemopoietic stem cell transplant or SOT.
· Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
· Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
PTLD; Supportive care and Re-transplantation
· G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
· Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re-trans- plantation is low.
· Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be consid- ered before re-transplantation, but a longer period may be needed (2C).
This article shed light on the management of post-transplant lymphoproliferative disease, detailing its diagnosis and treatment. PTLD:
Its lymphoid tissue proliferation provoked by immunocompromised status post transplantation.it accounts for 21% of all cancer incidence is solid organ transplantation.
It occurred predominantly in the first post-transplant year, however, several other papers pointed towards its equal prevalence after the first-year post transplantation. EBV:
considered the major etiologic factor in triggering tumoral process. B lymphocytes are principal cells of PTLD. 20-40 % are EBV negative PTLD, reported usually after the first year. PTLD prevalence in different organs transplantation:
In adult population its more prevalent in multiorgan transplant patient, then Intestinal transplant, lung transplant, cardiac and least in kidney transplant recipients. Types:
4 subtypes are recognized:
1]Non-destructive, Plasmacytic , associated with EBV.
2]Polymorphic, B cells mature admix with t lymphocytes. EBV associated.
3]Monomorphic, resemble lymphoma subtypes. can be EBV negative.
4]Classical Hodgkins lymphoma, EBV related. Recommendation for diagnosis:
1]Excisional or incisional diagnosis is essential in diagnosis. otherwise, core needle biopsy.
2] CT for staging where PET-CT is not available.
3] PET-CT is gold standered for staging of PTLD.
Management of PTLD:
Management has to be planned by a multidisciplinary team involving transplant physician, oncologist, hemato-oncologist.
the main strategy entails reduction of immunosuppression medication, as it might enhance the immune system to control abnormal proliferation of lymphocytes.
The plan depends on how critical the patients, stage and grade of PTLD is. As follows: Reduction in Immunosuppresant RIS
1] In stable patients:
Azathioprine and MMF to be stopped.
CNi dose reduced 50%, continue Cs with 10 mg
2] Critical patient
To stop MMF, and Aza.
reduce CNi by 75%.
For rechecking of PTLD progression within 2-4weeks. The second line therapy
Rituximab:
375 mg 4 weekly doses.
R-CHOP protocol for 4 weekly cycles.
Introduction:
This article is a guideline regarding management of adult post-transplant recipients diagnosed with PTLD.
PTLD accounts for 21% of all cancers in post-transplant recipients and is common malignancy after skin cancer. Majority of PTLD is in EBV positive recipients, among solid organ transplant recipients, renal transplant patients have the lowest incidence of PTLD (0.8–2.5%). Diagnosis, Staging and Scoring:
1. Excision biopsy is recommended for accurate PTLD sub-classification and for providing sufficient material for subsequent investigations.
2. Staging should be recorded using the Ann Arbor classification or the Lugano classification.
3. Staging with a CT is recommended in all patients where PET-CT is not available.
4. A management plan should be agreed by a multidisciplinary team (MDT), including a transplant physician, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
5. International Prognostic Index (IPI) is recommended prognostic score. Management of PTLD: Reduction of immunosuppression (RIS):
1. RIS partially restores T-cell function, and may be the only treatment required for low-risk patients who have early lesions, low-stage disease and non-bulky disease.
2. Monitor for rejection.
3. Response should be assessed within 2–4 weeks and if complete remission (CR) is obtained, then no other therapy is needed.
4. Patients who achieve partial remission can be further monitored for 2-4 weeks or Rituximab can be considered.
5. American guidelines on RIS :
a. Limited disease Reduction by 25% of all immunosuppression
b. Extensive disease — not critically ill: Reduction of CNIs by 50% Consider stopping azathioprine/MMF Maintain prednisolone 7.5/10 mg/day
c. Extensive disease — critically ill: Stop all agents except for maintaining prednisolone 7.5/10 mg/day. Rituximab +/- chemotherapy:
1. Front-line therapy for monomorphic CD20-positive B-cell PTLD.
2. Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab.
3. Four cycles of R-CHOP-21, (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF), immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab. Radiotherapy, antivirals, IVIG:
1. The role of radiotherapy as a component of treatment for PTLD is undefined.
2. A retrospective analysis suggested that adults with limited-stage disease, irrespective of the histological subtype, can obtain CRs after surgical resection or radiotherapy, usually with concurrent RIS.
3. Treatment with anti-viral medication, IVIG and interferon is not recommended outside clinical trials. Treatment of relapse or refractory PTLD:
Adaptive immunotherapy, in EBV positive PTLD which did not respond to RIS, Rituximab or chemotherapy. 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
One of the falls out of necessary immunosuppression in solid organ transplantation is the development of lymphoproliferative disease which is the second most common malignancy after skin can in these groups of people.
It has been shown to account for 21% of all cancers of solid organ transplant recipients as compared to 4-5% seen in immunocompetent individuals and EBV has been linked with a strong association with its occurrence. The highest incidence is seen in lung transplants while the least is found in kidney transplants.
Diagnosis and staging
Ancillary investigations needed to strengthen the diagnosis
Excisional biopsy is needed for tissue diagnosis of PTLD
Classification
Ann Arbo classification
Lugano classification- this requires the use of PET-CT
PTLD type
Non-destructive
Polymorphic
Monomorphic
Classical Hodgkin lymphoma
THE MULTIDISCIPLINARY APPROACH TO CARE
Recommendation
All cases of PTLD should be discussed at the hemato-oncology MDT meeting with an experience in PTLD management and with input from an organ transplant physician
All diagnostic material should be reviewed by a hematopathologist
The identified adverse risk factor in different prognostic scoring
poor performance status
EBV negative tumour
monomorphic histology
older age
graft involvement
CNS involvement
raised lactate dehydrogenase level
Management of PTLD
Reduction of immunosuppression
Rituximab+/- chemotherapy
Radiotherapy
Antiviral, IVIG, and interferon-alfa treatment
Therapy for relapsed PTLD
Adoptive immunotherapy
Recommendation for other forms of PTLD
all patients with an uncommon form of PTLD should be considered for RI as part of the initial treatment
treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity
patient with CNS-PTLD should be offered treatment with RI, followed by a combination of chemotherapy with Rituximab in suitable patients depending on adequate organ function and patient comorbidity
local radiotherapy +/- corticosteroid with RI where fitness and comorbidity are limiting factors may be offered in CNS-PTLD
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD
for re-transplantation, a minimum of one year or longer has to be considered before trying another surgery
Conclusion
The success achieved in new immunosuppressive therapy has also come with attendant problems like PTLD which has also a strong association with EBV. There are various forms of histological classifications of PTLD with different methods of therapy and some of them are novel. Re- transplantation is possible even even a graft is lost to the disease, but average of 2 years is needed for this to be done,
Introduction: Post-transplant lymphoproliferative diseases are a spectrum of disorders resulting from lymphoid proliferations by immunosuppressive medications used post SOT. Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population. PTLD is the second most common malignancy after skin cancer with a significant mortality. PTLDs are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, in the first year post SOT. EBV-negative cases account for 20–40% of PTLD usually occurs after the first year of transplantation, with a second peak of incidence occurring at 10 years post SOT. In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%) followed by lung transplants (3–10%), heart transplants (2–8%), liver transplants (1–5.5%), pancreatic transplants (0.5–5%) and renal transplant recipients having the lowest incidence of PTLD (0.8–2.5%).
Diagnosis and staging: – Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A). – Staging with a CT is recommended in all patients where PET-CT is not available (1A). “ – Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Multidisciplinary approach to care: – All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A). “ – All diagnostic material should be reviewed by a haematopathologist (1A).
Prognostic scoring: – The Ghobrial prognostic score allocated one point for ECOG (Eastern Cooperative Oncology Group) > 2, but its utility was limited due to a majority of patient having monomorphic disease (96%) and only 16% having graft involvement. – International Prognostic Index (IPI) for non-Hodgkin lymphoma. – Risk factors in various prognostic scoring systems are: poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia.
Management of PTLD: 1. Reduction of immunosuppression: – Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B). – Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B). 2. Rituximab +/# chemotherapy: – Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B). – 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 (1B). – Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B). – Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B). – Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
3. Radiotherapy: – Used incorporation with chemotherapy in some sort of PTLDs. – may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse, and localised extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
4. Antivirals, intravenous immunoglobulin and interferon-alpha treatment: – Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
5. Therapy for relapsed or refractory PTLD: – Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B). – Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C). – Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C). – Adoptive immunotherapy is a permissive modality of treatment in some R/R PTLD.
Burkitt lymphoma-like PTLD: · R-CHOP with concurrent RIS could be considered a reasonable option for Burkitt-like PTLD. However, dose-adjusted EPOCH-R with appropriate CNS prophylaxis may also represent a clinically appropriate option in selected patients aiming to achieve curative therapy. Plasmablastic and plasma-cell myeloma PTLD: · Treat as for the plasmacytoid dyscrasia disease in the immunocompetent patients. T-cell lymphoma PTLD: · Combined RIS with anthracycline-based chemotherapy, in patients with good cardiac function. Hodgkin lymphoma PTLD: · Combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function. · BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone), Eescalated BEACOPP or BEACOPDac (dacarbazine substituted for procarbazine) should only be considered and used with caution in patients with particularly high-risk disease. Extra-nodal marginal zone lymphoma – PTLD: · EBV-positive MALT lymphoma may respond well to RIS, Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option. · Radiotherapy is an effective treatment. Post-transplant lymphoproliferative disease affecting the central nervous system: · Intrathecal chemotherapy and whole-brain radiotherapy. · Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate with rituximab. Recommendations: – All patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C). – Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C). – Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C). – Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C). – Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care: – G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B). Re-transplantation: – Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations, attributed to immunosuppression post transplantation. It account for 21% of all cancers of SOT recipients, mostly due to B lymphocytes and are Epstein–Barr virus (EBV)-associated.
PTLD has 2 peaks of occurrence, either 1st year (Usually EBV associated) or the second peak of incidence occurring at 10 years (EBV negative ).
Among all SOT, renal transplant recipients having the lowest incidence of PTLD (0.8–2.5%). Diagnosing and staging
diagnostic material should be accompanied by relevant clinical information including :
· The date of transplant.
· Immune suppression regimen.
· Organ type.
The guidelines recommends a surgical excisional or incisional biopsy or a core needle biopsy is an alternative (1A). Staging either with a CT or a PET-CT (1A). Multidisciplinary approach to care
MDT approach to be used for All cases , haemato-oncology experience in PTLD management, with input from the organ transplant physicians (1A). and all diagnostic material should be reviewed by a haematopathologist (1A). Management of PTLD Reduction of immunosuppression (RIS) is the mainstay, including stopping azathioprine and MMF and reduction of CNIs ( by 30–50%) and corticosteroids, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B) Rituximab +/# chemotherapy
1. Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B). 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 (1B).
2. Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
3. Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
4. Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
5. PET-CT should be considered for interim and end of-treatment response assessment where available (1C). Radiotherapy: Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C). while if the disease is localised, radiotherapy may be offered concurrently with RIS (2C). TherapyforrelapsedorrefractoryPTLD is recommended to offerautologous stem cell transplant and /or adoptive immunotherapy. Patients with CNS-PTLD should be offered treatment with
1. RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
2. Local radiotherapy +/# corticosteroids (2C).
3. Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C). Re-transplantation can be offered after minimum of one year, but a longer period may be needed (2C).
Front-line management of PTLD in adult SOT— A British Society for Haematology Guidelines
PTLD is the second most prevalent malignancy in adult recipients of solid organ transplants, behind skin cancer, and poses a significant mortality risk.
The risk is increased when an EBV-negative recipient receives a transplant from an EBV-positive donor, when there is strong immunosuppression such as ATG induction and tacrolimus-based maintenance therapy, when immunosuppression is at its peak in the first year after transplantation, and when transplanted organs such as the small bowel and heart-lung.
90% of PTLD are EBV-positive and derived from B cells, with the remaining 10% deriving from T cells.
Histomorphological description categorizes PTLD into four groups.
1-Non-destructive; includes plasmacytic hyperplasia, infectious mononucleosis-like cells, and florid follicular hyperplasia. Most EBV-associated cases are early PTLD.
2-Polymorphic; B-cell maturation stages with T cells, EBV-associated in >90% instances.
3-Monomorphic; 60–80% of PTLD are DLBCL, Burkitt lymphoma, plasma cell myeloma, or plasmacytoma. Indolent B-cell lymphomas and T-cell neoplasms are diagnosed less often. EBV-negative monomorphic PTLD.
4-Classical Hodgkin Lymphoma: This is classical Hodgkin lymphoma and usually (>90%) associated with EBV.
Treatment of PTLD
1- Immunosuppression reduction:
The guidelines propose eliminating azathioprine and MMF and reducing CNIs by 30–50% while maintaining or reducing corticosteroids in all patients whenever possible under the advice of the transplant physician with graft function monitoring (1B). Patients receiving RIS alone should be assessed for disease response at 2–4 weeks to see if they need additional treatment (1B).
2-Rituximab/chemotherapy:
The guidelines suggest rituximab monotherapy for CD20-positive PTLD patients who don’t react to RIS (1B). Patients who achieve CR or complete metabolic remission (CMR) (Deauville 3) after four cycles of weekly standard-dose rituximab should get four more three-weekly treatments (1B).
Four cycles of R-CHOP-21 immunochemotherapy are indicated for patients who fail to achieve CR or CMR (with Deauville 3) after four cycles of weekly standard-dose rituximab or clinically advance during these four cycles (1B).
Rituximab plus anthracycline-based therapy (usually R-CHOP-21) is advised with RIS for patients with clinically aggressive lymphoma with serious organ impairment at any time (1B).
All individuals with SOT or suspected renal or cardiac impairment should have formal cardiac and renal function testing (1B).
PET-CT should be evaluated for interim and end-of-treatment response assessment when available (1C).
3-Radiotherapy:
-Selected PTLD patients may receive involved-field radiation according to conventional protocols for certain histological subtypes (2C).
– Radiotherapy may be used with RIS in localized illness (2C).
4-Antivirals, intravenous immunoglobulin, and interferon-alpha treatment are not indicated outside clinical trials (1C).
5- Refractory cases- relapses following the CHOP therapy;
If a good remission is obtained, intense second-line chemotherapy followed by an autologous stem cell transplant.
Use immunotherapy (EBV-specific T cells, EBVSTs in situations of relapse and resistance).
6- Retransplantation: following a full year of remission (with better matched donor to reduce immunosuppression, avoid ATG, minimize use of tacrolimus to the least possible dose)
Post-transplant lymphoproliferative disease PTLD is the second common cancer posttransplant after skin cancer, and represent 21% of cancers post solid organ transplant SOT.
Its incidence bimodal, one in the first year post transplant and one mode at 10 years post-transplant, also EBV as a causative agent can happen early and EBV negative origin occurs in the late period post-transplant.
In addition, PTLD is common more in multiorgan transplant and intestinal transplant, and least common in renal transplant recipient among all SOT.
Excisional biopsy for diagnosis and staging is important for management; role of Positron Emission Tomography–Computed Tomography (PET-CT) in the staging of PTLD is less well defined when compared to lymphoma.
PTLD can be categorized as: non destructive type, polymorphic, monomorphic, and classical Hodgikin lymphoma.
Investigations needed:
1- CBC, liver enzymes, liver function tests, renal function tests, calcium, LDH, uric acid.
2- Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres.
3- Bone marrow biopsy is indicated and some selected patients it may not be clinically needed or appropriate.
4- Echocardiography
5- Assessment of the function of the transplanted organ
6- All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response Where available, PET-CT scan should be utilized for staging over CT scan.
All cases should be submitted for discussion from MDT essentially include hematologist and oncologist.
No accepted universal prognostic scoring system for PTLD because of varying risk factors, heterogeneity of the patients and treatments.
Management of PTLD:
1- Reduction of immunosuppression RIS:
Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab (1B).
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
PET-CT should be considered for interim and endof-treatment response assessment where available (1C).
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
In localised disease, radiotherapy may be offered concurrently with RIS (2C).
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
· Diagnosis and stagingEstablishing a tissue diagnosis of PTLD can be challenging and all diagnostic material should be accompanied by relevant clinical information including the date of transplant, immune suppression regimen and organ type.
In addition, PET-CT may have a role in the diagnostic work-up as demonstrated in a retrospective study published by Montes de Jesus et al They reported a sensitivity of 85% and specificity of 90% with a positive predictive value of 83% and a negative predictive value of 92% in PTLD.
Despite the limitations of these PTLD data, a staging PET-CT, where available, should be performed in line with recommendations for FDG-avid lymphomas in the immunocompetent patients.
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Staging with a CT is recommended in all patients where PET-CT is not available(1A).
Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B)
· PTLD type DescriptionNon-destructive Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia.
Most cases are EBV-associated and usually present as early PTLD.
Polymorphic A spectrum of B-cell maturation stages with admixture of T cells, EBV-associated in >90% cases.
Monomorphic Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large.
B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma.
Much less commonly indolent B-cell lymphomas, usually mucosa-associated lymphoid tissue lymphoma[5,11,12] and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative.
70% of these lesions are reported to have cytogenetic abnormalities, including trisomy 9 and 11 or both, loss of 17p and rearrangement of 8q24 (MYC)
· Baseline investigationsElectrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH).
Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres.
All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response.
Details should include; date of transplant, organ type and immunosuppresion regimen.
All patients require assessment of the function of the transplanted organ, ideally directed by the transplant physician.
CMV, cytomegalovirus; CT, computed tomography; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; PET, positron emission tomography; PTLD, post-transplantation lymphoproliferative disease.
It is recommended that the lead MDT should be the lymphoma MDT and where possible, a representative of the transplant team should attend. MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haematopathologist (1A)
· Prognostic scoringThere is no universally accepted prognostic scoring system specific for PTLD. This is a result of most prognostic scores included varying risk factors, heterogeneous patients or treatments and often being retrospective or single-institution series.
The Ghobrial prognostic score allocated one point for ECOG (Eastern Cooperative Oncology Group) > 2, monomorphic disease and graft involvement to demonstrated significant for overall survival (OS) but its utility was limited due to a majority of patient having monomorphic disease (96%) and only 16% having graft involvement.
28 In addition, another prognostic score, the PTLD Prognostic Index, is a variation of the IPI with baseline factors of age, ECOG performance status and LDH.
· Management of PTLDGiven the rarity of the diagnosis and the histological heterogeneity together with the medical complexity of the patients, there are no data available from randomised trials to inform management.
For the rarer subtypes and in the relapsed/refractory setting, treatment decisions are informed by small case series and case reports.
For the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL), there are robust data from prospective phase II studies that have informed existing treatment algorithms.
For the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL), there are robust data from prospective phase II studies that have informed existing treatment algorithms. 23,24
· Reduction of immunosuppressionWhere safe to do so, immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team.
Where RIS is being considered as the sole initial treatment, response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond.
The response to RIS was assessed early between two and four weeks and failure of RIS was followed by sequential treatment with rituximab and subsequently by CHOP chemotherapy in adult B-cell PTLD.
RIS should be considered in conjunction with other therapies, in patients who have risk factors which include clinically aggressive PTLD Ann Arbor stage ≥III, elevated LDH and more than one extra-nodal site or a high-risk IPI.
Disease response assessment is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond .
· Or withdrawal of all immunosuppressant drugs except for corticosteroidsCNIs, calcineurin inhibitors; MMF, mycophenolate mofetil; PTLD, post-transplantation lymphoproliferative disease; RIS, reduction in immunosuppression; SWOG, Southwest Oncology Group. ASCT, autologous stem cell transplant; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; G-CSF, granulocyte-colony stimulating factor; IPI, international prognostic index; IV, intravenous; PJP, Pneumocystis jirovecii; PR, partial remission; RIS, reduction of immunosuppresion; PTLD, post-transplantation lymphoproliferative disease; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone.
47% at 27!5 months (R) CHOP, (Rituximab) cyclophosphamide, doxorubicin, vincristine, prednisolone; CR/CRu, complete remission/response/unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival; PR, partial remission; PTLD, post-transplantation lymphoproliferative disease. Rituximabmonotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
· Therapy for relapsed or refractory PTLDThere are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD.
76–78 In patients who are unresponsive to rituximab, using R-CHOP is a reasonable and logical approach.
23,24,79 A sequential approach as in front-line therapy can be considered if relapse post rituximabmonotherapy occurs late.
Patients with R/R PTLD post R-CHOP have a poor longterm survival with OS < 20% as conventional salvage approaches with consolidation autologous stem cell transplantation (ASCT) are challenging to deliver in SOT patients.
78,79 Extrapolating treatments from R/R DLBCL in immunocompetent patients is reasonable 80–83 but this approach has little evidence in R/R PTLD.
Particular attention should be paid to the toxicities of salvage chemotherapy in relation to the underlying SOT and patient comorbidities.
Patients should be offered enrolment in a clinical trial where available
· Adoptive immunotherapyEBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV-.
Autologous or allogeneic EBV-directed CTLs should be considered in patients with R/R EBV-positive.
89 This is similar to the results demonstrated by Prockop et al where a 54% ORR in 13 PTLD patients who were refractory to rituximab was reported.
Trials using CTL for PTLD are small, but the results appear promising and the recent development of chimaeric antigen receptor (CAR)-T cells reported for B-cell malignancies 91,92 suggests that this technology could have a future role in the treatment of PTLD.
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Peripheral T-cell lymphomas (PTCL) are a rare form of PTLD
They typically occur later after SOT and are often associated with poor outcome.
· Hodgkin lymphoma PTLDClassical Hodgkin lymphoma-type PTLD (HL-PTLD) is rare and data on optimal therapy are lacking.
Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate (HD-MTX) with rituximab, is the standard for immunocompetent primary CNS lymphoma 113,114 but may be challenging to administer safely due to comorbidities, typically renal failure or SOT dysfunction in CNS-PTLD patients.
This approach has been adopted in CNS-PTLD patients with some success.
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
· Supportive careSignificant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection. 42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group.
Significant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection.
42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group.
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered.
116,117 Age is an important risk factor for developing FN which can partly be prevented by G-CSF.
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered. 116,117 Age is an important risk factor for developing FN which can partly be prevented by G-CSF. 116,117
· FindingsEBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years. 6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD. EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.
6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD.
43–45 Treatment-related mortality (TRM) was reduced to 13% compared to retrospective case series with front-line CHOP therapy which documented TRMs of up to.
Limited disease Reduction by 25% of all immunosuppression not critically ill Reduction of CNIs by 50%.
Reduction of CNIs by 50% and further reduction by 50% if not in complete remission by day 14.
Reduce glucocorticoids by 50%, with a lower limit of prednisone of.
Reduce CNIs by 50% and maintain steriods.
With reports of up to 50% mortality following infection.
With reports of up to 50% mortality following infection. 42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group
· Given the degree of immunosuppression in patients withPTLD, strong consideration should be given to antibiotic, antifungal and antiviral prophylaxis during therapy, if treatment is associated with neutropenia as per local protocols.
Prophylaxis with co-trimoxazole or equivalent should be considered in all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia.
Surveillance for CMV infections should continue in patients with PTLD with guidance from the transplant physician or team.
Patients with past hepatitis B or C infection should be managed in conjunction with a hepatologist.
118 Regular monitoring of liver function is required through treatment, and monitoring of hepatitis B viral load should be considered as per the guidance outlined by NICE CG165 118 or as directed by the hepatologist.
Patients with HIV should be managed under joint care with their HIV physician
II. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline Summary
Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.
The majority of cases in the western world are derived from B lymphocytes and Epstein–Barr virus (EBV), particularly in the first year post SOT.
Diagnosis and staging
patients with post-transplant therapy lymphoma (PTLD) are crucial for patient management and should be recorded using the Ann Arbor classification or Lugano classification .
All diagnostic material should be accompanied by relevant clinical information including date of transplant and immunosupression regimen.
PET-CT should be performed in line with recommendations for FDG-avid lymphomas in the immunocompetent patients.
PET-CT may also have a role in the diagnostic work-up as demonstrated in a retrospective study by Montes de Jesus et al.
Magnetic resonance imaging (MRI) or CT imaging of the brain, orbits and sinuses is recommended for patients with suspected central nervous system (CNS) or craniofacial disease.
Diagnostic lumbar puncture for cerebrospinal fluid analysis is also recommended.
A surgical excisional or incisional biopsy is advised whenever possible to establish a diagnosis.
A core needle biopsy is an alternative if this is not possible .
All patients should undergo staging with a CT if a PET-CT is unavailable .
When a PET-CT is available, it should be used for staging in accordance with the advice for FDG-avid lymphoma .
Multidisciplinary approach to care
A management plan should be agreed by a core multidisciplinary team (MDT) which should include trans-plant physicians, haemato-oncologists, radiologists and radiologists.
The MDT process should be in line with the 2016 NICE guideline ‘Haematological cancers: improving outcomes’.
All cases should be discussed with involvement from the doctors performing organ transplants at a meeting of the haemato-oncology MDT that has experience with PTLD .
A haematopathologist should review all diagnostic materials.
Prognostic scoring
There is no universally accepted prognostic scoring system for treatment-related death from lymphoma (PTLD).
The Interational Prognostic Index (IPI) for non-Hodgkin lymphoma has a number of different scoring systems.
Management of PTLD
For the rarer subtypes and in the relapsed/re- fractory setting, management decisions are informed by small case series and case reports.
Reduction of immunosuppression
Ris-up- pression (RIS) aims to partially restore T-cell func- tion.
This may be the only treatment required for a select group of patients with low-risk patients who have early lesions, low-stage disease and non-bulky disease.
If RIS is being considered as the sole initial treat- ment, response should be assessed within 2–4 weeks.
The European and American guidelines recommend a range of approaches depending on the clinical picture and the extent of the patient’s disease.
RIS should be followed by sequential treatment with rituximab and CHOP (cyclophos- phamide, doxorubicin, vincristine, prednisolone) in adult B-cell patients with post-transplant thrombosis.
A more pragmatic approach that should be adopted is to follow the criteria for entry into the prospective phase II PTLD-1 trial.
It should be considered in conjunction with other thera- pies, particularly in patients with high risk factors such as aggressive PTLD and elevated LDH.
When possible, it is advised that all patients reduce their immunosuppression by eliminating azathioprine and MMF and cutting back on CNIs by 30% to 50% while maintaining or reducing corticosteroids, with the assistance of the transplant physician monitoring graft function .
It is advised that patients receiving RIS alone have an early disease response assessment (at 2-4 weeks) so that additional treatment can be started in those who do not respond.
Rituximab +/# chemotherapy
Front-line therapy for monomorphic CD20-positive B-cell PTLD Rituximab is a monoclonal anti-CD20 antibody that has become a standard of care in patients with polymorphic PTLD.
The commonest form of PTLD has a CD20-positive, B-cell histology similar to DLBCL.
This approach resulted in a median OS of 6.6 years and a clear plateau on the PFS curve.
In the PTLD-1/3 trial, patients with CD20-positive polycystic ovary syndrome (PCOS) who had failed initial treatment with rituximab were switched to four cycles of R-CHOP-21.
G-CSF was mandated during chemotherapy and prophylaxis against pneumocystis jirovecii (PJP) was recommended.
Patients with a low risk of disease progression are defined as those who achieve a CR after the first four courses of rituximab monotherapy.
This strategy is likely to reduce grade 3–4 leucopenia, infection and subsequently the TRM, but retain a similar OS.
Not all patients will be candidates for the combination chemotherapy and radiotherapy treatment described above.
Using less toxic regimens (such as single-agent rituximab, corticosteroids, oral etoposide and alkylating agents) can be considered in selected patients.
Liaison with the transplant team to make an individual assessment of the current cardiac allo-ngraft structure and function is recommended.
Polymorphic CD20-positive B-cell PTLD
Rarely, polymorphic CD20-positive B-positive PTLD can have overlap with Hodgkin Lymphoma PTLD and thus the management would be as described in the Hodgkins Lym- phoma section.
These cases have been included in the PTLD-1 trial and are treated with the same treatment as monomorphic CD20 positive B-cell PTLD.
Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) (with Deauville ≤ 3) after initial treatment with the drug, according to the US Department of Veterans Affairs (VA).
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at risk of developing an aggressive form of systemic thrombosis (SOT) or other potentially life-threatening disease.
Radiotherapy
The role of radiotherapy as a component of treatment for patients with polycystic ovary-lung disease (PTLD) is unclear, but it has been suggested that 7–25% of patients with PTLD are treated with radio-therapy in their initial management.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Treatment with anti-viral agents and/or arginine buty- rate, IVIG and IFNa is not recommended outside clinical trials .
Involved-field radiotherapy may be offered in line with standard protocols for specific histological subtypes .
Therapy for relapsed or refractory PTLD
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD.
In patients who are unresponsive to rituximab, using R-CHOP is a reasonable and logical approach.
Extrapolating treatments from R/R DLBCL in immunocompetent patients is reasonable.
Adoptive immunotherapy
Patients with relapsed/refractory patients with Epstein-Barr disease (EBV-BDL) should be carefully selected for intensive second-line chemotherapy fol- lowed by autologous stem cell transplant if a good recovery is achieved , according to the authors.
Burkitt lymphoma-like PTLD
Burkitt lymphoma-like PTLD has many features in common with spo- radic Burkitt lymphomas, but some differences can be observed.
A strong association with EBV is described, along with an association with 11q aberrations in patients with typical histopathological features but without a Mycotome rearrangement.
Plasmablastic and plasma-cell myeloma PTLD
Patients with two distinct forms of plasma-cell myeloma (PTLD) should be treated for the plasmacytoid dyscrasia disease in the immunocom- petent.
RIS should be incorporated into the management algorithm of PTLD to provide guidance on how best to manage the disease.
T-cell lymphoma PTLD
ASCT can be reasonably adopted on T-cell lymphoma patients in the setting of PTCLNOS (not otherwise specified) PTLD.
A reasonable approach in patients with adequate cardiac function is to combine RIS with anthracycline-based chemotherapy.
There are no published cases describing the use of ASCT in first remission in this setting.
Hodgkin lymphoma PTLD
Hodgkin lymphoma-type PTLD (HL-PTLD) is rare and data on optimal therapy are lacking.
Combination chemotherapy with ABVD with or without radiotherapy may represent a safe and efficacious option in patients with normal cardiac and pulmonary function.
Extra-nodal marginal zone lymphoma – PTLD
Extra-nodal marginal zone lymphoma – PTLD SOT is estimated to increase the risk of developing MALT lym- phoma by two- to threefold.
The predominant site of involvement of MALT lymphoma is gastric, although there are isolated cases of colonic and small-bowel involvement.
Is a disease of the central nervous system that affects between 10 and 20% of patients who have received a stem cell transplant.
The risk of CNS lymphoma is elevated in SOT recipients, but it remains within the range of 10 to 20% in PTLD.
RIS is routinely performed, usually alongside radio- therapy resulting in an ORR of 75% in one series 111.
Chemotherapy with rituximab and high-dose methotrexate (HD-MTX) is the standard for immunocompetent primary CNS lymphoma , but may be challenging to administer safely in patients with a compromised central nervous system (CNS-PTLD).
Extrapolating regimens from immunocom- petent can be considered on a case-by-case basis
Patients with less common forms of post-transluminal polycystic ovary syndrome (PTLD) should be considered for treatment with radiotherapy with ris as part of their initial management , the World Health Organization (WHO) has advised.
Supportive care
Patients with a history of CMV infection or hepatitis B or C infection should be monitored by a hepatologist.
G-CSF should be offered to all patients with diagnosis of PTLD (1B) and PJP prophylaxis is recommended for those receiving chemotherapy and radiotherapy, according to the World Health Organization (WHO) Guidelines for Treatment of Post-Chemotherapy Liver Disease (PCLD) have been published by the WHO.
Re-transplantation
May be considered after successful control of PTLD as the risk of recurrence of PTLD after re-trans- plantation is low.
A period of one year should be considered as a minimum before re-plantation depending on the organ and clinical need.
PTLDs are sub-classified into four histopathological categories as;
—————————————————————————————– 1-Non-destructive;
Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia. Most cases are EBV-associated and usually present as early PTLD.
2-Polymorphic;
A spectrum of B-cell maturation stages with admixture of T cells, EBV -associated in >90% cases.
3-Monomorphic;
Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma . Much less commonly indolent B-cell lymphomas, usually mucosa -associated lymphoid tissue lymphoma and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative.
4-Classical Hodgkin Lymphoma ;
Morphologically this fulfils the conventional criteria for the diagnosis of classical Hodgkin lymphoma and is generally (>90%) associated with EBV .
Diagnosis and staging; —————————————————————————
The guidelines recommend the following ;
1-Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
2-Staging with a CT is recommended in all patients where PET-CT is not available (1A).
3-Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Essential pre-treatment baseline evaluation for all patients diagnosed with PTLD;
——————————————————————————————————–
1-full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH).
2-Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres .
3-Bone marrow biopsy is indicated and some selected patients it may not be clinically
needed or appropriate .
4-Echocardiography where appropriate and potentially when cardiotoxic agents are being used .
5-Fertility-preserving treatments, such as sperm cryopreservation for male and referral to a fertility specialist in female patients, should be considered for eligible patients .
6-Details should include; date of transplant, organ type and immunosuppresion regimen .
7-all patients require assessment of the function of the transplanted organ, ideally directed by the transplant physician .
8-All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at
diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response .
9-Where available, PET-CT scan should be utilised for staging over CT scan .
Multidisciplinary approach to care; —————————————————————-
The guidelines recommend the following ;
1-All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
2-All diagnostic material should be reviewed by a haematopathologist (1A).
Prognostic scoring ; ——————————————————–
a number of adverse risk factors have been identified in various prognostic scoring systems including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia .
Management of PTLD; ———————————————– 1-Reduction of immunosuppression ;
The guidelines recommend the following ;
1-Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, unde rthe guidance of the transplant physician with surveillance of graft function (1B).
2-Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
2-Rituximab +/- chemotherapy ;
The guidelines recommend ;
1- Rituximab monotherapy;
is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
2- 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 (1B).
3-Four cycles of R-CHOP-21 immunochemotherapy ;
Are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
4-Rituximab plus anthracycline-based therapy (typically
R-CHOP-21);
is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
5-Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
6-PET-CT should be considered for interim and end- of-treatment response assessment where available (1C).
3-Radiotherapy;
The guidelines ;
1-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
2- In localised disease, radiotherapy may be offered concurrently with RIS (2C).
4-Antivirals, intravenous immunoglobulin and interferon-alpha treatment ;
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD; ——————————————————————-
The guidelines recommend ;
1-Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Adoptive immunotherapy; ——————————————————-
The guidelines recommend ;
1-Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
2-Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
The less common PTLD ; ———————————————————-
1-Burkitt lymphoma-like PTLD
2-Plasmablastic and plasma-cell myeloma PTLD
3-T-cell lymphoma PTLD
4-Hodgkin lymphoma PTLD
5-Extra-nodal marginal zone lymphoma – PTLD
The guidelines recommend ;
1-It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
2-Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Post-transplant lymphoproliferative disease affecting the central nervous system; ———————————————————————————————
The guidelines recommend ;
1-Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
2- Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
3- Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care ; ————————————————–
The guidelines recommend ;
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation; ——————————————
The guidelines recommend ;
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
PTLD represents a spectrum of lymphoid proliferations disorders in immunosuppressed SOT recipient. It accounts for 21% of cancers and associated with a significant mortality. The highest incidence occur in the first year after transplantation. However, late occurrence is prevalent.
The majority are B lymphocytes and EBV associated. EBV-negative PTLD account for 20–40%, occur usually after the first year.
The highest incidence occurs in multiorgan, intestinal and intrathoracic transplants. Renal transplants have the lowest incidence. Diagnosis and staging
Excision biopsy is recommended to provide sufficient material and enable accurate sub-classification. incisional or core needle biopsy are alternatives.
Staging PET-CT, where available, CT where PET-CT is not available
MRI or CT of the brain, orbits and sinuses is recommended for suspected CNS or craniofacial disease along with CSF analysis for cytology and flow cytometry. Multidisciplinary approach to care
All PTLD cases should be discussed at a haemato-oncology MDT, with input from transplant physicians, pathologist and radiologist. Prognostic scoring
There is no universally accepted scoring system specific for PTLD, however adverse risk factors include:
Poor performance status
EBV-negative tumour
Graft involvement
Monomorphic histology
Older age
CNS or bone marrow involvement
Raised LDH and hypalbuminaemia Management of PTLD
No data available from randomised trials to inform management. Reduction of immunosuppression
Reduction in immunosuppression by stopping antimetabolite and reducing CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended whenever possible with surveillance of graft function
Response should be assessed at 2–4 weeks. Rituximab +/# chemotherapy can be initiated if no response. Rituximab +/ – chemotherapy
If no response to RIS, Rituximab should be considered in CD20-positive PTLD.
For patients who obtain CR or complete metabolic remission after four cycles of weekly rituximab, consider further four cycles three-weekly .
For patients who fail to obtain clinical or metabolic remission after four cycles or who progress during treatment, consider Four cycles of R-CHOP-21
R-CHOP-21 with RIS for should be considered in aggressive disease with critical organ compromise.
Assess cardiac and renal function in all patients. Interim and end of-treatment PET to assess response Radiotherapy
Radiotherapy may be considered in localized disease and certain histological subtypes Antiviral
No evidence to support anti-viral, arginine butyrate, IVIG or IFNa. Relapse/Refractory disease
Second-line chemotherapy should be considered in selected cases with relapse following standard chemotherapy.
In EBV-positive PTLD, EBV-specific CTLs should be considered where available.
Patients should be offered clinical trials where available. Other Type of Lymphoma
RIF should be offered to all patients; Further therapies may be offered based on comorbidities. CNS PTLD
RIS should be offered to all patient, Chemotherapy+/- rituximab if patient is fit, otherwise radiotherapy +/- steroids with RIS can be considered.
EBV-specific CTL can be considered for EBV-positive cases. Supportive treatment
PJP prophylaxis should be offered to all patients with G-CSF for those receiving chemotherapy. Re-transplantation
A minimum of one year wait before re-transplantation, longer time may be needed.
That is an excellent summary and very well structured reply. I wish you could give the heading ‘Introduction’ to first paragraph). Headings and sub-headings make it easier to read. What is your analysis of level of evidence of this study?
Front-line management of PTLD in adult SOT— A British Society for Haematology Guideline
Summary:
· PTLD is 2nd most common malignancy after SOT in adults (21% of cases), (after skin cancer) with significant mortality.
· The risk is increased with EBV negative recipient receiving from EBV +ve donor, strong immunosuppression as ATG induction, TAC based maintenance therapy, peak in 1st year post transplant (max immunosuppression stage), and long time after transplantation, certain organ transplantation as intestine and heart-lung transplantation.
· 90 % of cases are EBV +VE and of B cell origin.
· Diagnosis and staging:
o Tissue biopsy is the golden standard for definitive diagnosis and histopathology determination whether (none destructive, monomorphic or polymorphic, classic Hodgkin disease).
o Excisional /incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
· Basic investigations are required before commencing ttt:
o as CBC, electrolytes, serum uric acid, ca, LDH, liver and kidney function.
o PCR for EBV, CMV, HIV and serology for HBV, HCV.
o BMA and echo as indicated.
· CT neck, chest, abdomen and pelvis for initial staging and to monitor response to ttt thereafter. BET scan for staging if available.
· Staging with a CT is recommended in all patients where PET-CT is not available.
· Patients with suspected CNS involvement, CT and MRI brain with CSF analysis (cytology and flowcytometry). Management plan:
· Multidisciplinary team (transplant team, oncologist, radiologist, pathologist, psychiatry).
· Poor prognostic factors: as old age, monomorphic histology, EBV -ve, CNS, BM and multiple sites involvement, elevated LDH nad hypalbuminemia.
· Treatment includes many steps: 1. Reduction of immunosuppression (RIS) (sufficient alone in low-risk patients which have early lesions, low-stage disease and non-bulky disease):
· Assess response after 2-4 weeks.
· Close monitor the graft function and surveillance for rejection.
· If no at least partial remission, Rituximab should be started.
· No consensus about how to reduce immunosuppression, mostly we sop antiproliferative (MMF and azathioprine), reduce CNI by 50% and keep steroid 7.5-10 mg/day. 2. Rituximab ± sequential chemotherapy (CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone);
· After failed RIS alone after 2-4 weeks.
· Aggressive PTLD Ann Arbor stage III, elevated LDH and > one extra-nodal site or a high-risk IPI.
· Complete stoppage of IS is reasonable in kidney transplantation (as return to dialysis is still an option, unlike heart and lung transplantation).
· 4 cycles of weekly IV rituximab at standard dose (375 mg/m2) then assess response as some patients will respond to rituximab monotherapy.
· Cases with no response (no complete remission or worsening with rituximab) should be followed by 4 cycles of standard-dose CHOP chemotherapy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 day.
· Mandatory granulocyte colony-stimulating factor (G-CSF) and chemoprophylaxis against pneumocystis Jirovecii.
· Treatment related mortality (TRM) as cardiotoxicity (by doxorubicin) and severe myelosuppression by cyclophosphamide, that makes it more judicious to use selective agents in particular patients (not all chemotherapeutic agents).
· Response to treatment can be assessed by CT; however, PET-CTis more sensitive tool for response assessment and should be utilised where available. 3. Radiotherapy:
· In rare forms of PTLD, tends to be incorporated with the chemotherapy as in nasal natural killer/T-cell lymphoma. Treatment regimen tends to follow lymphoma protocols.
· Local disease in the orbit.
4. Anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
5. Refractory cases (relapsed after CHOP protocol);
· intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
· Adoptive immunotherapy as (EBV specific T lymphocytes), EBVSTs in relapsed and refractory cases).
6. Retransplantation: after 1 year of complete remission (with better matched donor to reduce immunosuppression, avoid ATG, minimize use of tacrolimus to the least possible dose)
You have used too much of bold in the middle part of your write-up. Typing in bold or in capitals amounts to shouting. Is one year wait enough? What is the current practice in your department or in your region?
· Diagnosis and staging
Establishing a tissue diagnosis of PTLD can be challenging and all diagnostic material should be accompanied by relevant clinical information including the date of transplant, immune suppression regimen and organ type.
In addition, PET-CT may have a role in the diagnostic work-up as demonstrated in a retrospective study published by Montes de Jesus et al They reported a sensitivity of 85% and specificity of 90% with a positive predictive value of 83% and a negative predictive value of 92% in PTLD.
Despite the limitations of these PTLD data, a staging PET-CT, where available, should be performed in line with recommendations for FDG-avid lymphomas in the immunocompetent patients.
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Staging with a CT is recommended in all patients where PET-CT is not available(1A).
Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B)
· PTLD type Description
Non-destructive Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia.
Most cases are EBV-associated and usually present as early PTLD.
Polymorphic A spectrum of B-cell maturation stages with admixture of T cells, EBV-associated in >90% cases.
Monomorphic Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large.
B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma.
Much less commonly indolent B-cell lymphomas, usually mucosa-associated lymphoid tissue lymphoma[5,11,12] and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative.
70% of these lesions are reported to have cytogenetic abnormalities, including trisomy 9 and 11 or both, loss of 17p and rearrangement of 8q24 (MYC)
· Baseline investigations
Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH).
Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres.
All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response.
Details should include; date of transplant, organ type and immunosuppresion regimen.
All patients require assessment of the function of the transplanted organ, ideally directed by the transplant physician.
CMV, cytomegalovirus; CT, computed tomography; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; PET, positron emission tomography; PTLD, post-transplantation lymphoproliferative disease.
It is recommended that the lead MDT should be the lymphoma MDT and where possible, a representative of the transplant team should attend. MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haematopathologist (1A)
· Prognostic scoring
There is no universally accepted prognostic scoring system specific for PTLD. This is a result of most prognostic scores included varying risk factors, heterogeneous patients or treatments and often being retrospective or single-institution series.
The Ghobrial prognostic score allocated one point for ECOG (Eastern Cooperative Oncology Group) > 2, monomorphic disease and graft involvement to demonstrated significant for overall survival (OS) but its utility was limited due to a majority of patient having monomorphic disease (96%) and only 16% having graft involvement.
28 In addition, another prognostic score, the PTLD Prognostic Index, is a variation of the IPI with baseline factors of age, ECOG performance status and LDH.
· Management of PTLD
Given the rarity of the diagnosis and the histological heterogeneity together with the medical complexity of the patients, there are no data available from randomised trials to inform management.
For the rarer subtypes and in the relapsed/refractory setting, treatment decisions are informed by small case series and case reports.
For the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL), there are robust data from prospective phase II studies that have informed existing treatment algorithms.
For the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL), there are robust data from prospective phase II studies that have informed existing treatment algorithms. 23,24
· Reduction of immunosuppression
Where safe to do so, immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team.
Where RIS is being considered as the sole initial treatment, response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond.
The response to RIS was assessed early between two and four weeks and failure of RIS was followed by sequential treatment with rituximab and subsequently by CHOP chemotherapy in adult B-cell PTLD.
RIS should be considered in conjunction with other therapies, in patients who have risk factors which include clinically aggressive PTLD Ann Arbor stage ≥III, elevated LDH and more than one extra-nodal site or a high-risk IPI.
Disease response assessment is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond .
· Or withdrawal of all immunosuppressant drugs except for corticosteroids CNIs, calcineurin inhibitors; MMF, mycophenolate mofetil; PTLD, post-transplantation lymphoproliferative disease; RIS, reduction in immunosuppression; SWOG, Southwest Oncology Group. ASCT, autologous stem cell transplant; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; G-CSF, granulocyte-colony stimulating factor; IPI, international prognostic index; IV, intravenous; PJP, Pneumocystis jirovecii; PR, partial remission; RIS, reduction of immunosuppresion; PTLD, post-transplantation lymphoproliferative disease; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone.
47% at 27!5 months (R) CHOP, (Rituximab) cyclophosphamide, doxorubicin, vincristine, prednisolone; CR/CRu, complete remission/response/unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival; PR, partial remission; PTLD, post-transplantation lymphoproliferative disease. Rituximabmonotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
· Therapy for relapsed or refractory PTLD
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD.
76–78 In patients who are unresponsive to rituximab, using R-CHOP is a reasonable and logical approach.
23,24,79 A sequential approach as in front-line therapy can be considered if relapse post rituximabmonotherapy occurs late.
Patients with R/R PTLD post R-CHOP have a poor longterm survival with OS < 20% as conventional salvage approaches with consolidation autologous stem cell transplantation (ASCT) are challenging to deliver in SOT patients.
78,79 Extrapolating treatments from R/R DLBCL in immunocompetent patients is reasonable 80–83 but this approach has little evidence in R/R PTLD.
Particular attention should be paid to the toxicities of salvage chemotherapy in relation to the underlying SOT and patient comorbidities.
Patients should be offered enrolment in a clinical trial where available
· Adoptive immunotherapy EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV-.
Autologous or allogeneic EBV-directed CTLs should be considered in patients with R/R EBV-positive.
89 This is similar to the results demonstrated by Prockop et al where a 54% ORR in 13 PTLD patients who were refractory to rituximab was reported.
Trials using CTL for PTLD are small, but the results appear promising and the recent development of chimaeric antigen receptor (CAR)-T cells reported for B-cell malignancies 91,92 suggests that this technology could have a future role in the treatment of PTLD.
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Peripheral T-cell lymphomas (PTCL) are a rare form of PTLD
They typically occur later after SOT and are often associated with poor outcome.
· Hodgkin lymphoma PTLD
Classical Hodgkin lymphoma-type PTLD (HL-PTLD) is rare and data on optimal therapy are lacking.
Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate (HD-MTX) with rituximab, is the standard for immunocompetent primary CNS lymphoma 113,114 but may be challenging to administer safely due to comorbidities, typically renal failure or SOT dysfunction in CNS-PTLD patients.
This approach has been adopted in CNS-PTLD patients with some success.
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
· Supportive care
Significant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection. 42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group.
Significant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection.
42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group.
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered.
116,117 Age is an important risk factor for developing FN which can partly be prevented by G-CSF.
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered. 116,117 Age is an important risk factor for developing FN which can partly be prevented by G-CSF. 116,117
· Findings EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years. 6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD. EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.
6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD.
43–45 Treatment-related mortality (TRM) was reduced to 13% compared to retrospective case series with front-line CHOP therapy which documented TRMs of up to.
Limited disease Reduction by 25% of all immunosuppression not critically ill Reduction of CNIs by 50%.
Reduction of CNIs by 50% and further reduction by 50% if not in complete remission by day 14.
Reduce glucocorticoids by 50%, with a lower limit of prednisone of.
Reduce CNIs by 50% and maintain steriods.
With reports of up to 50% mortality following infection.
With reports of up to 50% mortality following infection. 42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group
· Given the degree of immunosuppression in patients withPTLD, strong consideration should be given to antibiotic, antifungal and antiviral prophylaxis during therapy, if treatment is associated with neutropenia as per local protocols.
Prophylaxis with co-trimoxazole or equivalent should be considered in all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia.
Surveillance for CMV infections should continue in patients with PTLD with guidance from the transplant physician or team.
Patients with past hepatitis B or C infection should be managed in conjunction with a hepatologist.
118 Regular monitoring of liver function is required through treatment, and monitoring of hepatitis B viral load should be considered as per the guidance outlined by NICE CG165 118 or as directed by the hepatologist.
Patients with HIV should be managed under joint care with their HIV physician
Front-line management of the post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Introduction:
this document is an updated guideline and details the recommendations for the front-line management of adult patients with an established diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT).
Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.
PTLD is a common malignancy after skin cancer and is associated with a significant cancer-related mortality
The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, particularly in the first year post-SOT. EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%) followed by lung transplants, heart, liver transplants, pancreatic transplants, and renal transplant recipients having the lowest incidence of PTLD (up to 2.5%).
Diagnosis and staging:
>Recommendations: – Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
– Staging with a CT is recommended in all patients where PET-CT is not available (1A).
– Where available a PET-CT should be utilized for staging in line with the recommendation for FDG-avid lymphoma (1B).
>Categories of PTLD:
– Non-destructive Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia. Most cases are EBV-associated and usually present as early PTLD
– Polymorphic A spectrum of B-cell maturation stages with admixture of T cells, EBV-associated in >90% cases
– Monomorphic Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma. Much less commonly indolent B-cell lymphomas, usually mucosa-associated lymphoid tissue lymphoma and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative. Approximately 70% of these lesions are reported to have cytogenetic abnormalities, including trisomy 9 and 11 or both, loss of 17p and rearrangement of 8q24 (MYC)
– Classical Hodgkin Lymphoma Morphologically this fulfils the conventional criteria for the diagnosis of classical Hodgkin lymphoma and is generally (>90%) associated with EBV >baseline investigations:
– Full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH) Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titers
– Bone marrow biopsy is indicated and for some selected patients it may not be clinically needed or appropriate > All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A). > All diagnostic material should be reviewed by a hematopathologist(1A).
Management of PTLD:
Recommendations:
1st line – Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
– Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
> if an Extensive disease or critically ill, stop all agents except for maintaining prednisolone 7.5/10 mg/day.
2nd line -Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
-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 (1B). ” Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
-Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
– Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
– PET-CT should be considered for interim and end-of-treatment response assessment where available (1C).
3rd line-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
– In localized disease, radiotherapy may be offered concurrently with RIS (2C).
– Treatment with anti-viral agents and/or arginine butyrate, IVIG, and IFN alpha is not recommended outside clinical trials (1C)
Adoptive immunotherapy– Patients who relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
– Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
– Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C). Post-transplant lymphoproliferative disease affecting the central nervous system
-It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C)
–Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
– Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
–Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
– Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C). Supportive care
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered
strong consideration should be given to antibiotic, antifungal (e.g. fluconazole) and antiviral (e.g. acyclovir) prophylaxis during therapy, particularly if treatment is associated with neutropenia as per local protocols. Prophylaxis with co-trimoxazole or equivalent should be considered in all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia (PJP). Surveillance for CMV infections should continue in patients with PTLD with guidance from the transplant physician or team. Re-transplantation
-Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
What do you mean by ‘a longer period may be needed’? You have used too much of bold, italics and underline at the same time in your write-up just before ‘management’ heading. Is one year wait enough? What is the current practice in your department or in your region?
The article deals with British Society of Hematology guidelines for management of post transplant lymphoproliferative disorder (PTLD) in adult sold organ transplant (SOT) patients.
Introduction:
PTLD consists of 21% of all cancers in SOT recipients, derived mainly by B cells, and could be either Epstein-Barr virus (EBV) associated (60-80% within first year post-transplant) or EBV-negative (20-40% occurring after first year and later at 10 year post-transplant). PTLD incidence is most common in multiorgan and intestinal transplant with least incidence in renal transplants.
4 histopathological categories of PTLD include non-destructive, polymorphic, monomorphic, and classical Hodgkin’s lymphoma.
Diagnosis and Staging: A biopsy (excisional or incisional) is recommended for diagnosing PTLD. Staging with a computed tomogram (CT) of neck chest, abdomen and pelvis is recommended and PET-CT (positron emission tomography – CT) should be utilized, if available. Once diagnosed, patients should undergo detailed baseline evaluation including detailed history, current medication regimen details, and lab tests including full blood count, electrolytes, renal function and liver function tests, lactate dehydrogenase (LDH), and virology (hepatitis B, Hepatitis C, HIV, cytomegalovirus – CMV, EBV DNA tires, EBV serology). Echocardiography and fertility preserving treatments should be done as per clinical status of the patient. Cardiac and renal function assessment is required in patients. PET-CT should be used for interim and end-of treatment assessment, if available.
Management of PTLD: It should involve a multidisciplinary approach including transplant physician, hemato-oncologist, hematopathologist, radiologist and radiation-oncologist. Treatment involves reduction of immunosuppression (RIS), rituximab, chemotherapy and other measures.
B cell PTLD
RIS: For early lesion, low-stage and non-bulky disease, RSI in form of stopping antimetabolite, reducing calcineurin inhibitor dose by 30-50%, and continuing steroids is done. The patient is monitored for next 2-4 weeks and no other treatment id required if complete remission achieved.
Riruximab: In case of partial remission/ no response to RIS in CD20-positive B cell PTLD, or aggressive Ann Arbor stage III or IV, elevated LDH, or extra-nodal site or high-risk IPI (international prognostic index), 4 weekly cycles of injection Rituximab 375 mg/m2 are given. In case complete remission is achieved, 4 more cycles of rituximab are given 3 weekly.
Chemotherapy: In case complete remission is not achieved with rituximab alone, or if the disease progressed, chemotherapy in form of R-CHOP 21 (Doxorubicin, cyclophosphamide, vincristine, and prednisolone) every 3 weeks for 4 cycles should be given. It should be accompanied by GCSF (Granulocyte colony stimulating factor) and pneumocystis jirovecii prophylaxis.
Radiotherapy: It can be used for treatingPTLD involving orbit, isolated central nervous system (CNS), or localized extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT). In nasal natural killer/ T-cell lymphoma, radiotherapy and chemotherapy can be combined.
Antivirals, Intravenous immunoglobulin (IVIG), interferon anlpha and arginine butyrate are not recommended outside clinical trials.
Relapse/ refractory PTLD: sequential approach for intensive second-line chemotherapy followed by autologous stem cell transplant (if a good remission is achieved) can be used for relapse. Enrolment in clinical trials should be offered for refractory patients.
Adoptive immunotherapy: EBV specific cytotoxic T lymphocyte (CTL) can be used in relapsed/ refractory EBV positive PTLD.
Burkitt lymphoma like PTLD: R-CHOP with RIS, or EPOCH-R (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and rituximab) can be used.
Plasmablastic and plasma-cell myeloma PTLD: RIS with treatment as for plasmacytoid dyscrasia disease.
T-cell lymphoma PTLD: Treatment involves RIS and chemotherapy.
Hodgkin lymphoma PTLD: RIS with chemotherapy – ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy will be required.
Extranodal marginal zone lymphoma PTLD: RIS with rituximab with or without radiotherapy.
CNS PTLD: RIS, intrathecal chemotherapy (with or without rituximab) and whole-brain radiotherapy can be used. Local radiotherapy with or without corticosteroids can be used. EBV-specific CTLs can also been used, if available.
Re-transplantation: Risk of recurrence is low, hence retransplant can be offered after minimum 1 year of remission, but a longer period is needed. Avoid antithymocyte globulin induction in re-transplant.
We have never undertaken any patient with PTLD for re-transplant. I have based my comment on the article on PTLD.
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
Front-line management of the post-transplantation lymphoproliferative disorder in adult solid organ recipient patients- A British Society for hematology Guideline.
Summary: In solid organ transplant, the PTLD is more common second to skin cancer, and represent 21% of all cancers, compared to 4-5% in the immunocompetent population. PTLD associated with significant mortality. Occur as early as within one year and as late as 10 years, and mostly derived from B-lymphocytes, and EBV associated. Incidence is rated as follows:
Multi-organ and intestinal transplant, 20%.
Lung transplant, 3-10%.
Heart transplant, 2-8%.
Liver transplant, 1-5.5%.
Pancreatic transplant, 0.5-5%.
Renal transplant recipients, have the lowest rate, 0.8-2.5%.
Histological diagnosis:
Non-destructive: known as early PTLD, features plasmatic hyperplasia, lymphocyte-like mononucleosis changes, florid follicular hyperplasia, EBV associated.
Polymorphic: B-cell maturation stages mixed with T-cell, EBV >90% associated.
Monomorphic: subclasses according to the lymphoma subtype; 60-80% of PTLD, as follow; ((i)) Diffuse large B-cell lymphoma, DLBCL. ((ii)) Burkitt lymphoma. ((iii)) Plasma cell myeloma. ((iv)) Plasmacytoma.
Classical Hodgkin Lymphoma: >90% are EBV associated.
Base-line investigation:
Chemistry panel.
Virology screening; HIV, Hepatitis, B, C, EBV, and CMV/EBV DNA titer.
Bone marrow biopsy, indicated in some cases.
Echocardiology.
Fertility-preserving treatment.
Transplantation details.
CT scan staging.
PET-CT, if available.
Recommendations:
Where possible a surgical excisional biopsy is recommended to establish a diagnosis, where this is not possible, a core needle biopsy is an alternative (1A).
Staging with a CT is recommended in all patients where PET-CT is not available (1A).
Where available a PET-CT should be utilized for stagging in line with the recommended for FDG-avid lymphoma (1B).
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a hematopathologist (1A).
Management of PTLD:
Immunosuppressant reduction RIS: Sole treatment, balanced risk to save great function and to partially activate T-lymphocyte, the condition should be assessed within 2-4 weeks, if no CR, consider Rituximab+/- chemotherapy.
American guidelines on RIS; Reduction by 25% of all IS. for limited disease, while reduction of CNIs by 50%, stop AZA/MMF, keep pred, 7.5/10 mg/d in extensive not critically ill patients, and stop all agents except pred, 7.5/10 mg/d in critically ill patients.
European Renal Guidelines on RIS; stop AZA, and methotrexate, reduce CNIs by 50% and keep steroids, or all stop except pred.
If a response occurs with RIS, watch and wait.
If no response; start Rituximab and observe if the response completes 4 cycles, if not CR or failed start R-CHOP.
Recommendation:
Reduction in IS by stopping AZA/MMF and reduction of CNIs by 30-50% while maintaining CST, is recommended in all patients whenever possible, under transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2-4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Recommendation:
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or CMR after 4 cycles of weekly standard-dose rituximab (1B).
Four cycles of R-CHOP-21 immunochemotherapy are recommended in a patient who fails to obtain CR or CMR after four cycles of weekly standard dose rituximab or who clinically progresses during these four cycles(1B).
Rituximab plus anthracycline-based therapy (R-CHOP 21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
Radiotherapy: Retrospective analysis suggests that adults with the limited-stage disease, whatever histological subtype, can remit completely after surgical resection, or radiotherapy, usually with RIS. Antiviral, IVIG, and INF-alpha: No demonstrative data to suggest a benefit of use. Recommendation:
Involved-field radiotherapy may be offered to selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
In localized disease, radiotherapy may be offered concurrently with RIS (2C).
Treatment with anti-viral agents and /or arginine butyrate, IVIG, and IFN-alpha are not recommended outside clinical trials (1C).
Therapy for relapse or refractory PTLD:
No prospective data to suggest treatment.
Limited evidence bases are built on case reports.
Patients with R/R PTLD post-R-CHOP have a poor long-term survival rate.
Adoptive immunotherapy: EBV-CT-lymphocyte immunotherapy offers another approach to the treatment of EBV-positive PTLD, utilizing either the recipient’s own cells or HLA-matched ones. Recommendation:
Patients who relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Treatment of PTLD with EBV-specific CLTs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Burkitt lymphoma-like PTLD:
strongly associated with EBV.
Rituximab alone does not induce sufficient remission.
R-CHOP-like regiment with concurrent RIS, results in CR.
T-cell lymphoma PTLD:
Rare form of PTLD.
Occur late and associated with poor outcomes.
Evidence bases are limited to reported cases.
Combined RIS with anthracycline-based chemotherapy is advised.
Hodgkin lymphoma PTLD: HL-PTLD regimen includes combination chemotherapy with ABVD with or without radiotherapy along with RIS. Central nervous system affection PTLD:
Higher in SOT recipients, but less percentage of all PTLD.
Histologically appear monomorphic, high grade, and EBV related.
Generally, the prognosis is considered poor.
Intensive chemotherapy, plus rituximab.
Recommendation:
It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithm outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Patients with CNS-PTLD should be offered treatment with RIS, followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
Local radiotherapy +/- CST with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CND-PTLD (1C).
Re-transplantation is dedicated to clinical need and organ type. A minimum of 1 year may be considered before re-transplantation, but a longer period may be needed (2C).
That is an excellent summary and very well structured reply. You have used too much of bold, italics and underline at the same time in your write-up. Typing in bold or capitals amounts to shouting! What is your analysis of level of evidence of this study?
Lymphoproliferative disorders is prevelant in recioient ofSolid organ transplantation (SOT )account for 21% of all cancers SOT recipients, as compared with 4–5% within the immunocompetent population and they are associated with a significant cancer-related mortality.The reported incidence varies according to patient age, transplant type and the degree of immunosuppression being highest in intestinal transplant { up to 20 % )and lowest in renal transplant ( 0.8-2.5%). most of PTLD cases are associated with EPV and derived from B lymphocyte lineage
Diagnosis and staging Diagnosis :In order to diagnose a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
If not possible , a core needle biopsy is an alternative Staging with PET-CT is recommended
if not available a CT is recommended in all patients management MDT including hematologist, haematopathologist, nephrologist and oncologist immunosuppression modulation by
· stopping antimetabolites (azathioprine and MMF) and
· reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids
· this is indicated for all patient with close observation of the graft function
· response to be evaluated from 2- 4 weeks for complete remission ( CR) or not to take decision for 2nd line introduction if there is no CR for patients who are CD20 positve ” Rituximab monotherapy is recommended as 375 mg/m2 weekly for 4 weeks with 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 ” if there is failure to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles Four cycles of R-CHOP-21 immunochemotherapy are recommended (1B). For aggressive lymphoma or critical organ affection both immunosuppression reduction with ” Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended .
· consider chemotherapy side effects and graft function if there is relapse after CHOP consider intensive therapy like second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved in patients with EBV positive PTLD consider EBV specific cytotoxic T lymphocytes for less common form of PTLD including : Burkitt lymphoma-like PTLD, Plasmablastic and plasma-cell myeloma PTLD, T-cell lymphoma PTLD, Hodgkin lymphoma PTLD and Extra-nodal marginal zone lymphoma – PTLD should underwent reduction of IS in addition to same line of management of non transplanted patients
· for PT:D affecting central nervous system : according to clinical presentation , either RIS followed by combination of RTx with chemotherapy or use both at same time in clinically relevant cases Supportive care
Antibiotic
Antifungal
G- CSF
Prophylaxis for PJP by using cotrimoxazole
Surveillance for CMV, HBv viral load
Seeking consultation for related specialties during treatment Retransplantation
Wait for 1 year or more according to evaluation
Summary of recommendations of the British society of hematology:
Recommendation for diagnosis:
1- Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. core needle biopsy is an alternative.
2- Staging using CT scan if PECT-CT is not available
3- When available, PET-CT scan is used for staging in line with the recommendation of FDG-avid lymphoma.
4- PET-CT should be considered for interim and end of treatment response assessment where available
Management:
1- All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians.
2- Reduction of immunotherapy (RIS):
Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond.
3- NON-responder to RIS:
Rituximab monotherapy (4 weekly dose of 375 mg/m2 IV) is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab (1B).
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles.
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
3- Other treatment modalities:
In localised disease, radiotherapy may be offered concurrently with RIS (2C).
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFN-alpha is not recommended outside clinical trials.
4- Therapy for refractory or relapsing PTLD:
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
Treatment of PTLD with EBV-specific CTLs should be considered where available with refractory r relapsing EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available.
5- Less common forms of PTLD (Burkitt lymphoma, plasma cell lymphoma, T cell lymphoma, HL):
It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management and follow the same algorithm for standard of care but with caution because of the potential toxicity and comorbidity.
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD
6- Supportive therapy:
G-CSF is recommended for patients receiving chemotherapy and pneumocystis jirovecii pneumonia (PJP) prophylaxis should be offered to all patients with diagnosis of PTLD.
7- Re-transplantation:
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed
I wish you could type heading in bold or underline or in italics. That would make it easier to read. WHat do you mean by ‘a longer period may be needed’? Is one year wait enough? What is the current practice in your department or in your region?
I- it should be clear that it is not my own word, it is the recommendations of the British society of hematology.
II- I don not remember that we did re-transplant or patient with previous lymphoma
But according to the review published by Dr. Halawa: Time to re-transplant: Approximately two years of time should elapse after successful PTLD management.
ref: 1- Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46.
Please summarise this article
This is an updated British society for haematology guidelines (2021) for the front-line management of adult patients with an established diagnosis PTLD following SOT
PTLD account for 21% of all cancers of SOT recipients (4–5% in the immunocompetent)
In the adults, multiorgan and intestinal transplants have the highest incidence of PTLD (20%)
Diagnosis and staging
A comprehensive pre-treatment evaluation is required
A tissue diagnosis accompanied by clinical information including the date of transplant, immune suppression regimen and organ type
Staging should be recorded using the Ann Arbor classification or the Lugano classification which is the recommended classification for staging following PET-CT in 18F-fluorodeoxyglucose -avid (FDG-avid) nodal lymphomas
PET-CT in the staging of PTLD is less well defined when compared to lymphoma in the immunocompetent
MRI or CT imaging of the brain, orbits and sinuses is recommended for patients with suspected central CNS or craniofacial disease
Diagnostic LP for CSF analysis, including cytology and flow cytometry, is recommended for patients with suspected CNS involvement
Surgical excisional or incisional biopsy is recommended where possible for diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A)
Where PET-CT is not available, staging with a CT is recommended in all patients, (1A)
A staging PET-CT, where available, should be performed in line with recommendations for FDG-avid lymphomas in the immunocompetent patients (1B)
Multidisciplinary approach to care
A management plan should be agreed by a MDT which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists (in line with the 2016 NICE guideline (NG47), ‘Haematological cancers: improving outcomes)
Consider the patient’s general health, the histological subtypes, clinical stage, the SOT function, the degree of immunosuppression, and the modalities of therapy available
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A)
All diagnostic material should be reviewed by a haematopathologist (1A)
Prognostic scoring
There is no universally accepted prognostic scoring system specific for PTLD
Poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH and hypoalbuminaemia
IPI score for non-Hodgkin lymphoma: age, stage of disease, EGOG performance status, extra-nodal site involvement and LDH. Low (0, 1, 2 points) and high is (3, 4, 5 points). Has a significant effect on overall survival (OS) and treatment-related mortality, but did not have an effect on progression-free survival (PFS)
A low IPI risk (0–2 points) exhibiting a superior OS compared to high IPI risk (≥3 points) at three years (OS 78% vs 54%, respectively)
The PTLD Prognostic Index: a variation of the IPI (age, ECOG performance status and LDH)
The IPI is a pragmatic choice of up-front score to use
Management of PTLD
Reduction of immunosuppression (RIS)
For low-risk patients early lesions, low-stage disease and non-bulky disease
Response should be assessed within 2–4 weeks.
Close monitoring for rejection is crucial in these patients who are in complete remission and maintained at RIS
PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks or further rituximab-based treatment may be considered
RIS should be considered in conjunction with other therapies, in patients who have risk factors (clinically aggressive PTLD Ann Arbor stage ≥III, elevated LDH and more than one extra-nodal site or a high-risk IPI)
RIS by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B)
Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B)
Rituximab +/-chemotherapy Front-line therapy for monomorphic CD20-positive B-cell PTLD
RIS and if denotes a complete remission, watch and wait
If no response to RIS, 4 weekly 375 mg m2 rituximab iv. If CR or CMR occurred, 4*3-weekly 375 mg m2 rituximab iv. If no CR or CMR, 4 cycles of CHOP-21 Polymorphic CD20-positive B-cell PTLD
Treated with the same as monomorphic CD20-positive B-cell PTLD
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B)
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 (1B)
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B)
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B)
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B)
Radiotherapy
Radiotherapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localised extra-nodal marginal zone lymphomas of the MALT type
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C)
In localised disease, radiotherapy may be offered concurrently with RIS (2C)
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C)
Relapsed or refractory PTLD therapy (R/R)
No data to guide management
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B)
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C)
Adoptive immunotherapy
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C)
An overall response rate (ORR) was 52% in 33 patients who had failed initial therapy
Burkitt lymphoma-like PTLD
R-CHOP with concurrent RIS could be considered for Burkitt-like PTLD (as in diffuse large B-cell lymphoma in the immunocompetent patient)
The CNS should always be assessed for overt or occult involvement at baseline and CNS prophylaxis should be strongly considered
Plasmablastic and plasma-cell myeloma PTLD
No data; treat as for the plasmacytoid dyscrasia disease in the immunocompetent
T-cell lymphoma PTLD (PTCL)
Rare, occur later and are often associated with poor outcome
RIS with anthracycline-based chemotherapy (in patients with adequate cardiac function)
Hodgkin lymphoma PTLD
It is Rare. Standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy
Extra-nodal marginal zone lymphoma – PTLD
The predominant site of involvement of MALT lymphoma is gastric (skin, colonic and small-bowel are rare)
Treatment options include RIS, rituximab and radiotherapy
PTLD affecting the CNS
The risk of CNS lymphoma is between 10 and 20% of PTLD
Typically monomorphic, high grade B-cell lymphoma and all are EBV-positive
Usually multifocal and detectable by MRI but tissue biopsy is recommended given that opportunistic infections may present with similar radiological findings
The overall prognosis is poor
Treatment is RIS, radiotherapy and intrathecal chemotherapy
Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate (HDMTX) with rituximab, is the standard for immunocompetent primary CNS lymphoma (challenging here)
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C)
Local radiotherapy +/-corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C)
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C)
It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C)
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C)
Supportive care
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B)
Re-transplantation
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C)
That is a very detailed summary and very well structured reply. I wish you could type sub-heading under the heading of Diagnosis and Staging in bold or underline or in italics. That would make it easier to read. Is one year wait enough? What is the current practice in your department or in your region?
INTRODUCTION;.
-Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.
-PTLD is a common malignancy after skin cancer and is associated with a significant cancer-related mortality.
-Recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%).
DIAGNOSIS;. –Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
-Where this is not possible, a core needle biopsy is an alternative.
-Staging with a CT is recommended in all patients where PET-CT is not available.
-End-of-treatment PET-CT appears to have moderate sensitivity (71%) and specificity (73%) for predicting relapse but a higher negative predictive value of 92%. MANAGEMENT OF PTLD;.
-Immediate reduction in immunosuppression (RIS).
-Close monitoring for rejection.
-Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function.
-Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond. -Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
-Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab.
-Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles.
–Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise.
-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes.
-Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
-Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD.
-Patients with relapsed/refractory PTLD should be offered clinical trials where available.
-It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management.
-Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity.
-Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD.
–G-CSF is recommended for patients receiving chemotherapy.
–PJP prophylaxis should be offered to all patients with diagnosis of PTLD.
–Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed.
That is a very detailed summary and very well structured reply. Is one year wait enough? What is the current practice in your department or in your region?
Thanks so much Prof,Ajay
-The ideal time gap between PTLD remission and listing for retransplantation is not clear.
-The British Transplantation Society guidelines recommend a period of at least 1 year from the control of PTLD to retransplantation to minimize the risk of PTLD recurrence,
-In our Practice;patient may underwent for a second kidney transplantataion surgery after 2-3 years from having achieved complete remission of PTLD.and after clearance from Hematology & Oncology.
Introduction
PTLD is the second most common malignancy after skin cancer in solid organ recipients. It accounts for 21% of all malignancy in solid organ recipients in comparison to 4-5% in general population. Its incidence depends on the patient’s age, type of organ transplanted and level of immunosuppression. Majority of the cases are B cell derived associated with EBV and occur in the first year post-transplant. However EBV negative PTLD though rare can occur after 1 year post-transplant and a second peak seen 10 years post.
Diagnosis and staging
Excisional biopsy required where possible to make a diagnosis, core biopsy may be done in instances an excision biopsy not feasible.
Staging should be done via the Ann Arbor or Lugano staging.
Where possible a PET scan should be done for staging for it is able to detect sites that could be missed with a CT scan.
CT scan neck, chest, abdomen and pelvis should be done at diagnosis to determine treatment and for a possible baseline to determine response to treatment.
Patients with possible CNS involvement require MRI/CT brain, sinuses and orbit, a lumbar puncture with CSF analysis for flow cytometry and cytology should also be done.
Prognosis
No universally accepted scoring system.
Poor prognostic factors include:
Poor performance status
EBV-negative tumour
Graft involvement
Monomorphic histology
Older age
CNS or bone marrow involvement
Raised lactate dehydrogenase (LDH)
Hypoalbuminaemia
Treatment
Multidisciplinary approach. 1.Reduced immunosuppression.
Only required treatment in low risk patients (early lesions, non-bulky and low stage disease). Asses in 2-4 weeks. Those who have achieved complete remission no need for further treatment. Partial remission can wait further for another 2-4 weeks or can add rituximab.
How to reduce varies per guidelines. American guidelines recommended 25% reduction for limited disease of all immunosuppression. Extensive disease and not critically ill 50% reduction of CNI, withdrawal of antimetabolite and maintenance of steroids at 7.5-10mg/day. Extensive disease and critically ill withdrawal of all and maintaining only on steroids 7.5-10mg/day.
European guidelines have almost similar recommendation.
Close monitoring of the graft to avoid rejection. 2.Rituximab
Front line for monomorphic CD20+ B cell PTLD which is the component form.
Patients unresponsive to reduced immunosuppression should receive 4 weekly cycles of Rituximab.
Patients who achieve complete remission are considered low risk and should receive further 3 weekly doses of rituximab.
Patients who fail to achieve remission are considered high risk and switched to 4 cycles R-CHOP with mandatory PJP prophylaxis and G-CSF. 3.Radiotherapy
Role undefined.
Maybe considered for localised monomorphic or Hodgkins lymphoma combined with reduced immunosuppression.
Maybe considered for extra-nodal sites eg the orbits and exclusive CNS relapse.
Effective treatment for MALT.
Rare forms of PTLD can be incorporated with chemotherapy.
Dose and fractional regimen are like those of normal lymphoma. 4.Other treatments
There is paucity of data on the use of antivirals, intravenous immunoglobulin and intravenous alpha interferon.
Treatment for relapsed or refractory
Patients who relapse after R-CHOP have a poor longterm survival.
They should be offered second line chemotherapy followed by autologous stem cell transplantation where feasible.
There is a role of adaptive immunotherapy where donor EBV specific cytotoxic T lymphocytes are infused in the recipient; where they induce a T cell mediated immune response to the abnormal B cells.
Supportive care
Due to high rate of treatment related mortality supportive care should be offered to all patients on immunochemotherapy.
Prophylaxis with G-CSF should be offered if the patient is at risk of febrile neutropenia.
Other prophylactic treatments include antibiotics, antiviral and antifungals.
Co-trimoxazole for PJP prophylaxis should be offered to all.
Patients with HIV/HCV/HIV should be closely monitored.
Re-transplantation.
Risk of recurrence is low after successful control of PTLD.
Timing depends on clinical need and the organ type.
Minimum wait period of 1 year should be considered however longer wait period maybe required.
That is a very detailed summary and very well structured reply. Is one year wait enough? What is the current practice in your department or in your region?
Thank you.
In my region prevalence of PTLD is low thus not much experience.
One year maybe a short duration, maybe a wait period of 2 years would be adequate.
Diagnosis of PTLD should be based on histological evaluation using excisional or incisional biopsy, and if not feasible core needle biopsy is an alternative, and the diagnostic material should be assessed by haematopathologist.
Staging of PTLD ad assessment of response is best done using PET-CT scan and if not available CT is an alternative.
Management of PTLD patients should be multidisciplinary including a haemato-oncology team with experience in PTLD management.
All patient with PTLD should stop antimetabolite , reduce CNI by 30-50 % and maintain or reduce steroid whenever possible this should occur 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.
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.
CD20-positive PTLD patients who undergo complete remission or complete metabolic remission (with Deauville ≤ 3) after Rituximab induction should receive Rituximab consolidation (4 cycles of Rituximab given every 21 days).
CD20-positive PTLD patients who fail to obtain complete remission or complete metabolic remission (with Deauville ≤ 3) or who progress after Rituximab induction should receive 4 cycles of R-CHOP-21 every 21 days.
CD20-positive PTLD 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.
Patients who relapsed after the initial R-CHOP therapy should be offered a second line chemotherapy, and if attain complete remission, autologous stem cell transplant is recommended.
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.
CNS-PTLD is aggressive (multifocal high grade monomorphic lymphoma B cell lymphoma), all patients are EBV positive with poor prognosis .Treatment options In patients with CNS-PTLD line includes reduction of immunosuppression , R-CHOP local radiotherapy, steroids and adoptive immunotherapy (in EBV+ patients).
Treatment of less common forms of lymphoma (Burkitt lymphoma-like PTLD, Plasmablastic and plasma-cell myeloma PTLD, T-cell lymphoma PTLD, Hodgkin lymphoma PTLD and Extra-nodal marginal zone lymphoma – PTLD) includes reduction of immunosuppression together with the standard protocols given for non-transplant patients.
All patients receiving chemotherapy should be offered G-CSF and PJP prophylaxis.
Re-transplantation can be offered to patients who fail the graft after the development of PTLD but after a minimum of 1 year of complete remission.
Introduction:
PTLD is the second most common post transplant malignancy, and it associated with significant cancer related mortality. Its incidence differs according patient`s age, transplant type & intensity of immunosuppression. Most PTLD cases associated with EBV infection, which is prevalent in first year post transplantation. About 20-40% of PTLD case are not associated with EBV infection with peak incidence after 10 years post transplantation.
PTLD incidence higher in multi-organ transplant(20%) followed by lung transplant(3-10%), heart transplant(2-8%), liver transplant(1-5.5%), pancreatic transplant(0.5-5%) and renal transplant(0.8-2.5%).
PTLD subtypes include: non destructive, polymorphic, monomorphic & classical Hodgkin lymphoma.
Diagnosis:
Baseline evaluation of all patients (CBC, graft function, liver enzymes, LDH, renal function and viral screen).
Surgical excision or incisional biopsy.
CT image for staging if PET-CT not available (recommended in all patients).
Multidisciplinary team (hematoma-oncology, hematopathology, transplant physician, radiation oncology & radiologist) needed to discuss the treatment regimens.
Adverse risk factors in prognostic scoring system:
poor performance status.
EBV negative tumor
graft involvement
monomorphic subtype
old age
CNS or bone marrow involvement
high LDH
low serum albumin
PTLD treatment:
Reduction of immunosuppression: it is the only required treatment for low risk patients. Stop antimetabolites, reduce 30-50% of CNI dose with maintained steroid under supervision of transplant physicians.
Rituximab +/- chemotherapy:
Rituximab used when RIS failed CD20 positive PTLD
patient with CR or CMRuse further 4 3/week cycle of rituximab.
R-CHOP recommended if CM or CMR didn’t achieved with rituximab.
Aggressive clinical disease & critical organ dysfunction after RIS, R-CHOP is recommended.
Assessment of cardiac unction & infection before starting treatment is essential.
Treatment response assessed by PET-CT if available.
3.Radiotherapy: May be considered for some extra nodal sites (orbit), isolated CNS relapse & MALToma.
4.Antiviral, IVIG & INT-alpha treatment: not recommended outside clinical trials.
Treatment of relapsed PTLD:
Post R-CHOP relapse patients should receive second line chemotherapy followed by autologous stem cell transplant after remission
Treatment with EBV-specific CTL if available R/R EBV+ve PTLD.
Refractory or relapsed PTLD patients should afford for clinical trails if available.
Treatment of less common PTLD forms:
initial treatment with RIS.
CNS PTLD treated with RIS followed by R-CHOP for suitable patients.
Radiotherapy may afford
EBV-specific CLT can be used for EBV+ve CNS-PTLD.
PJP prophylaxis & G-CSF is mandatory
Re-transplantation offered according clinical need & organ type at least 1 year after remission.
PTLD a common malignancy in SOT after skin cancer and is associated with a significant cancer-related mortality.
It accounts for 21% of all cancers in SOT, and the reported incidence varies according to patient age, transplant type and the degree of immunosuppression.
The majority are derived from B lymphocytes and are EBV-associated, particularly in the first year post SOT.
EBV-negative cases account for 20–40% of PTLD and usually occur after the first year of transplantation.
Diagnosis and staging:
o Relevant clinical information; the date of transplant, IS regimen and organ type.
o Tissue biopsy ( preferred excisional) are recommended to enable accurate PTLD sub-classification.
o Comprehensive pre-treatment evaluation.
o Accurate staging and response assessments are crucial for patient management.
o Staging using PET-CT and if not available CT
o Using Ann Arbor classification.
o If CNS- involvement suspected: consider brain/ orbit and sinuses CT or MRI with CSF analysis.
-PTLDs are sub-classified histopathological into; Non-destructive, Polymorphic, Monomorphic and Classical Hodgkin Lymphoma
Management of PTLD: Multidisciplinary approach to care
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
Reduction of immunosuppression RIS:
Aims to partially restore T-cell function.
RIS as sole initial treatment may require for early lesions, limited disease, low-stage disease and non-bulky disease.
European renal guideline for RIS:
– Stopping azathioprine and MMF
– Reduction of CNIs by 30–50%
– Maintaining or reducing corticosteroids, is recommended in all patients whenever possible.
· Close monitoring for rejection.
· Early disease response assessment (at 2–4 weeks) by CT.
– If patient achieve CR; keep monitoring.
– If PR achieved or in those that fail to respond; further treatment needed.
· For high risk individuals RIS in conjunction with other therapies.
Rituximab +/# chemotherapy Front-line therapy for monomorphic CD20-positive B-cell PTLD: The commonest form
Recommended for patients with CD20-positive PTLD who fail to respond to RIS as initial therapy.
The international phase II PTLD-1 trial established sequential therapy.
Four cycles of weekly IV RTX at standard dose (375 mg/m2) followed by:
Four further three-weekly cycles of RTX are recommended in patients who obtain CR.
Four cycles of standard-dose CHOP-21 chemotherapy in patients who fail to obtain CR.
Alongside mandatory G-CSF and prophylaxis against PJP was recommended
Favorable outcomes compared with RTX monotherapy alone in term of OS, TRM.
Using dose-attenuated treatment or alternative less toxic treatment regimens can be considered in cardiac transplant patients, allograft vasculopathy.
If disease progress or critical organ compromise at any time during RTX monotherapy or before interim staging, re-staging should be performed prematurely, and RCHOP- 21 should be considered to commence immediately if progression is confirmed.
PET-CT should be considered for interim and end of treatment response assessment where available
Polymorphic CD20-positive B-cell PTLD:
Data are limited and they are treated with the same algorithm as monomorphic CD20-positive B-cell PTLD.
Radiotherapy:
The role of radiotherapy as a component of treatment for PTLD is undefined.
Studies suggested that adults with limited-stage disease, regardless of the histological subtype, can obtain durable CRs after surgical resection or radiotherapy, usually with concurrent RIS.
It may be considered for localized disease, some extra-nodal sites, such as the orbit, isolated CNS relapse and MALT.
The dose and fractionation regimen tends to follow normal lymphoma protocols.
Antivirals, IVIG and interferon-alpha treatment: Data are limited and is not recommended outside clinical trials.
Therapy for relapsed or refractory R/R PTLD:
A sequential approach as in front-line therapy can be considered if unresponsive to RTX or relapse post RTX monotherapy occurs late.
Patients with R/R PTLD post R-CHOP have a poor long-term survival with OS < 20% as conventional salvage approaches with consolidation (ASCT) are challenging to deliver in SOT patient.
Utilize EBV-specific CTLs either the recipient’s own cells to generate autologous EBV-directed CTLs or a bank of partially HLA matched EBV-specific CTLs to generate a T-cell immune-mediated response to these abnormal B cells.
Should be considered in patients with R/R EBV-positive PTLD.
Burkitt lymphoma-like PTLD
R-CHOP with concurrent RIS could be considered a reasonable option for Burkitt-like PTLD as in DLBCL in the immunocompetent patient.
The CNS should always be assessed for overt or occult involvement at baseline and CNS prophylaxis should be strongly considered.
Plasmablastic and plasma-cell myeloma PTLD;
Rare form
Treat as for in the immunocompetent alongside RIS.
T-cell lymphoma PTLD
Rare form, occur later and associated with poor outcome.
Combine RIS with treatment algorithms used in immunocompetent patients, caution due to potential toxicity and patient comorbidity
Hodgkin lymphoma PTLD:
Rare form.
Standard combination chemotherapy with ABVD with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function.
Extra-nodal marginal zone lymphoma – PTLD
The predominant site of involvement of MALT lymphoma is gastric.
Treatment algorithms are heterogeneous and poorly standardized.
PTLD affecting the CNS.
Typically monomorphic, high grade B-cell lymphoma and all are EBV-positive.
Usually multifocal and detectable by MRI but tissue biopsy is recommended given that opportunistic infections may present with similar radiological findings.
The overall prognosis is generally considered poor.
RIS, intrathecal chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity and whole-brain radiotherapy.
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
Supportive care:
G-CSF prophylaxis : Significant TRM following infection to prevent FN.
Antibiotic, antifungal (e.g. fluconazole) and antiviral (e.g. acyclovir) prophylaxis during therapy, particularly if treatment is associated with neutropenia as per local protocols.
PJPProphylaxis with co-trimoxazole should be considered in all patients.
Surveillance for CMV and other viruses especially in individuals with previous history HBV, HCV, HIV.
Re-transplantation
Can be considered after successful control of PTLD as the risk of recurrence of PTLD after is low.
The timing of re-transplantation depends on the specific organ and clinical need.
A minimum period of one year should be considered before re-transplantation depending on the organ and clinical need.
Introduction
Lymphoproliferative disorders represent 21% of all cancers of SOT recipients.
Post-transplant lymphoproliferative disease occur due to lymphoid proliferations caused by immunosuppression after SOT.
PTLD commonly occurs after skin cancer with high mortality rate ,it can develop early or late after transplantation but it’s highest incidence of occurrence is with multiorgan or intestinal transplantation ,followed by lung transplant ,then heart transplant ,then liver transplant then pancreatic transplant then the smallest incidence is with renal transplant.
PTLD is derived from B lymphocyte and is associated with EBV Diagnosis and staging
PTLD is divided into 4 histopathological categories which are non destructive, poly morphic ,monomorphic and classical Hodgkin lymphoma.
Diagnosis is difficult and staging requires using the Ann Arbor classification or the Lugano classification for staging lymphomas although using PETCT for PTLD staging is less well defined in comparison to lymphoma.
In fact PETCT has beneficial role in PTLD diagnosing , staging ,detecting new involved sites and post treatment relapse to some extent.
For cases with possible CNS involvement MRI ,CT imaging and CSF analysis will be needed.
-Surgical excisional or incisional biopsy is needed for diagnosis (alternative core needle biopsy) and PET CT is needed (alternative is CT ) for staging Multidisciplinary care
(MDT) need to involve transplant physicians, haemato-oncologists, haematopathologists,
radiation-oncologists and radiologists. Prognostic scoring
There is not a standardised prognostic scoring for PTLD ,however some ominous risk factors were acknowledged involving including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH and hypoalbuminaemia. PTLD management Reduction of Immunosuppression(RIS)
Can be done if applicable under transplant team supervision, representing the only therapy for low risk early stage disease, along with follow up for 2-4 weeks because in case of failure to reach complete remission , alternative treatment can be started in addition to close monitoring of rejection.
Cases who reached partial remission with RIS can either followed and be reassessed within 2-4 weeks or rituximab based therapy can be started.
There are American, SWOG and European Renal Guidelines for RIS.
It is recommended to RIS by stopping azathioprine and MMF ,decreasing CNIs to 30–50% and maintaining or reducing corticosteroids also early disease assessment is adviced for cases on RIS onlt in order to start alternative treatment soon if RIS alone failed. Rituximab +/- chemotherapy
– Monomorphic CD20-positive B-cell PTLD which is the most common PTLD forum.
Rituximab is used for treatment of polymorphic PTLD, or monomorphic DLBCL-like PTLD, unresponsive to initial RIS.
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wasnot achieved —4 cycles of CHOP21
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If RIS failed —-4 weekly IV Rituximab will be given —-If CR
was achieved—4X 3weekly IV Rituximab
A trial that used sequential 4 cycles of weekly IV Rituximab, followed by four cycles of standard-dose CHOP-21 chemotherapy every 21 days with GCSF and prophylaxis against PJP demonstrated better outcomes than using Rituximab alone also TRM was less in R-CHOP21 group compared to CHOP21 group.
At the same time some patients can not tolerate the combination therapy so attenuated or less toxic regimens can be tailored for them.
Special considerations are needed to be taken in each individual case as cardiac transplant recipents with vasculopathy can experience preserved LV EF HF
– Polymorphic CD20-positive B-cell PTLD treatment algorithms similar to monomorphic due to paucity of data on polymorphic
It includes IV Rituximab of 4 weekly standard cycle as monotherapy for cases who did not respond to RIS initially followed by 4 more 3 weekly cycles for cases with CMR while cases who did not reach remission can receive 4 cycles of RCHOP21.
Along with cardiac and renal assessment for SOT recipients.
PETCT is needed for evaluation of treatment response. Radiotherapy
A study proposed that adults with early-stage disease, apart from the histological subtype, can achieve CRs after surgical resection or radiotherapy, usually with concurrent RIS.
Radiotherapy can be applied for some extra-nodal sites, as the orbit, isolated CNS relapse and for localised extra-nodal marginal zone lymphomas of the MALT.
Radiotherapy with chemotherapy regimens can be used in nasal NK/T-cell lymphoma Antivirals, IVIG and interferon-alpha treatment
are not adviced outside clinical trials Therapy for relapsed or refractory PTLD
R/R PTLD cases post R-CHOP have poor prognosis, extrapolating treatments from R/R DLBCL in
immunocompetent patients can be offered, but with little evidence in R/R PTLD. Adoptive immunotherapy
EBV positive PTLD and R/R EBV-positive PTLD can be treated by EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy without graft rejection risk and the outcomes were acceptable.
These T lymphocytes are either autologous or extracted from a bank of partially matched HLA EBV-specific CTLs.
Chimeric antigen receptor (CAR)-T cells used for B-cell malignancies suggests it’s possible
role in the treatment of PTLD. Burkitt lymphoma-like PTLD
Rituximab monotherapy cannot induce remission
R-CHOP with concurrent RIS can be used for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immunocompetent patient ,Dose-adjusted EPOCH-R with CNS prophylaxis can be suitable in selected patients. Plasmablastic and plasma-cell myeloma PTLD
No sufficient data is available therefore RIS along with plasmacytoid dyscrasia disease in the immunocompetent cases can be used T-cell lymphoma PTLD
It is a rare forum ,that occurs late post SOT , it has a poor prognosis .
RIS with anthracycline-based chemotherapy was proposed for therapy .
Immunocompetent patients with T-cell lymphoma treatment algorithm can be applied. Hodgkin lymphoma PTLD
It is rare with no much data available, it is supposed to occur late after SOT.
HL-PTLD patients with normal cardiac and pulmonary function can be treated by standard combination chemotherapy with ABVD(doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy alongside RIS .
BEACOPP , Eescalated BEACOPP or BEACOPDac is an option in patients with high-risk disease but toxicities must be considered. Extra-nodal marginal zone lymphoma – PTLD
It’s risk increase with SOT.
Stomach is the most common site to be affected in MALT lymphoma, also colonic and small bowel involvement were dteceted.
EBV-positive MALT lymphoma occurs in the skin and can respond to RIS.
Rituximab monotherapy or Radiotherapy in certain cases are other options. CNS involvement in PTLD
CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive.
It is multifocal as detected by MRI and tissue biopsy can be needed.
Median OS is 33–47 months.
RIS with intrathecal chemo and whole brain radiotherapy ,outcomes were acceptable.
Systemic chemotherapy with CNS penetration is the standard for primary CNS lymphoma in immunocompetent.
Rituximab with RIS can be used in patients unfit for chemotherapy.
EBV-specific CTLs can be used in patients with EBV-positive CNS-PTLD post HSCT or SOT Supportive care
G-CSF as primary prophylaxis can be useful in patients with PTLD having high TRM.
Antibiotic ,antiviral and antifungal treatment can be considered for cases with neutropenia
PJP prophylaxis in all PTLD cases
CMV surveillance is adviced, patients with HBV ,HCV or HIV need to be treated .
Retransplant
Can be considered after PTLD control as it’s recurrence rate is low post transplant.
One year gap is considered as a minimum period before re-transplantation varing according to the organ and clinical need.
Post-transplant lypmphoproliferative disorder is one of the common malignancies due to immune-suppression in solid organ transplantation (SOT)
Represent 21% of all cancers of SOT patient versus 4 -5% in immune-competent hosts.
It is mostly originated from B lymphocytes and occur in the first year post SOT
Associated with EBV but20 t0 40% may be EBV-negative and presents beyond the first year with peak incidence at around 10 years
Diagnosis and staging:
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A)
Staging with a CT is recommended in all patients where PET-CT is not available (1A)
Where available a PET-CT should be utilized for staging in line with the recommendation for FDG- avid lymphoma (1B)
Multidisciplinary approach to care:
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haemato-pathologist (1A).
Management of PTLD:
Reduction of immune-suppression:
-Low risk patients, early and non-bulky disease
-Review within 2 to 4weeks to check for response, if CR no further action
-Close monitoring for rejection
-PR, monitor for another 2 to4 weeks or consider rituximab
Rituximab +/- chemotherapy (Sequential therapy):
-Indicated for monomorphic CD20 +ve PTLD
-Rituximab (4 cycles) follow by CHOP 21 ( 4 cycle every 21 days) = PTLD-1
-Rituximab monotherapy in low-risk patient = PTLD-2
Polymorphic CD-20 +ve PTLD:
-Limited data
-Treated the same as monomorphic CD20 +ve PTLD
-Rarely treated as HL
Radiotherapy: For localized disease e.g., MALT
Antiviral, IVIG and interferon treatment: Limited data
Refractory/ relapsed PTLD: this is very challenging but one would try R-CHOP after failure to respond to rituximab monotherapy.
Adoptive immunotherapy: this is promising in future, and it is based on EBV-specific T-lymphocytes. Another approach is donor lymphocytes infusion.
Other forms of PTLD with limited data on treatment:
Burkitt lymphoma
Plasmablastic and plasma cell myeloma
T-cell lymphoma
Hodgkin lymphoma: standard ABVD
Extra-nodal marginal Zone lymphoma e.g., MALT type: Rituximab monotherapy, Radiotherapy
CNS-PTLD: Reduction of immune-suppression, rituximab monotherapy, Adoptive immunotherapy. Generally, it should be handled case by case bases.
Supportive therapy:
G-CSF: primary prophylaxis
Anti-fungal prophylaxis: Fluconazole
Antiviral prophylaxis: Acyclovir
PJP prophylaxis: co-trimoxazole
CMV surveillance
Hepatitis B/C patients should be managed with hepatologist
This updated guideline talks about the first treatment for adults with post-transplant lymphoproliferative disease (PTLD) after solid organ transplantation (SOT).
Lymphoid proliferations caused by immunosuppression after SOT cause post-transplant lymphoproliferative illness.
SOT patients’ malignancies are 21% lymphoproliferative, compared to 4–5% in immunocompetent people.
After skin cancer, PTLD is a prevalent malignancy in adult SOT patients and is linked to high cancer mortality.
Diagnosis and staging:
Tissue diagnosis of PTLD is difficult and requires clinical information, including transplant date, immune suppression treatment, and organ type. Excisional biopsy samples are best for PTLD sub-classification and auxiliary studies.
For diagnosis, surgical excisional or incisional biopsy is recommended.
If not, a core needle biopsy may be done (1A).
Patients without PET-CT should be staged with CT (1A).
As with FDG-avid lymphoma, PET-CTs should be used for staging when available (1B).
Categories of PTLD:
Non-destructive: Includes plasmacytic hyperplasia, infectious mononucleosis-like lymphocytes, and florid follicular hyperplasia. EBV-associated early PTLD patients predominate.
polymorphic: B-cell maturation stages with T cells, EBV-associated in >90% instances.
monomorphic: DLBCL, Burkitt lymphoma, plasma cell myeloma, plasmacytoma, 60–80% of PTLD. Indolent B-cell lymphomas and T-cell neoplasms are rarer. EBV-negative monomorphic PTLD. 70% of these lesions had trisomies 9 and 11 or both.
Classical Hodgkin lymphoma: This meets the morphological criteria for classical Hodgkin lymphoma, and EBV is usually (>90%) the cause.
Management of PTLD:
All patients should be discussed with organ transplant specialists by PTLD-experienced haemato-oncology MDTs (1A).
Hematopathologists should evaluate all diagnostic material (1A).
Reduction of immunosuppression: The clinical picture and illness severity determine the American guidelines’ approach.
Immunosuppression should be lowered in all transplant patients by getting rid of azathioprine and MMF and lowering CNIs by 30–50% while keeping or lowering corticosteroids. Graft function should be monitored (1B).
“Early disease response evaluation (at 2–4 weeks) is recommended for patients who are only getting RIS so that those who don’t respond can get more treatment” (1B).
Lines of Treatment:
“CD20-positive PTLD patients who fail RIS should get rituximab monotherapy (1B).
Four more three-weekly cycles of rituximab are recommended in patients who achieve CR or complete metabolic remission (CMR) (with Deauville 3) after four cycles of weekly standard dose (1B).
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to achieve CR or CMR or who clinically progress during these four cycles (1B).
Rituximab with anthracycline-based treatment (usually R-CHOP-21) is advised with RIS for patients with clinically aggressive lymphoma and serious organ impairment at any time after diagnosis (1B).
“All patients with SOT or suspected renal or cardiac impairment should have a formal cardiac and renal function evaluation (1B).
PET-CT should be evaluated for intermediate and end-of-treatment response evaluations when available (1C).
Standard methods for specific histological subtypes of PTLD may allow for involved-field radiation in some cases (2C).
Radiotherapy may be used with RIS (2C) for localized illness. Outside clinical trials, antivirals, arginine butyrate, IVIG, and IFNa are not advised (1C).
If a good remission is obtained after R-CHOP, relapsed patients should be carefully chosen for rigorous second-line chemotherapy and autologous stem cell transplant (2B).
R/R EBV-positive PTLD should be treated with EBV-specific CTLs if available (1C).
Clinical studies for relapsed/refractory PTLD should be provided when available (1C).
Depending on organ function and comorbidities, CNS-PTLD patients should have RIS followed by combined chemotherapy with rituximab (1C).
“Local radiation +/# corticosteroids with RIS for CNS-PTLD (2C)
if fitness and comorbidities are restricted.” EBV-positive CNS-PTLD may benefit from EBV-specific CTL (1C).
Re-transplantation:
Clinical necessity and organ type determine re-transplantation. Before re-transplantation, one year is recommended, although longer may be required (2C).
o Form a MDT which includes – Transplant physicians haemato -oncologist haematopathologist Radiologist Radiation oncologist
o For diagnosis – surgical excisional Or incisional biopsy recommended. alternatinge is Core needle biopsy. If PET CT is not available then staging with a CT is recommended. If available PET CT should be done for staging
o All biopsy samples to be revised by haemato pathologist.
o All cases to be discussed at haemato oncology MDT meeting.
Adverse risk factors in PTLD Raised LDH Hypoalbuminemia cNS or bone marrow involvement older age mono morphic histology graft involvement EBV negative tumour poor performance status.
file:////Users/prakashghogale/Library/Group%20Containers/UBF8T346G9.Office/TemporaryItems/msohtmlclip/clip_image002.jpg
o Other scoring systems – Ghobrial prognostic score International Prognostic Index PTLD prognostic index
Management of PTLD
o Reduction of immunosuppression may be sufficient in patients with low risk disease. Assess response within 2-4 weeks of reducing immuno suppression. Whether CR | PR acheived Watch out for rejection
Strategy to reduce immunosuppression Stop anti metabolites Decrease CNI by 30-50% Maintain Or reduce steroids
In presence of- clinically aggressive disease Ann Arbor stage > III Elevated LDH high risk IPI more than one extranodal site Use other strategy with reduction of immunosuppression.
Rituximab + / – chemotherapy If unresponsive to RIS
file:////Users/prakashghogale/Library/Group%20Containers/UBF8T346G9.Office/TemporaryItems/msohtmlclip/clip_image002.jpg 4 cycles of weekly intravenous rituximab at 375mg/ m2 followed by 4 cycle of standard dose CHOP – 21 chemotherapy. 50 mg/m2 doxorubicin 750 mg/m2 cyclophosphamide 1.4 mg /m2 vincristine 50 mg/m2 prednisolone. every 21 days
along with G – CSF
In the PTLD 1/3 trial first R IS fails 4 cycles of Rituximab interim CT at Day 50 if CR – low risk, then Further 4 cycles of 3 weekly Rituximab and then stop. if no CR acheived or if progression present, then high risk, 4 cycles of R- CHOP 21. along with G-CSF and PCP prophylaxis.
Low risk further redefined in PTLD -2 who acheive a CR with first 4 cycles of Rituximab monotherapy. those who acheina PR and IPI of 0-2.
PET- CT to be done for inthim staging and end of treatment response if available.
file:////Users/prakashghogale/Library/Group%20Containers/UBF8T346G9.Office/TemporaryItems/msohtmlclip/clip_image002.jpg Radio therapy – with RIS in localised monomorphic type DLBCL and Hodgkin lymphoma PTLD with RIS +/ – on taximats in DLBCL if patient not eligible For intensive chemotherapy. Orbit PTLD isolated CNs relapse localised MALT
No role of- Antivirals intravenous immunoglobulin
Retractory PTLD Poor prognosis
Adoptive immuno therapy in those who relapse post R-CHOP intensive second line chemotherapy to be given. if remission acheived then do autologous stem cell transplant.
Burkit lymphoma like PTLD R I S with R- CHOP Assess CNs
T cell lymphoma PTLD RIS plus anthracycline based chemotherapy.
Hodgkin lymphoma PTLD RIS plus ABVD chemotherapy ( Doxorubicin, b leomycin,
file:////Users/prakashghogale/Library/Group%20Containers/UBF8T346G9.Office/TemporaryItems/msohtmlclip/clip_image002.jpg Vinblastine,dacarbarine ) with or without radio therapy.
Extra nodal marginal zone lymphoma – PTLD Rituximab monotherapy
CNS PTLD RIS, In tracranial chemotherapy, and whole brain radiotherapy.
Supporting Care G-CSF Antibiotic, antifungal, antiviral Prophylaxis
Re transplantation Minimum 12-24 months before re transplant considered. Recurrence rare
I wish you could type the heading of first para as Introduction. Under this main heading, I wish you could type sub-headings in bold or underline or in italics. That would make it easier to read. Your write-up looks like lecture notes. . What is your analysis of level of evidence of this study?
Lymphoproliferative disorders account for 21% of all cancers of SOT. The majority of cases are derived from B lymphocytes and are EBV associated. Incidence of PTLD in renal transplant is about 0.8 to 2.5 %.
PTLD are subclassified into four histopathological categories
.. Non- destructive
.. Polymorphic
.. Monomorphic
.. Classical Hodgkin lymphoma
Diagnosis and staging
* surgical excisional or incisional biopsy is recommended to establish diagnosis. If it is not possible, a core needle biopsy is an alternative.
* PET -CT is recommended for staging. If it is not available, CT can be used .
Management of PTLD
1. Reduction of immunosuppression
* Reduction of immunosuppression by stopping Azathioprine and MMF and reduction of CNI by 30 to 50 % with maintaining corticosteroids is recommended when possible with monitoring of graft function.
* Early disease response assessment ( at 2 to 4 weeks ) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond.
2.Rituximab +/- chemotherapy
* Rituximab monotherapy is recommended for patients with CD20 positive PTLD who fail to respond adequately to RIS as initial therapy
* Four further three weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission after four cycles of weekly standard dose rituximab.
* Four cycles of R-CHOP-21 immunotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard dose rituximab or who clinically progress during these four cycles.
*Rituximab plus R-CHOP-21 is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise.
*Cardiac and renal function follow up.
3.Radiotherapy
* In localized disease, radiotherapy may be offered concurrently with RIS.
*Treatment with anti-viral agents, IVIG is not recommended outside clinical trials.
4. Therapy for replased or refractory PTLD
* patients that relapse post-R-CHOP should be carefully selected for intensive second line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
* Treatment of PTLD with EBV specific CTLs should be considered where available with R/R EBV positive PTLD.
5.Supportive care
G- CSF is recommended for patients receiving chemotherapy and pneumocystitis Jirovecii pneumonia.
Diagnosis and staging
excision biopsy samples are recommended
Patients with PTLD require a comprehensive pre-treatment evaluation
Staging should be recorded using the Ann Arbor classification or the Lugano classification
following Positron Emission Tomography–Computed Tomography (PET-CT)
The role of PET-CT in the staging of PTLD is less well defined when compared to lymphoma
PET-CT detected additional sites of disease in 28% of cases, resulting in upstaging in 15% when compared to CT alone.
End-of-treatment PET-CT appears to have moderate sensitivity (71%) and specificity (73%)
●Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
●Where this is not possible, a core needle biopsy is an alternative (1A).
● Staging with a CT is recommended in all patients where PET-CT is not available (1A).
●Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
●All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
●All diagnostic material should be reviewed by a haematopathologist (1A).
●Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
●Staging with a CT is recommended in all patients where PET-CT is not available (1A).
●Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
PTLD categorizes
○ Non-destructive
○Polymorphic
○Monomorphic
○ Classical Hodgkin Lymphoma
Management of PTLD
Immunosuppression reduction
●Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
●Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab +/chemotherapy
●Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
●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 (1B).
●Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
●Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
●Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
● PET-CT should be considered for interim and endof-treatment response assessment where available (1C).
Radiotherapy
● Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C). In localised disease, radiotherapy may be offered concurrently with RIS (2C).
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
●Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD
●Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
●Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C). Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Other recommendations
●It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
●Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
●Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
●Local radiotherapy +/corticosteroids with RIS where f itness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
●Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
●G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
● Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
This article is an updated guideline of the recommendations for the front-line management of adult patients with an established diagnosis of post-transplant lymphoproliferative disease.
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
” Staging with a CT is recommended in all patients where PET-CT is not available (1A).
” Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
” All diagnostic material should be reviewed by a haematopathologist (1A).
” Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
” Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
” 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 (1B).
” Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
” Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
” Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
PET-CT should be considered for interim and endof-treatment response assessment where available (1C). Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
” In localised disease, radiotherapy may be offered concurrently with RIS (2C).
” Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B)
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
” Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C)
” It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
” Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
” Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy withrituximab in suitable patients depending on adequate organ function and comorbidity (1C).
” Local radiotherapy +/-corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
” Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
PTLD is the second most common malignancy in SOT, with the lung having the highest rate.
It needs a high index of clinical suspicion, biopsy to confirm the diagnosis,CT scan and PET scan for staging.
PTLD types are four:
1. Classic Hodgkin lymphoma
2. Non-destructive
3. Polymorphic
4. Monomorphic (the worst type)
Management of PTLD:
1. The base of treatment is the reduction of immunosuppression. Stop MMF, reduce CNIs (30-50%) associated with graft function monitoring and evaluating its response at 2-4 weeks and if no response was observed, further treatment is indicated
2. Rituximab monotherapy for CD20-positive PTLD with a standard weekly dose for four cycles of rituximab.
3. If fail to respond to monotherapy, four cycles of R-CHOP-21 immuno-chemotherapy are recommended.
4. Rituximab plus anthracycline-based therapy (typically R-CHOP-21) combined with a reduction of Is in aggressive lymphoma with critical organ compromise.
5. Assessment of cardiac and renal function
6. PET scan to evaluate treatment.
7. Radiotherapy: for selected patients with specific histologic subtypes if localized, at the same time of IS reduction.
Therapy for relapsed or refractory PTLD:
-Patients that relapse after R-CHOP should be selected for intensive second-line chemotherapy followed by autologous stem cell transplant (2B)
Introduction: Lymphoproliferative disease is the second most common malignancy after SOT due to immunosuppression and EBV-related infection, with the highest rate among lung TX.
Diagnosis:
1. Excisional biopsy and if not possible core needle biopsy
2. Staging by CT scans when PET scan is not available.
3. PET scan when available for staging.
PTLD types are four:
1. Classic Hodgkin lymphoma
2. Non-destructive
3. Polymorphic
4. Monomorphic (the worst type)
Multidisciplinary approach: MDT with a hemato-oncology specialist, an organ transplant physician radiologist recommended, and a hematopathologist.
Adverse risk factors:
· Poor performance status
· EBV negative tumor
· Older age
· Graft involvement
· Monomorphic histology
· CNS or BM involvement
· Higher LDH and lower albumin
Management of PTLD:
1. The base of treatment is the reduction of immunosuppression. Stop MMF, reduce CNIs (30-50%) associated with graft function monitoring and evaluating its response at 2-4 weeks and if no response was observed, further treatment is indicated
2. Rituximab monotherapy for CD20-positive PTLD with a standard weekly dose for four cycles of rituximab.
3. If fail to respond to monotherapy, four cycles of R-CHOP-21 immuno-chemotherapy are recommended.
4. Rituximab plus anthracycline-based therapy (typically R-CHOP-21) combined with a reduction of Is in aggressive lymphoma with critical organ compromise.
5. Assessment of cardiac and renal function
6. PET scan to evaluate treatment.
7. Radiotherapy: for selected patients with specific histologic subtypes if localized, at the same time of IS reduction.
· Treatment of relapsed or refractory PTLD: autologous stem cell TX ± adoptive immunotherapy
· CNS-PTLD:
1. Combination chemotherapy with rituximab after IS reduction
2. Local radiotherapy with corticosteroids
3. EBV-specific VST for EBV-positive ones.
· Retransplantation: after at least one year but maybe a longer period.
PTLD represents around 21% of cancers of SOT recipients.
Management of PTLD:
-Reduction in immunosuppression by stopping azathioprine and MMF .
-Reduction of CNIs by 30–50% .
-Maintaining or reducing corticosteroids.
-Early disease response assessment .
-Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
-Four further three-weekly cycles of Rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose Rituximab (1B).
-Four cycles of R-CHOP-21chemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ! 3) after four cycles of weekly standard-dose Rituximab or who clinically progress during these four cycles (1B).
-Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
Therapy for relapsed or refractory PTLD:
-Patients that relapse after R-CHOP should be selected for intensive second-line chemotherapy followed by autologous stem cell transplant (2B).
Post-transplant lymphoproliferative disease is a spectrum of disorders that come from lymphoid proliferations that occur as a result of immunosuppression following SOT. These lymphoid proliferations might be caused by the transplant itself or by immunosuppression. In SOT recipients, lymphoproliferative disorders account for 21% of all malignancies, whereas in immunocompetent populations, the same disorders account for between 4% and 5% of all cancers.1 Adult SOT recipients have an increased risk of developing PTLD, which is the second most prevalent malignancy after skin cancer and is associated with a considerable mortality rate due to cancer.1 The age of the patient, the type of transplant, and the level of immunosuppression all have an impact on the incidence that is recorded. In the past, it was claimed that PTLD was diagnosed in patients at the highest rate during the first year after receiving a transplant.
Diagnosis and staging
It can be difficult to establish a tissue diagnosis of PTLD, and any diagnostic material should be supported by relevant clinical information, such as the date of the transplant, the immune suppression regimen, and the organ type. Excision biopsy samples are advised whenever possible since they allow for correct PTLD sub-classification and provide sufficient material for later auxiliary examinations.
Prognostic scoring
There is no prognostic grading system that is specific to PTLD that is universally acknowledged by physicians. This is due to the fact that the majority of prognostic scores comprised a diverse range of risk factors, a wide variety of patients or treatments, and were either retrospective or conducted by a single institution. However, a number of adverse risk variables have been discovered in several prognostic scoring systems. These risk factors include poor performance status, an EBV-negative tumor, graft involvement, monomorphic histology, older age, central nervous system (CNS) or bone marrow involvement, elevated lactate dehydrogenase (LDH), and hypoalbuminemia.
Reduction of immunosuppression
According to the patient’s clinical presentation and the severity of the disease, the American guidelines advise following a different course of treatment.
As can be seen in Table III, a similar methodology was utilized in a prospective trial of sequential RIS that was carried out according to the clinical picture by the Southwest Oncology Group (SWOG) using Protocol S9239. At the time, this methodology was regarded as the gold standard. Historically, some standards suggest halting full immune suppression in certain therapeutic conditions. However, this should not be done unless specifically directed to do so by the transplant team, nor should it be done unless it is absolutely required.
Rituximab +/# chemotherapy
Primary therapy for patients with monomorphic CD20-positive B-cell peripheral T-cell lymphoma
The most common type of PTLD has a CD20-positive, B-cell monomorphic histology, which is similar to that of DLBCL (see the next section for information on how to treat another subtype).
A monoclonal anti-CD20 antibody called rituximab can be used to treat people with polymorphic PTLD or monomorphic PTLD that looks like DLBCL who have not responded to first-line RIS treatment. This treatment has become the standard of care. The international phase II PTLD-1 trial39 found that four cycles of weekly intravenous rituximab at standard dose (375 mg/m2) followed by four cycles of standard-dose CHOP-21 chemotherapy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide; 1.4 mg/m2 vincristine; 50 mg/m2 prednisolone) every 21 days along with mandatory G-CSF worked best.
The low-risk category was refined further in the ongoing PTLD-2 research by taking into account the initial response to rituximab monotherapy as well as the IPI at the time of diagnosis. These findings were based on the data that were available from PTLD-1 and PTLD-1/3. Patients who achieve a complete remission (CR) following the first four cycles of rituximab monotherapy and patients whose illness progression index (IPI) is 0–2 and who obtain a partial remission at interim staging are considered to have a low chance of their disease progressing further. This method increases the number of patients with PTLD who only require rituximab monotherapy. It also has a good chance of reducing grade 3–4 leucopenia, infection, and ultimately the TRM while keeping the OS the same.
Radiotherapy
There is a lack of clarity on the function of radiotherapy in the overall treatment of PTLD. 7–25% of cases had radiotherapy incorporated into their initial management, and retrospective, non-randomized, heterogeneous case series include patients who were treated largely with RIS and/or chemotherapy.
According to the findings of a retrospective study, people with limited-stage illness, regardless of the histological subtype, are able to get durable CRs following surgical resection or radiotherapy, typically in conjunction with concomitant RIS.
Polymorphic CD20-positive B-cell PTLD
There is a paucity of data available about the management of polymorphic CD20-positive B-cell PTLD; hence, these cases have been incorporated into the PTLD-1 trial. As a result, the same approach that is used for the treatment of monomorphic CD20-positive B-cell PTLD is used for these cases as well.28,30,39 Polymorphic PTLD can very rarely overlap with Hodgkin lymphoma PTLD, in which case the treatment would be the same as what is mentioned in the Hodgkin lymphoma PTLD section.
Therapy for relapsed or refractory PTLD
There are no prospective data available to advise the treatment of patients who have refractory or relapsed PTLD (also known as R/R PTLD). Case reports from a variety of histological subtypes make up the entirety of the evidence base. R-CHOP is a method that is sensible and logical to use with patients who do not respond to treatment with rituximab.23,24,79 If relapse after rituximab monotherapy happens at a late stage, one option that can be investigated is a sequential approach similar to that used in front-line therapy.
Adoptive immunotherapy
EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy could be a new way to treat PTLD that is positive for EBV while lowering or getting rid of the chance of graft rejection at the same time. EBV-specific CTLs make a T-cell immune response to these abnormal B cells by using either the recipient’s own cells to make autologous EBV-directed CTLs or a bank of partially HLA-matched EBV-specific CTLs. This action removes the threat that the abnormal B cells pose.
Burkitt lymphoma-like PTLD
There are several differences that may be seen between Burkitt-like PTLD and sporadic Burkitt lymphoma, despite the fact that there are many similarities between the two. There is a significant correlation with EBV, and there is also a relationship with 11q abnormalities in patients who show typical histological characteristics but do not have a clear MYC rearrangement. Both of these associations are found in patients.
Plasmablastic and plasma-cell myeloma PTLD
There is a paucity of data on these subtypes to recommend a standardized approach, and therefore it is reasonable to treat as for the plasmacytoid dyscrasia disease in immunocompatibility. RIS should be incorporated into the management algorithm.
Hodgkin lymphoma PTLD
Classical Hodgkin lymphoma-type peripheral T-lymphoid nodule lymphoma (HL-PTLD) is uncommon, and there is a dearth of data regarding the most effective treatment. Patients diagnosed with PTLD are often barred from participation in clinical trials, which instead rely heavily on data collected from case series.The data collected by SEER-Medicare at the population level in the United States reveal that HL-PTLD develops rather late, at a median of 88 months after SOT.
Extra-nodal marginal zone lymphoma – PTLD
It is anticipated that exposure to SOT doubles or perhaps triples a person’s risk of developing extra-nodal marginal zone lymphoma.Gastric involvement is the most common manifestation of MALT lymphoma, but there have also been reports of the cancer spreading to the colon and the small intestine in rare instances.
There is a wide variety of treatment algorithms, and they are not well standardized. In rare cases, EBV-positive MALT lymphoma might develop in the skin; in these cases, RIS treatment might be effective in the first stages of the disease.
Supportive care
Significant TRM has been documented in patients with PTLD who were treated with combined immunochemotherapy. There have been reports of as much as a 50 percent mortality rate following infection in these patients. Therefore, the use of G-CSF as the main prophylaxis in this patient population is acceptable and recommended.
It is recommended that prophylactic administration of G-CSF be considered whenever there is a risk of febrile neutropenia (FN) that is higher than 20% for any and all planned cycles of treatment. Age is a significant risk factor for developing FN, which can be mitigated to some extent by receiving G-CSF treatment.
Re-transplantation
After PTLD has been successfully controlled, re-transplantation may be an option to consider because there is a low likelihood of the disease returning following re-transplantation. 69 patients who underwent re-transplantation had satisfactory results, according to the findings of an investigation by the Organ Procurement and Transplant Network and the United Network.
After a mean follow-up of nearly two years, all of the patients were still alive, and 89% of the grafts had some level of functionality. The recurrence of PTLD following retransplantation was shown to be uncommon, with only one patient acquiring the condition after two years, according to more recent research that included 52 patients.
Recommendation
The clinical need as well as the type of organ will determine whether or not re-transplantation is performed. Before re-transplantation, a wait of at least one year may be considered, although it’s possible that a longer time frame may be required.
This article handling the updated guideline and recommendations
for management of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT) in adults.
Lymphoproliferative disorders represents 21% of all cancers of SOT recipients, in contrast to only 4–5% within the immunocompetent population.
Most of the cases at the first year with another peak at 10 years.
The diagnosis is by tissue biopsy for accurate PTLD sub-classification.
A detailed evaluation is needed before treatment.
Recommendations
” Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Where this is not possible, a core needle biopsy is an alternative (1A).
” Staging with a CT is recommended in all patients where PET-CT is not available (1A).
” Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma
Management of PTLD :
1- Immunosuppression reduction
Recommendations
” Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended
in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
” Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
2- Rituximab +/- chemotherapy
Recommendations
” Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
” Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab (1B).
” Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
” Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive
lymphoma with critical organ compromise (1B).
3 Radiotherapy
4- Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Recommendations
” Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
” In localised disease, radiotherapy may be offered concurrently with RIS (2C).
” Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
5- Adoptive immunotherapy
Recommendations
” Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remissin is acheived (2B).
for uncommon types of PTLD:
Recommendations
” It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
” Treatment of less common forms of PTLD with standard- of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
” Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
” Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
” Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
6- Supportive care
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
PTLD is a complication of immunosuppressive medications in solid organ transplant recipients which is the second common malignancy and accounts for 21% of all malignancy in those recipients. PTLD usually occur in the first-year post-transplantation.Diagnosis of PTLD can be difficult especially getting a tissue biopsy, staging of PTLD is important for classification and arranging for further treatment.
Poor prognostic factors of PTLD include the following:1-Poor performance status and older age of the patient.2-EBV negative tumor.3-PTLD involving the graft.4-Mono-morphic histology.5-PTLD involving CNS or Bone Marrow.6-PTLD associated with high LDH.
Treatment options for PTLD:a-Reduction of immune-suppression.b-Supportive care: use G-CSF for primary prophylaxis against febrile neutropenia.b-Rituximab +/-Chemotherapy: for polymorphic and mono-morphic CD20-positive B-cell PTLD.c-Radiotherapy: undefined role.d-Treatment of refractory and relapsing PTLD: use R-CHOP chemotherapy is a reasonable option.e-Adoptive immunotherapy: EBV-CTL immunotherapy is a treatment option for EBV +ve PTLD, this treatment reduces the risk of graft rejection.f-Burkitt’s lymphoma like PTLD: is strongly associated with EBV.g-Plasmablastic and plasma cell myeloma PTLD: is managed with standard approach.h-Hodgokin’s lymphoma PTLD: occurs late at 88 months post-transplant.i-Re-transplantation can be considered after PTLD therapy because the risk of recurrence is low and at least one year to wait before re-transplantation is recommended.
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.1 In adult SOT recipients, PTLD is a common malignancy after skin cancer and is asso- ciated with a significant cancer-related mortality.1 The reported incidence varies according to patient age, transplant type and the degree of immunosuppression. Historically, PTLD has been reported to occur most frequently in the first year following transplantation.
Diagnosis and staging
Establishing a tissue diagnosis of PTLD can be challenging and all diagnostic material should be accompanied by rele- vant clinical information including the date of transplant, immune suppression regimen and organ type. Where possi- ble, excision biopsy samples are recommended to enable accurate PTLD sub-classification and to provide sufficient material for subsequent ancillary investigations.
Prognostic scoring
There is no universally accepted prognostic scoring system specific for PTLD. This is a result of most prognostic scores included varying risk factors, heterogeneous patients or treat- ments and often being retrospective or single-institution ser- ies. However, a number of adverse risk factors have been identified in various prognostic scoring systems including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia
Reduction of immunosuppression
The American guidelines recommend an alternative approach according to the clinical picture and the extent of the disease.
A prospective study of sequential RIS accord- ing to the clinical picture conducted by the Southwest Oncology Group (SWOG) on Protocol S9239 had a similar approach, which was then considered best practice32 as shown in Table III. Historically, some guidelines suggest stopping all immune suppression in certain clinical scenarios. However, this should only be done with guidance from the transplant team and only if absolutely necessary.
Rituximab +/# chemotherapy
Front-line therapy for monomorphic CD20-positive B-cell PTLD
The commonest form of PTLD has a CD20-positive, B-cell monomorphic histology similar to DLBCL (see later sections for management of another subtype.
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 unre- sponsive to initial RIS. The international phase II PTLD-1 trial39 established sequential therapy of four cycles of weekly intravenous rituximab at standard dose (375 mg/m2) fol- lowed by four cycles of standard-dose CHOP-21 chemother- apy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1!4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF).
Based on the data available from PTLD-1 and PTLD-1/3 the low-risk group was refined further in the ongoing PTLD-2 study taking into account the initial response to rituximab monotherapy and the IPI at diagnosis. Patients with a low risk of disease progression are defined as those who achieve a CR after the first four courses of rituximab monotherapy and those with an IPI of 0–2 who achieve a partial remission at interim staging. This strategy increases the number of PTLD patients who only require rituximab monotherapy and is likely to reduce grade 3–4 leucopenia, infection and subsequently the TRM, but retaining a similar OS.
Radiotherapy
The role of radiotherapy as a component of treatment for PTLD is undefined. Retrospective, non-randomised heteroge- neous case series include patients treated predominantly with RIS and/or chemotherapy, with 7–25% of cases having radio- therapy included in their initial management.
A retro- spective analysis suggested that adults with limited-stage disease, regardless of the histological subtype, can obtain dur- able CRs after surgical resection or radiotherapy, usually with concurrent RIS.
Polymorphic CD20-positive B-cell PTLD
Data on the management of polymorphic CD20-positive B- cell PTLD are limited, and these cases have been included in the PTLD-1 trial. Therefore, they are treated with the same algorithm as monomorphic CD20-positive B-cell PTLD as described above.28,30,39 Rarely, polymorphic PTLD can have an overlap with Hodgkin Lymphoma PTLD and thus the management would be as described in the Hodgkin Lym- phoma PTLD section.
Therapy for relapsed or refractory PTLD
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD. The evi- dence base is limited to case reports across various histologi- cal subtypes. In patients who are unresponsive to rituximab, using R-CHOP is a reasonable and logical approach.23,24,79 A sequential approach as in front-line ther- apy can be considered if relapse post rituximab monotherapy occurs late.
Adoptive immunotherapy
EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV- positive PTLD whilst avoiding the risk of graft rejection. EBV-specific CTLs utilise either the recipient’s own cells to generate autologous EBV-directed CTLs or a bank of par- tially HLA-matched EBV-specific CTLs to generate a T-cell immune-mediated response to these abnormal B cells.
Burkitt lymphoma-like PTLD
Burkitt-like PTLD has many features in common with spo- radic Burkitt lymphoma, but some differences can be observed. A strong association with EBV is described,93 along with an association with 11q aberrations in patients present- ing with typical histopathological features but without a demonstrable MYC rearrangement.
Plasmablastic and plasma-cell myeloma PTLD
There is a paucity of data on these subtypes to recommend a standardised approach and therefore it is reasonable to treat as for the plasmacytoid dyscrasia disease in the immunocom- petent. RIS should be incorporated in the management algo- rithm.
Hodgkin lymphoma PTLD
Classical Hodgkin lymphoma-type PTLD (HL-PTLD) is rare and data on optimal therapy are lacking. Patients with PTLD are typically excluded from clinical trials with data largely from cases series.78,101,102 SEER-Medicare population-level US data suggest that HL-PTLD occurs late, at a median of 88 months post SOT.
Extra-nodal marginal zone lymphoma – PTLD
SOT is estimated to increase the risk of extra-nodal marginal zone lymphoma by two- to threefold.The predominant site of involvement of MALT lymphoma is gastric, although isolated cases of colonic and small-bowel involvement are described.
Treatment algorithms are heterogeneous and poorly standardised. Occasionally EBV-positive MALT lym- phoma occurs in the skin and may respond well to RIS in the first instance.
Supportive care
Significant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection. It is therefore appropriate to use G-CSF as primary prophylaxis in this patient group.
Prophylactic administration of G-CSF if the risk of febrile
neutropenia (FN) is >20% for all planned cycles of treatment.
should be considered. Age is an important risk factor.
for developing FN which can partly be prevented by G- CSF.
Re-transplantation
Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re-trans- plantation is low. The Organ Procurement and Trans- plant Network/United Network analysis reported favourable outcomes in 69 patients who underwent re-transplantation.
all patients were alive and 89% of grafts were functioning after a mean fol- low-up of approximately two years. A more recent review of 52 patients reported that recurrence of PTLD after re-trans- plantation was rare, with only one patient developing PTLD at two years.
Recommendation
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be consid- ered before re-transplantation, but a longer period may be needed (2C).
This Article is is an updated guideline and details the recommendations for the front-line management of adult patients with an established diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation.
Diagnosis and staging:
surgical excisional or incisional biopsy is should be done to confirm the diagnosis. If not a core needle biopsy is an option (1A).
All patients must have a CT where PET-CT is not available (1A).
If PET-CT is available should be utilized for staging in line with the recommendation for FDG-avid lymphoma (1B)
Multidisciplinary approach to care:
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haematopathologist (1A)
Management of PTLD:
Reduction of immunosuppression:
Stop azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, for all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) should be done to those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab +/- chemotherapy:
Rituximab monotherapy should be given for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
4 further 3-weekly cycles of rituximab are given to patients who obtain CR or complete metabolic remission (CMR) (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab (1B).
4 cycles of R-CHOP-21 immunochemotherapy are given to patients who fail to obtain CR or CMR (with Deauville ≤ 3) after 4 cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B)
Radiotherapy: Its role uncertain.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment:
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
In localized disease, radiotherapy may be offered con[1]currently with RIS (2C). ” Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD:
There is no data to guide the treatment.
Adoptive immunotherapy:
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B)
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Post-transplant lymphoproliferative disease affecting the central nervous system:
It is recommended that all patients with the less com[1]mon forms of PTLD be considered for RIS as part of their initial management (1C).
Treatment of less common forms of PTLD with stan[1]dard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C). ” Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care:
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation:
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Level of evidence is 1
This document provides updated guidelines for the front-line management of adult patients with post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT). PTLD is a spectrum of disorders resulting from lymphoid proliferations that occur due to immunosuppression following SOT. PTLD is a common malignancy in adult SOT recipients and is associated with significant cancer-related mortality. Accurate diagnosis and staging are crucial for patient management. A surgical biopsy is recommended to establish a diagnosis, and staging with PET-CT is recommended where available. A multidisciplinary approach to care is necessary considering various factors, including histological subtypes, clinical stage, and SOT function.
PTLD
Management of post-transplant lymphoproliferative disorder (PTLD) is challenging due to the rarity of the disease and its histological heterogeneity. Reduction in immunosuppression is the first-line treatment for low-risk PTLD patients with early lesions, low-stage disease, and non-bulky disease.
Response should be assessed within 2-4 weeks, and alternative strategies should be initiated for non-responders. Close monitoring for rejection of the solid organ transplant is essential in these patients. Reduction in immunosuppression should be considered in conjunction with other therapies for high-risk patients with aggressive PTLD.
Recommendations include reducing immunosuppressive medications, assessing early disease response, and close monitoring of graft function under the guidance of the transplant physician.
RITUXIMAB
For patients with monomorphic CD20-positive B-cell PTLD who fail to respond to initial reduction in immunosuppression (RIS), rituximab is recommended as the standard of care.
The international phase II PTLD-1 trial established sequential therapy of four cycles of weekly intravenous rituximab at standard dose followed by four cycles of standard-dose CHOP-21 chemotherapy every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF).
Patients who achieve complete remission (CR) or complete metabolic remission (CMR) with rituximab monotherapy may receive further four doses of rituximab and stop therapy. For patients who do not respond adequately, further chemotherapy options are available with caution to avoid treatment-related mortality. PET-CT is recommended for interim and end-of-treatment response assessment where available.
RADIOTHERAPY
The role of radiotherapy in the treatment of PTLD is undefined, and it is often included in initial management for 7-25% of cases. Localised monomorphic DLBCL and Hodgkin lymphoma PTLD may be considered for radiotherapy in combination with RIS, RIS +/# rituximab, or standard practice outside of PTLD. Radiotherapy is also used for rare forms of PTLD such as nasal natural killer/T-cell lymphoma, and the dose and fractionation regimen follow normal lymphoma protocols.
Antivirals and Immunoglobulins:
Limited data on effective response to antiviral agents or immunoglobulins in EBV-positive lymphoproliferative disorders.Treatment not recommended outside clinical trials.
This Article is is an updated guideline and details the recommendations for the front-line management of adult patients with an established diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation .
PRETREATMENT ASSESSMENT
The pretreatment evaluation of patients with PTLD both determines the extent of the disease and provides information about the individual’s comorbidities that are likely to have an impact on treatment options.
While most elements of the patient’s history are pertinent to the problem at hand, some are particularly relevant to treatment selection. These include the patient’s performance status and comorbidities, the type of transplant, the immunosuppressive regimen used, the status of the graft, the potential impact of graft failure, and the presence of graft-versus-host disease (in hematopoietic cell transplant recipient)
In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with PTLD:
●Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase (LDH), albumin, HIV, hepatitis B, Epstein-Barr virus (EBV) serology with quantitative polymerase chain reaction (PCR), and cytomegalovirus (CMV) PCR.
●Contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis should be performed in patients suspected of having PTLD. This study provides critical information on the measurement of disease prior to treatment, and aids in staging .When available, a combined positron emission tomography (PET)/CT scan as a measure of disease activity should be obtained.
●Assessment of the function of the transplanted organ.
●Unilateral bone marrow aspiration and biopsy is suggested for patients with cytopenias.
●If involvement of the central nervous system is suspected, further evaluation should include gadolinium-enhanced magnetic resonance imaging (MRI) of the head and cerebral spinal fluid (CSF) analysis.
●A study of cardiac function (eg, echocardiogram or MUGA) should be performed for patients with a history of cardiac disease (and no heart transplant) and for those who plan to undergo anthracycline-based chemotherapy (eg, R-CHOP).
●Men and women with child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures.
Treatment-
Reduction of immunosuppression -Where safe to do so, immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team. RIS aims to partially restore T-cell function. Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function. Where RIS is being considered as the sole initial treatment, response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond. If a complete remission (CR) is obtained, then no other therapy may be required in patients with low risk factors.Close monitoring for rejection of the SOT by the relevant transplant team is crucial in these patients who are in CR and maintained at RIS.Patients that achieve a PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks or further rituximab-based treatment may be considered as described in the section Rituximab +/chemotherapy.
Rituximab +/chemotherapy–All patients with PTLD should be considered for RIS and early assessment of response at 2–4 weeks needs to be undertaken. Sequential therapy with rituximab should be started in patients with CD20-positive PTLD, who fail to achieve adequate response to RIS alone. Following re-assessment after initial rituximab treatment, patients in CR should be considered for a further four cycles of rituximab and those not in CR should be treated with four cycles of R-CHOP-21.Rituximab is not effective in CD20 negative PTLD ,where reduction of immunosuppression(RIS) and Chemotherapy are main treatment.
Radiotherapy –For patients with localized disease and those with central nervous system involvement, involved-field radiation therapy, alone or in combination, may be beneficial.
Therapy for relapsed or refractory PTLD-Patients with R/R PTLD post R-CHOP have a poor longterm survival.Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD . Patients with relapsed/refractory PTLD should be offered clinical trials where available.
Post-transplant lymphoproliferative disease affecting the central nervous system-Although the risk of CNS lymphoma is elevated in SOT recipients, it remains between 10 and 20% of PTLD.The histology of CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive.Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity . Local radiotherapy +/corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD .Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
Supportive care-Prophylactic administration of G-CSF for the risk of febrile neutropenia (FN) should be considered.Prophylaxis with co-trimoxazole or equivalent should be considered in all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia (PJP).Given the degree of immunosuppression in patients with PTLD, strong consideration should be given to antibiotic, antifungal (e.g. fluconazole) and antiviral (e.g. acyclovir) prophylaxis during therapy, particularly if treatment is associated with neutropenia as per local protocols.
Re-transplantation-Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re-transplantation is low.Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed .
Level of Evidence– 1
INTRODUCTION:
This article is an updated guideline of the British society for hematology with regards to management of a diagnosed case of Post-transplant lymphoproliferative disorder in solid organ transplant patients.
PTLD remains a considerable concern is post-transplant patients accounting for 1/5th of all post-transplant cancers. It has a bimodal peak, during first year and at 10 years post-transplant. Majority are B cell associated secondary to EBV infection. As compared to other organs, renal transplantation is associated with lower incidence of PTLD.
DIAGNOSIS & STAGING:
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.
It should be staged according to the Ann Arbor or Lugano classification (based on imaging modality used). FDG-PET scan is recommended as investigation of choice for both staging as well as monitoring of disease.
MULTIDISCIPLINARY APPROACH:
It is recommended to have a multidisciplinary team management for PTLD involving transplant physician, haem-oncologist, pathologist, radiologist and radiation oncologist.
PROGNOSTIC SCORING:
There are many prognostic scoring systems in use, although none is universally accepted. The Ghobrial prognostic score, International Prognostic index (IPI) & PTLD prognostic index are all available and each has its own drawbacks. However the IPI has shown to predict overall survival with statistical significance.
MANAGEMENT:
Due to histological subtypes and rarity of certain subtypes there is no consensus for treatment of PTLD and most evidence is based on case series, however for the most common monomorphic diffuse large B cell lymphoma there is strong evidence from phase II clinical trials.
1. REDUCTION OF IMMUNOSUPPRESSION:
If graft function allows then reduction of immunosuppression it the first step of management. This implies stopping the antimetabolite, decreasing dose of CNI by 50-75% and reducing steroids to physiological dose.
For low risk cases this alone can achieve complete remission. Response to reduction should be assessed at 2-4 weeks. Monitoring graft function for signs of rejection is necessary. If complete remission is achieved then continue at lower dose of immunosuppression, in case of partial remission either reassess at 2-4 weeks interval or start rituximab (+/- chemotherapy).
For high risk cases reduction in immunosuppression should be accompanied by rituximab followed by CHOP (cyclophosphamide + vincristine + doxorubicin + prednisolone) regime if indicated.
2. RITUXIMAB (+/- CHEMOTHERAPY)
For Monomorphic CD-20 positive and polymorphic PTLD rituximab is the first line therapy following failure to respond to modification of immunosuppression. Rituximab + CHOP vs Rituximab followed by assessment and if not in remission then CHOP (high risk) have been studied in PTLD phase II trials.
3. RADIOTHERAPY:
Limited stage disease, localized disease, orbit and CNS disease and MALT type lymphoma are indications for radiotherapy, although the evidence for this is weak.
4. ANTI-VIRAL, IV IG & IFN alfa
No strong evidence is available for use of antiviral therapy, IV immunoglobulins or interferon alfa in the treatment of PTLD.
5. RELAPSE OR REFRACTORY DISEASE:
For rituximab refractory disease CHOP chemotherapy is recommended. For R-CHOP resistant / refractory disease no recommendations are available and patient should be offered enrolment into clinical trials followed by autologous stem cell transplant if remission is achieved.
6. ADOPTIVE IMMUNOTHERAPY:
Trials using EBV specific T lymphocytes are underway and show promising results.
7. UNCOMMON SUBTYPES OF PTLD
Burkitt lymphoma like, Plasmablastic and plasma-cell myeloma, T-cell lymphoma, Hodgkin lymphoma, extra-nodal marginal zone lymphoma subtypes of PTLD have no standardized data available to guide therapy. Guidelines recommend treatment of these subtypes as per guidelines available for immunocompetent patients with the added point of reduction in immunosuppression.
8. CNS involving PTLD
Any subtype can involve CNS but most common is monomorphic EBV associated PTLD with poorer prognosis as compared to no CNS involvement. Standard reduction of immunosuppression, Rituximab and chemotherapy and additionally radiotherapy and intrathecal chemotherapy are recommended. EBV specific T cell therapy can also help.
SUPPORTIVE CARE:
Treatment related mortality remains an issue. All patients should be given G-CSF prophylaxis as well as considered for prophylactic antibiotics, antifungals and antivirals. Viral infection monitoring should be done including CMV, Hepatitis B & C and HIV.
RE-TRANSPLANTATION:
After achieving complete remission for 1 year patient can safely be considered for re-transplantation.
What is the level of evidence provided by this article?
Level 1 as it is evidence based consensus guideline.
Shah, N., Eyre, T.A., Tucker, D., Kassam, S., Parmar, J., Featherstone, C., Andrews, P., Asgari, E., Chaganti, S., Menne, T.F., Fox, C.P., Pettit, S., Suddle, A., Bowles, K.M. and (2021), Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline. Br. J. Haematol., 193: 727-740. https://doi.org/10.1111/bjh.17421
Summary of the article:
After skin is the 2nd most common cancer occurring in about 12% of patients usually in 1st post transplantation year. Early onset PTLD, is usually of B- cell type is linked to EBV infection.
20-40 % of PTLD are EBV –ve occurring >1 year post transplantation.
Multiorgan and intestinal transplants have the highest incidence of PTLD (20%) followed by lung transplants (3–10%), heart transplants (2–8%).
Updated guideline and recommendations for front-line management of PTLD following Solid Organ Transplant (SOT) .
Diagnosis and staging : needs
1- Histopathologic diagnosis by tissue biopsy is recommended.
2- CT is recommended in all patients.
3- a PET-CT used for staging in FDG-avid lymphoma .
Multidisciplinary approach to care:
– All cases should be discussed at a haemato-oncology MDT and organ transplant physicians .
– All diagnostic material should be reviewed by a haematopathologist .
Reduction of immunosuppression:
1- Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids.
2- Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond .
Rituximab +/# chemotherapy:
1- Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy .
2- Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab .
3- Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles.
4- Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise .
5- Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
6- PET-CT should be considered for interim and end of-treatment response assessment where available.
Radiotherapy:
The role of radiotherapy as a component of treatment for PTLD is undefined.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment:
He data is limited.
Recommendations
1- Involved-field radiotherapy may be offered for selected patients with PTLD .
2- In localised disease, radiotherapy may be offered concurrently with RIS .
3- Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFN a is not recommended.
Therapy for relapsed or refractory PTLD:
There are no prospective studies and the data is limited to case reports.
Adoptive immunotherapy:
1- Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
2- Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD.
3- Patients with relapsed/refractory PTLD should be referred to clinical trials.
Burkitt lymphoma-like PTLD:
According to the studies , R-CHOP with RIS could be considered a reasonable treatment for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immunocompetent patient.
Plasmablastic and plasma-cell myeloma PTLD:
There is a paucity of data to recommend any a standardised approach
T-cell lymphoma PTLD:
Is a rare form of PTLD. occur later after SOT and are often has poor outcome.
Hodgkin lymphoma PTLD:
Combined chemotherapy of (doxorubicin, bleomycin, vinblastine, dacarbazine) +/- radiotherapy may represent a safe and effective treatment with RIS in HL-PTLD patients.
Extra-nodal marginal zone lymphoma – PTLD :
SOT is a risk factor for extra-nodal marginal zone lymphoma by 2-3 times. Treatment algorithms are heterogeneous and poorly standardised.
Post-transplant lymphoproliferative disease affecting the CNS :
1- It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management.
2- Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity .
3- Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity .
4- Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD.
5- Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD .
As asuportive care
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered
to all patients with diagnosis of PTLD.
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed .
Introduction
The immunosuppression following Solid Organ Transplantation (SOT) results in lymphoid proliferation which causes a spectrum of disorders which are represented as Post-Transplant Lymphoproliferative Disorder (PTLD). This article provides an updated form of guidelines for the frontline management of adult patients with PTLD.
Discussion
Summary:
PTLD represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT.
This document is an updated guideline and the recommendations for the management of adult patients with diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT).
PTLD type:
Non-destructive
Monomorphic
Polymorphic
Classical HL
Diagnosis and staging:
Excisional or incisional biopsy is recommended to establish a diagnosis.
Where available a PET-CT should be used for staging in line with the recommendation for FDG-avid lymphoma.
Prognostic scoring:
Poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypalbuminaemia.
Another we can use is International Prognostic Index (IPI) for non-Hodgkin lymphoma.
Management:
Multidisciplinary approach to care with a experienced haemato-oncology, hematopathology and organ transplant physicians.
Reduction of immunosuppression:
Rituximab +/- chemotherapy:
Front-line therapy for monomorphic CD20-positive B-cell PTLD who fail to respond adequately to RIS as initial therapy.
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles.
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
PET-CT should be considered for interim and end of-treatment response assessment where available
In localised disease, radiotherapy may be offered concurrently with RIS.
Relapse:
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD.
CNS PTLD:
Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD
Prophylaxis:
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis.
Re transplantation:
Re-transplantation is dictated by clinical need and organ type.
A minimum of one year may be considered before re-transplantation, but a longer period may be needed.
Lymphoproliferative disorders represent 21% of all cancers of SOT recipients.
Post-transplant lymphoproliferative disease occur due to lymphoid proliferations caused by immunosuppression after SOT.
PTLD commonly occurs after skin cancer with high mortality rate ,it can develop early or late after transplantation but it’s highest incidence of occurrence is with multiorgan or intestinal transplantation ,followed by lung transplant ,then heart transplant ,then liver transplant then pancreatic transplant then the smallest incidence is with renal transplant.
PTLD is derived from B lymphocyte and is associated with EBV
Diagnosis and staging
PTLD is divided into 4 histopathological categories which are non destructive, poly morphic ,monomorphic and classical Hodgkin lymphoma.
Diagnosis is difficult and staging requires using the Ann Arbor classification or the Lugano classification for staging lymphomas although using PETCT for PTLD staging is less well defined in comparison to lymphoma.
In fact PETCT has beneficial role in PTLD diagnosing , staging ,detecting new involved sites and post treatment relapse to some extent.
For cases with possible CNS involvement MRI ,CT imaging and CSF analysis will be needed.
-Surgical excisional or incisional biopsy is needed for diagnosis (alternative core needle biopsy) and PET CT is needed (alternative is CT ) for staging
Multidisciplinary care
(MDT) need to involve transplant physicians, haemato-oncologists, haematopathologists,
radiation-oncologists and radiologists.
Prognostic scoring
There is not a standardised prognostic scoring for PTLD ,however some ominous risk factors were acknowledged involving including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH and hypoalbuminaemia.
PTLD management
Reduction of Immunosuppression(RIS)
Can be done if applicable under transplant team supervision, representing the only therapy for low risk early stage disease, along with follow up for 2-4 weeks because in case of failure to reach complete remission , alternative treatment can be started in addition to close monitoring of rejection.
Cases who reached partial remission with RIS can either followed and be reassessed within 2-4 weeks or rituximab based therapy can be started.
There are American, SWOG and European Renal Guidelines for RIS.
It is recommended to RIS by stopping azathioprine and MMF ,decreasing CNIs to 30–50% and maintaining or reducing corticosteroids also early disease assessment is adviced for cases on RIS onlt in order to start alternative treatment soon if RIS alone failed.
Rituximab +/- chemotherapy
– Monomorphic CD20-positive B-cell PTLD which is the most common PTLD forum.
Rituximab is used for treatment of polymorphic PTLD, or monomorphic DLBCL-like PTLD, unresponsive to initial RIS.
wasnot achieved —4 cycles of CHOP21
If RIS failed —-4 weekly IV Rituximab will be given —-If CR
was achieved—4X 3weekly IV Rituximab
A trial that used sequential 4 cycles of weekly IV Rituximab, followed by four cycles of standard-dose CHOP-21 chemotherapy every 21 days with GCSF and prophylaxis against PJP demonstrated better outcomes than using Rituximab alone also TRM was less in R-CHOP21 group compared to CHOP21 group.
At the same time some patients can not tolerate the combination therapy so attenuated or less toxic regimens can be tailored for them.
Special considerations are needed to be taken in each individual case as cardiac transplant recipents with vasculopathy can experience preserved LV EF HF
– Polymorphic CD20-positive B-cell PTLD treatment algorithms similar to monomorphic due to paucity of data on polymorphic
It includes IV Rituximab of 4 weekly standard cycle as monotherapy for cases who did not respond to RIS initially followed by 4 more 3 weekly cycles for cases with CMR while cases who did not reach remission can receive 4 cycles of RCHOP21.
Along with cardiac and renal assessment for SOT recipients.
PETCT is needed for evaluation of treatment response.
Radiotherapy
A study proposed that adults with early-stage disease, apart from the histological subtype, can achieve CRs after surgical resection or radiotherapy, usually with concurrent RIS.
Radiotherapy can be applied for some extra-nodal sites, as the orbit, isolated CNS relapse and for localised extra-nodal marginal zone lymphomas of the MALT.
Radiotherapy with chemotherapy regimens can be used in nasal NK/T-cell lymphoma
Antivirals, IVIG and interferon-alpha treatment
are not adviced outside clinical trials
Therapy for relapsed or refractory PTLD
R/R PTLD cases post R-CHOP have poor prognosis, extrapolating treatments from R/R DLBCL in
immunocompetent patients can be offered, but with little evidence in R/R PTLD.
Adoptive immunotherapy
EBV positive PTLD and R/R EBV-positive PTLD can be treated by EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy without graft rejection risk and the outcomes were acceptable.
These T lymphocytes are either autologous or extracted from a bank of partially matched HLA EBV-specific CTLs.
Chimeric antigen receptor (CAR)-T cells used for B-cell malignancies suggests it’s possible
role in the treatment of PTLD.
Burkitt lymphoma-like PTLD
Rituximab monotherapy cannot induce remission
R-CHOP with concurrent RIS can be used for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immunocompetent patient ,Dose-adjusted EPOCH-R with CNS prophylaxis can be suitable in selected patients.
Plasmablastic and plasma-cell myeloma PTLD
No sufficient data is available therefore RIS along with plasmacytoid dyscrasia disease in the immunocompetent cases can be used
T-cell lymphoma PTLD
It is a rare forum ,that occurs late post SOT , it has a poor prognosis .
RIS with anthracycline-based chemotherapy was proposed for therapy .
Immunocompetent patients with T-cell lymphoma treatment algorithm can be applied.
Hodgkin lymphoma PTLD
It is rare with no much data available, it is supposed to occur late after SOT.
HL-PTLD patients with normal cardiac and pulmonary function can be treated by standard combination chemotherapy with ABVD(doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy alongside RIS .
BEACOPP , Eescalated BEACOPP or BEACOPDac is an option in patients with high-risk disease but toxicities must be considered.
Extra-nodal marginal zone lymphoma – PTLD
It’s risk increase with SOT.
Stomach is the most common site to be affected in MALT lymphoma, also colonic and small bowel involvement were dteceted.
EBV-positive MALT lymphoma occurs in the skin and can respond to RIS.
Rituximab monotherapy or Radiotherapy in certain cases are other options.
CNS involvement in PTLD
CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive.
It is multifocal as detected by MRI and tissue biopsy can be needed.
Median OS is 33–47 months.
RIS with intrathecal chemo and whole brain radiotherapy ,outcomes were acceptable.
Systemic chemotherapy with CNS penetration is the standard for primary CNS lymphoma in immunocompetent.
Rituximab with RIS can be used in patients unfit for chemotherapy.
EBV-specific CTLs can be used in patients with EBV-positive CNS-PTLD post HSCT or SOT
Supportive care
G-CSF as primary prophylaxis can be useful in patients with PTLD having high TRM.
Antibiotic ,antiviral and antifungal treatment can be considered for cases with neutropenia
PJP prophylaxis in all PTLD cases
CMV surveillance is adviced, patients with HBV ,HCV or HIV need to be treated .
Retransplant
Can be considered after PTLD control as it’s recurrence rate is low post transplant.
One year gap is considered as a minimum period before re-transplantation varing according to the organ and clinical need.
Introduction :
PTLD is not uncommon complication post SOT , its the 2nd most common malignancy after skin malignancy post transplant ( 21 % of all cancers ) , the incidence depends on the age , which organ is transplanted and type of immunosupression .
the majarty of cases occurs in the 1st year Post transplantation and associated with EBV infection , about 20-40 are EBV negative and occurs usually after the 1st year of transplantation .
there is four types of PTLD Non-destructive , Polymorphic , Monomorphic and Classical Hodgkin Lymphoma .
Diagnosis and staging :
MDT team should be involved in the management PTLD including : transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists
Prognostic scoring :
There is no universally accepted prognostic scoring system specific for PTLD till now , there is mang ongoing studied and trial to achieve that , but in general there is many adverse risk factors including : poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH , and hypoalbuminaemia .
Management :
1) Reduction of immunosupression .
The 1st line mangment for PTLD is reduction of immunosupression , in low risk patient and early disases this strategy could be the only treatment required for cure ,
there is many protocols for RIS according to the staging of diseaes
2) Rituximab +/- chemotherapy
3) Radiotherapy and Antivirals treatment
Therapy for relapsed or refractory PTLD
Adoptive immunotherapy:
Extra-nodal marginal zone lymphoma – PTLD
Post-transplant lymphoproliferative disease (CNS-PTLD)
Supportive care
Re-transplantation
Summary of the article:
PTLD is the second most common malignancy after skin cancer (21%) in transplant recipients; occur mostly in the first-year post-transplant, a second peak after around 10years have been noted.
Early onset PTLD, derived from B lymphocytes, are associated with EBV infection.
EBV-negative cases account for 20–40% of PTLD, occur >1 year after transplantation, with a second peak occurring about 10 years post-transplant.
Multiorgan and intestinal transplants have the highest incidence of PTLD (20%) followed by lung transplants (3–10%), heart transplants (2–8%).
This article composed of Updated guideline and recommendations for front-line management of PTLD following Solid Organ Transplant (SOT).
Diagnosis and Staging:
Clinical info, basic tests and viral assay; Bone marrow biopsy (selected cases)
Surgical excision / incisional / core needle biopsy is diagnostic – ancillary tests, markers, IHC
Staging with CT scan neck, chest abdomen and pelvis – for treatment plan, and as baseline to compare response to treatment.
(Fdg18) PET-CT scan is preferred over CT, in line with the recommendation for FDG-avid lymphoma (1B) – detected additional sites of disease in 28% of cases, upstaging in 15% compared to CT.
Special cases: Echocardiography (cardiotoxic drugs); Sperm cryopreservation
CNS or craniofacial involvement – MRI / CT imaging of brain, orbits and sinuses; CSF Flow-cytometry
Types of PTLD:
1. Non-destructive – florid follicular hyperplasia, early PTLD
2. Polymorphic – B-cell in stages of maturation, mixed with T cells; >90% EBV-associated
3. Monomorphic – 60–80% of PTLD; resemble diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma; 70% have cytogenetic abnormalities (Trisomy 9, 11; loss of 17p; rearrangement of 8q24 (MYC)
4. Classical HL – 90% associated with EBV
Prognostic scoring systems devised from adverse risk factors: poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH and hypo-albuminemia.
v International Prognostic Index (IPI) for non-Hodgkin lymphoma: is pragmatic choice
v Ghobrial prognostic score – has limited utility
v PTLD Prognostic Index: (variation of IPI) – Age, ECOG performance status, LDH
Management:
No RCT data available; Limited knowledge from case reports / case series
Multidisciplinary (MDT) meeting involving haemato-oncologist, haemato-pathologist experienced in PTLD management, organ transplant physicians.
1. Reduction of immunosuppression (RIS)
Stopping Azathioprine and MMF, and reduction of CNI by 25–50%; maintaining Prednisone 7.5-10mg; Frequent monitoring to look for rejection
– RIS aims to partially restore T-cell function.
– may suffice in patients with low-risk early lesions, low-stage, non-bulky disease
Assess response at 2-4 weeks – if no response à Retuxi +/- Chemo
2. Rituximab +/- chemotherapy:
Front-line treatment for monomorphic CD20-positive B-cell PTLD, who fail to respond adequately to RIS.
Evidence from International phase II PTLD-1 trial: sequential therapy of 4 cycles of weekly IV Rituximab (375 mg/m2) followed by 4cycles of CHOP-21 chemotherapy every 21 days, with GCSF support – median OS of 6.6 years and plateau on PFS curve, is better than Rituximab monotherapy alone (median OS 1.2–3.5 years).
Ø 2.A Rituximab monotherapy – recommended for CD20-positive PTLD, who fail to respond adequately to RIS initial therapy (1B).
Complete Response (CR) or complete metabolic remission (CMR) after 4 cycles of weekly Rituximab à 4 further three-weekly cycles of rituximab are recommended (1B).
Ø 2.B Failure to obtain Complete Response or CMR after 4 cycles of weekly Rituximab, or clinical progression during Rituximab monotherapy à 4 cycles of R-CHOP-21 chemotherapy recommended
3. Rituximab + Anthracycline therapy (R-CHOP-21) with RIS is directly recommended for patients diagnosed with clinically aggressive lymphoma with critical organ compromise (1B).
4. Local Radiation + RIS +/- Retuximab – may be offered in localised disease
Cardiac (2D Echo) and renal function assessment should be done in all SOT recipients or patients with renal or cardiac impairment (1B)
Interim or end of-treatment response assessment – by PET-CT (if available).
Relapse / Refractory cases:
Late Relapse post-Retuximab-monotherapy: sequential R-CHOP like front-line therapy
R/R PTLD post R-CHOP: poor long-term survival (OS < 20%) — patients should be carefully selected for salvage chemotherapy followed by consolidation autologous stem cell transplantation (ASCT).
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD
CNS PTLD:
10 and 20% of PTLD; high grade B cell lymphoma, mostly EBV positive (30-40% are EBV negative)
RIS à combination Retuxi + Chemotherapy – in suitable patients (adequate organ function and comorbidity)
Local Radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors
EBV-specific CTL can be considered for EBV-positive CNS-PTLD
Hodgkin lymphoma PTLD (HL-PTLD)
HL-PTLD had a five-year OS of 57% compared to 80% for HL-immunocompetent patients.
RIS + Combination Chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) +/- Radiation may represent a safe and efficacious option
Supportive care and Prophylaxis – G-CSF for patients receiving chemotherapy and PJP prophylaxis for all patients
Re-Transplantation
After successful control of PTLD, risk of recurrence of PTLD after re-transplantation is low.
Can plan depending on clinical need, organ type and availability.
Minimum waiting period – at least 1 year relapse free period may be considered, although longer period may be needed.
Summary
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT.This document is an updated guideline and the recommendations for the management of adult patients with diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT).
PTLD type
Non-distructive
Monomorphic
Polymorpjic
Classical HL
Diagnosis and staging
surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Where available a PET-CT should be used for staging in line with the recommendation for FDG-avid lymphoma
Prognostic scoring
Poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia. Another we can use is International Prognostic Index (IPI) for non-Hodgkin lymphoma
Management
Multidisciplinary approach to care with a expirenced haemato-oncology, haematopathologist and organ transplant physicians.
Reduction of immunosuppression
Rituximab +/- chemotherapy Front-line therapy for monomorphic CD20-positive B-cell PTLD who fail to respond adequately to RIS as initial therapy
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
PET-CT should be considered for interim and end of-treatment response assessment where available
In localised disease, radiotherapy may be offered concurrently with RIS .
Relapse
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD
CNS PTLD
Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD
Prophylaxis
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis
Re transplantation
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed.
PTLD AFTER SOLID ORGAN TRANSPLKANT – BRITISH SOCIETY FOR HEMATOLOGY
21 % OF ALL CANCER ARE PTLD
SECOND MOST COMMON AFTET SKIN ACNCER
ASSOCIATED WITH MORTALITY
SAME INCIDENCE EVEN AFTER 1 YEAR ( CONTRARY TO EARLIER BELIEF)
COMMON AFTER MULTI ORGAN AND INTESTINAL , LUNG , HEART, LIVER, PANCREAS AND LEAST IN KIDNEY ( DECREASING ORDER)
TYPES OF PTLD
– NON DESTRUCTIVE LIEK INFECTIOUS MONONUCLEOSIS
POLYMORPHIC – WITH T CELLS
MONOMORPHIC – B CELLS – MOST OF THE LESIONS ARE INCLUDED , BURKIT , MALT LYMPHOMA
CLASSIC HODGKINS LYMPHOMA
STAGING
APART FROM ROUTINE BLOOD LABS, EXCISION OR INCISIONAL BIOPSY IF POSSIBE TO SUBTYPE THE PTLD LESION
CT SCAN OF NECK , THORAX AND ABDOMEN
PET SCAN IS ADVISABLE
MRI FOR CNS INVOLVEMET
CSF EXAM
MDT APPROACH
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management,
with input from the organ transplant physicians
” All diagnostic material should be reviewed by a haematopathologist
POOR PROGNOSIS
poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or
bone marrow involvement, raised lactate dehydrogenase
(LDH) and hypoalbuminaemia.
MANAGEMENT
NO RCT AVAILABLE
REDUCTION OF IMMUNOSUPPRESSION (IS) TO RESTORE T CELL FUNCTION
STOPP AZATHIPRINE AND MMF
CNI REDUCTION 50% OR 75 % ON CLINICAL URGENCY
STERIOD REDUCTION TILL PHYSIOLOGICAL LEVEL OF 7.5 MG /DAY ON CLINICAL UREGENCY BASIS
IN CASE OF KIDNEY , REDUCTION IN IMMUNOSUPPRESSION IS MORE FEASIBLE AS ALTERNATIVE THERAPY FOR REJECTION IS AVAILABE
ASSES THE RESPONSE TO IS BY 2-4 WEEKS
IN CASE OF COMPLETE RESPONSE- REASSESSMENT AT 4-6 WEEKS IS ONLY REQUIRED
IN CASE OF PARTIAL RESPONSE , RETUXIMAB +/- CHOP
IN CASE OF FAILURE , RETUXIMAB AND THEN CHOP AS SEQUENTIAL THERAPY
MONOMORPHIC B CELL PTLD – WELL STUDIED EVIDENCE BASED THERAPY IS AVAILABE
4 WEEKLY DOSE OF RETUXIMAB 375 MG PER METER SQ FOLLOWED BY RESPONSE ASSESSMNET BY CT
IF COMPLETE RESPONSE – CONSIDR THE CASE AS LOW RISK
IF PARTIAL RESPONSE ON CT SCAN – CONSIDER CHOP CHEMO
ONE MORE CONCEPT IS RESPONSE ADAPTED TREATMENT WHEREIN RESPONSE TO RETUXIMAB IS TAKEN AS GOOD PROGNOSTIC FACTOR AND DISEASES IS LABELLED AS LOW RISK . THIS MINIMISES TREATMENT RELATED MORTALITY
POLYMORPHIC PTLD
ABOVE PRINCIPLES STILL APPLIES HERE
IN ADDITION , Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at
any time following diagnosis with clinically aggressive lymphoma with critical organ compromise
RADIOTHERAAPY
UNDEFINED ROLE
LIMITED DISEASE CAN BE TREATED WITH RESECTION AND RT PLUS RDUCTION IN IS
LYMPHOMA PROTOCOL TO BE FOLLOWED
RELPASED OR REFRACTORY DISEASE
R-CHOP CAN BE USED
ADAPTIVE IMMUNOTEHRAPY WITH EBV POSITIVE CYTOTOXIC T CELL IS UNDER TRAIL AND IS PROMISING
BURKITT LYMPHOMA LIKE PTLD
RETUXIMAB IS NOT FOUND TO BE USEFULL
R- CHOPP WITH REDUCTION OF IS IS THE CHOCE
T CELL LYMPHOMAA LIKE PTLD
LESS ROLE OF RETUXIMAB
R- CHOPP WITH REDUCTION OF IS IS THE CHOCE
HODGKIN LYMPHOMA PTLC
RETUXIMAB HAS LESS ROLE
CHEMOTHERAPY IS TEH CHOIC ALONG WITH REDUCTION OF IS
CNS LESION AS PTLD
The histology of CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive
CASE TO CASE BASIS
REDUCTION IN IS AND RAADIOTEHRAPY IS TEH CHOICE
MRI FOR ASSESSMENT
MANAEMENT OF TRM ( TREATMENT RELATED MORBIDITY )
LIBERAL USE OF G-CSF IN NEUTROPENIA WITH FEVER
COTRIAMAXAZOLE FOR PIP PROPHYLAXIS
FLUCONAZOLE FOR FUNGAL PREVENTION
RETRANSPLANTATION
SO FAR 27 KIDNEYS WERE RETRANSPLANTED WITH GAP OF 20-100 MONTHS POST TREATMENT
RECURRENCE OF PTLD IS RARE
Please summaries this article
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following solid organ transplant.
Lymphoproliferative disorders account for 21% of all cancers of solid organ transplant recipients, as compared with 4–5% within the immunocompetent population.
PTLD is a common malignancy after skin cancer.
EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation more severe than EBV positive patients.
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Reduction of Immunosuppression:
– It is the mainstay of therapy
– the EBV negative cases are less responsive.
– RI can reverse 20% – 80% of patients with PTLD.
– RI includes: CNI reduction by 50% , along with withdrawal of the
antimetabolites and maintain Steroids.
– In critically ill cases should consider withdrawal of all IS medications except
Steroids.
– Switch to mTORi.
– Monitoring allograft function for rejection.
– Assess disease response assessment early (at 2–4 weeks) by CT.
– If PR achieved or in those that fail to respond; can consider sequential therapy Rituximab +/- chemotherapy RCHOP- 21 used in addition to RI.
Rituximab therapy:
– CD20 +ve B-cell PTLD approached 75% of TR.
– The overall response to RTx monotherapy approached 44%-79%.
Chemotherapy R-CHOP- 21
– 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
· Post-transplant lymphoproliferative disease results from lymphoid proliferations that occurs due to immunosuppression following SOT.
· Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population
· PTLD is a common malignancy after skin cancer with different incidence according to patient age, transplant type and the degree of immunosuppression.
· The majority of cases in the western world are derived from B lymphocytes and are EBV-associated, particularly in the first-year post SOT.
· EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years
Diagnosis and staging
· Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
· Staging with a CT is recommended in all patients where PET-CT is not available (1A).
· Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
· Categories of PTLD: Non-destructive, Polymorphic, Monomorphic, and Classical Hodgkin Lymphoma
Multidisciplinary approach to care
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
· All diagnostic material should be reviewed by a haematopathologist (1A).
Management of PTLD
Reduction of immunosuppression:
· This may be the only treatment required for a select group of patients with low-risk patients which have early lesions, low-stage disease and non-bulky disease.
· After 2–4 weeks, if a complete remission (CR) is obtained, then no other therapy may be required in patients with low risk factors
· Patients that achieve a PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks or further rituximab-based treatment may be considered as described in the section Rituximab +/- chemotherapy
Recommendations
· Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
· Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab +/- chemotherapy
· Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
· 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 (1B).
· Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
· Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
· Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
· PET-CT should be considered for interim and endof-treatment response assessment where available (1C).
Radiotherapy
· Localised monomorphic type DLBCL and Hodgkin lymphoma (HL) PTLD could be considered for treatment with RIS and combined modality treatment in line with standard practice outside the setting of PTLD, or in combination with RIS +/- rituximab in DLBCL if the patient is not eligible for intensive chemotherapy.
· Radiotherapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localised extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
· Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
· In localised disease, radiotherapy may be offered concurrently with RIS (2C).
· Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Adoptive immunotherapy
· Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
· Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
· Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Burkitt lymphoma-like PTLD
· R-CHOP with concurrent RIS could be considered a reasonable option for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immunocompetent patient.
· However, dose-adjusted EPOCH-R with appropriate CNS prophylaxis may also represent a clinically appropriate option in selected patients aiming to achieve curative therapy, given clear data for efficacy and tolerability outside the PTLD setting.
T-cell lymphoma PTLD
· Combined RIS with anthracycline-based chemotherapy if good cardiac function.
Hodgkin lymphoma PTLD
· standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function.
Extra-nodal marginal zone lymphoma – PTLD
· SOT is estimated to increase the risk of extra-nodal marginal zone lymphoma by 2-3 folds.
· The predominant site of involvement of MALT lymphoma is gastric, although isolated cases of colonic and small-bowel involvement are described
· Occasionally EBV-positive MALT lymphoma occurs in the skin and may respond well to RIS in the first instance.
· Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option.
Post-transplant lymphoproliferative disease affecting the central nervous system
· Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
· Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
· Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care
· G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation
· Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Introduction
The term “post-transplant lymphoproliferative disease” refers to a variety of illnesses brought on by lymphoid proliferations as a result of immunosuppression after SOT.
PTLD is a common malignancy in SOT recipients, associated with significant cancer-related mortality.
PTLD is most common in the first year post-transplantation, with EBV-associated cases being the most common.
EBV-negative cases account for 20-40% of PTLD, with peak incidence at 10 years.
Diagnosis and staging
Excision biopsy samples should be utilized to permit precise sub-classification, and staging and response evaluations are crucial for proper PTLD diagnosis and therapy.
For PTLD management, staging and response assessments are crucial, and they should be documented using the Ann Arbor or Lugano categorization.
A multidisciplinary approach to care
A management plan should be agreed upon by a core multidisciplinary team (MDT) which should include
Transplant physicians,Haemato-oncologists,Hematopathologist,Radiation-oncologists and radiologists.Prognostic scoring
Although there is no widely used prognostic grading system for PTLD, detrimental risk factors such
· Low-performance status,
· EBV-negative tumor,
· Graft involvement,
· Monomorphic histology, Advanced age,
· CNS or bone marrow involvement,
· Elevated LDH,
· Hypoalbuminemia.
Management of PTLDReduction of immunosuppressionReduction in immunosuppression should be used to restore T-cell function in low-risk patients with early lesions, low-stage disease,
and non-bulky disease.
Rituximab +/− chemotherapy
Front-line therapy for monomorphic CD20-positive B-cell PTLD
PTLD has a CD20-positive, B-cell monomorphic histology similar to DLBCL. Patients with polymorphic PTLD who are not responding to first RIS are often treated with rituximab as standard care.
Polymorphic CD20-positive B-cell PTLD
Management of polymorphic CD20-positive B-cell PTLD is the same as monomorphic PTLD, with an overlap with Hodgkin Lymphoma PTLD.
RadiotherapyCurrently available analysis suggested that adults with the limited-stage disease, regardless of the histological subtype, can obtain durable complete remission after surgical resection or radiotherapy, usually with a concurrent reduction in immunosuppression.
Antivirals, intravenous immunoglobulin, and interferon-alpha treatment: Data is lacking to demonstrate effective EBV-positive lymphoproliferative disorders with antiviral agents or immunoglobulins. IFNα is not recommended for EBV-positive lymphoproliferative disorders due to a lack of data.
Therapy for relapsed or refractory PTLDIn patients who are unresponsive to rituximab, R-CHOP is a reasonable and logical approach for R/R PTLD, with a sequential approach if relapse occurs late. R/R PTLD post-R-CHOP has poor long-term survival with OS <20%.
Adoptive immunotherapy CTL immunotherapy offers an alternative to graft rejection in EBV-positive PTLD.
EBV-specific CTLs either use a bank of partly HLA-matched EBV-specific CTLs to produce autologous EBV-directed CTLs from the recipient’s own cells or use their own cells to produce T-cell immune-mediated responses against these aberrant B cells.
Supportive care
Prophylactic administration of G-CSF if the risk of febrile.
Antibiotic, antifungal (e.g. fluconazole), and antiviral (e.g. acyclovir) prophylaxis during therapy,
The advent of highly active antiretroviral therapy (HAART) has made chemotherapy much more tolerable in the HIV-infected non-transplant population with lymphoma.
Summary
Post-transplant lymphoproliferative disease occur as a result of immunosuppression post solid organ transplant- SOT .
Lymphoproliferative disorders account for 21% of all cancers of SOT recipients and it is a common malignancy after skin cancer. it depends upon age, transplant type and the degree of immunosuppression. Most cases are Epstein–Barr virus (EBV)-associated.
Accurate diagnosis and staging are important in planning treatment.if feasible excision biopsy should be done. Staging used are Ann Arbour classification.
also bood test i,e. full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH), HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres should be done
for Imaging CT is recommended in these patients. when available a PET-CT should also be done. with Multidisciplinary approach is needed.
Categories of PTLD
non-distructive
monomorphic
polymorpjic
classical HL
treatment includes Reduction in IS, chemotherapy, Ritux, Radiation, IVIG, adoptive therapy and even retransplantation.
For early stage and low risk cases MMF/AZA can be stopped, and CNI should be reduced by 50% with close monioring for rejection. Rituximab has become a standard of care in patients with polymorphic PTLD, or monomorphic DLBCL-like PTLD, who are unresponsive to initial therapy and CD20+.
If remission is not achieved with Rituximab alone or if disease progressive in nature then R -CHOP should be given
Radiotherapy may be considered for some extra-nodal sites, Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes.
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa are tried in cinical trials only and not recommended yet. 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. Intrathecal chemotherapy or radiotherapy can be considered if CNS involment is there.
Retransplant
This can consider but a waiting time of at least 2 years post complete remission.
Please summarize this article.
Post-transplantation lyphoproliferative disorder is complication of immunosuppression drugs. 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%.
Diagnosis and staging;
For accurate diagnosis the lesion needs excision biopsy and histology.
Baseline investigation, LDH, Urate, Lactate,
Viral serology, HIV, HCV, HBV, EBV, CMV/EBV titers,
Bone marrow biopsy,
Echocardiography,
CT chest, abdomen, and pelvis,
MRI brain,
Other special measures like cryopreservation for male and female sperm banking,
For further staging need PET-Scan to apply Lugano Classification.
Prognostic scoring;
Different prognostic scores are being utilized but no agreement yet, so till date there is no specific prognostic scoring system. Because not applicable, majority of patient up-to 96% have monomorphic disease. However, IPI has edge compared to others.
1. Ghobrial prognostic score,
2. International prognostic score,
3. PTLD prognostic index,
However, the risk factor can guide the prognosis like older age, EBV negative PTLD, CNS bone marrow involvement, monomorphic histology, elevated LDH and low albumin level serum.
Management;
The recipient developed PTLD will need multidisciplinary approach like dermatologist, surgeon, oncologist, hematologist, and radiologist.
Till for EBV-associated disease there is management consensus, but for rarer sub types and refractory disease there is no such randomized trails and guidelines.
Usually decision of therapy is made after according to extent of disease and clinical picture.
The European and American guidelines says to reduction of immunosuppression, usually is this done for low grade and low risk patients to restore T-cell function, usually respond.
If no response then second line treatment with rituximab +/- chemotherapy (CHOP).
If extensive disease stop agents except for maintaining prednisolone.
According to SWAG protocol stop antimetabolite agents, decrease cyclosporine by 75%, continue prednisolone.
Rituximab is indicated for monomarphic and polymorphic disease like DLBCL-like PTLD, total of four doses weekly bases, followed by four cycles of standard doses of CHOP-21 chemotherapy.
In aggressive disease with compromised organs rituximab plus anthracycline based regimen is recommended.
Patient with refractory disease post R-CHOP should be selected for second line chemotherapy followed by stem cell transplant.
Radiotherapy, its role is undefined, but can be used in specific histological and localized cases.
Adaptive immunotherapy;
For EBV positive PTLD there is another approach that is cytotoxic T-cell lymphocyte immunotherapy while avoiding the risk of rejection.
If available should be considered. In trail of total 33 patients who have failed initial therapy the overall response rate was 52%.
In addition another small trail shows promising result who were refractory to rituximab.
Post –transplant lymphoproliferative disease remains between 10 to 20% of PTLD. They should be treated initially by RIS and wait for response, if no response then should be considered for combination of chemotherapy.
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, Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT.
PTLD is a common malignancy after skin cancer and is associated with a significant cancer-related mortality.
PTLD has been reported to occur most frequently in the first year following transplantation.
The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, particularly in the first year post SOT. EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.
renal transplant recipients having the lowest incidence of PTLD ( 0.8–2.5 %).
Diagnosis and staging
Hx date of transplant, immune suppression regimen and organ type
excision biopsy samples
Positron Emission Tomography–Computed Tomography (PET-CT)
PET-CT detected additional sites of disease in 28% of cases, resulting in upstaging in 15% when compared to CT alone.
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative
• Staging with a CT is recommended in all patients where PET-CT is not available
• Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma
Multidisciplinary approach to care
management plan should be agreed by a core multidisciplinary team (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists
cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians .
• All diagnostic material should be reviewed by a haematopathologist
Management of PTLD
Reduction of immunosuppression
immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team.
This may be the only treatment required for a select group of patients with low-risk patients which have early lesions, low-stage disease and non-bulky disease. response should be assessed within 2–4 weeks
some guidelines suggest stopping all immune suppression in certain clinical scenarios. However, this should only be done with guidance from the transplant team and only if absolutely necessary.
Reduction of CNIs by 50% Consider stopping azathioprine/MMF Maintain prednisolone 7.5/10 mg/day
Rituximab +/chemotherapy
Front-line therapy for monomorphic CD20-positive B-cell PTLD
The commonest form of PTLD has a CD20-positive, B-cell monomorphic histology similar to DLBCL
The response to RIS was assessed early between two and four weeks and failure of RIS was followed by sequential treatment with rituximab and subsequently by CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy in adult B-cell PTLD.
Radiotherapy
retrospective analysis suggested that adults with limited-stage disease, regardless of the histological subtype, can obtain durable CRs after surgical resection or radiotherapy, usually with concurrent RIS.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
use of interferon alfa (IFNa) remains historical and there are no new developments to recommend its use outside of clinical trials.
Recommendations
• Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes
• In localised disease, radiotherapy may be offered concurrently with RIS
• Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials
Therapy for relapsed or refractory PTLD
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD. The evidence base is limited to case reports across various histological subtypes.
Adoptive immunotherapy
autologous or allogeneic EBV-directed CTLs should be considered in patients with R/R EBV-positive PTLD.
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD
• Patients with relapsed/refractory PTLD should be offered clinical trials where available
Burkitt lymphoma-like PTLD
Burkitt-like PTLD has many features in common with sporadic Burkitt lymphoma, but some differences can be observed. A strong association with EBV is described, along with an association with 11q aberrations in patients presenting with typical histopathological features but without a demonstrable MYC rearrangement.
Supportive care
Recommendation
• G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD
Re-transplantation
Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re-transplantation is low.
A period of one year should be considered as a minimum before re-transplantation depending on the organ and clinical need.
This article is about one of the important malignency that appear in post transpla peroid which is PTLD .THis type of malignancy the second common type of cancer after skin cancer in SOT.
PTLD is account foe 21% of malignancy in post TRX while it is only 4% in general populations .
PTLD is related to EBV + virus which is common in the first year post transplant while the EBV – IS associated with late onset .
How to diagnose PTLD
we need rutine work up including CBC,CMP,LFT,LDH CSF in case of CNS involvment .Echo as base line is mandatory as one of the chemotherapy traetmen t is cytotoxic to the heart .
staging of the PTLD IS Need to do excisional bviopsy as main corner and PET scan for staging purposes. Ct scan in case PET not available .
Reduction of IS is the main treatmen t for the low grade and non bulking disease , alomg with stop of antimetabolites medications . This group of patient need close follow up every 2 to 4 weeks for possible relaps .
Rituximab îs for treatment for EBV + PTLD and monomorphic disease with CD20+.Need to start by RIS and RTX every 4 weeks if CR occure that it other wise the patient may need to go for other type of chemotherapy like CHOP regime .
still the chemotherapy is depends on the type of lymphoma
Front-line management of PTLD in adult SOT— A British Society for Haematology Guidelines
Lymphoproliferative disorders (PTLD) is the second most prevalent malignancy in adult recipients of solid organ transplants, behind skin cancer, and poses a significant mortality risk.
The risk is increased when an EBV-negative recipient receives a transplant from an EBV-positive donor, when there is strong immunosuppression such as ATG induction and tacrolimus-based maintenance therapy, when immunosuppression is at its peak in the first year after transplantation, and when transplanted organs such as the small bowel and heart-lung.
90% of PTLD are EBV-positive and derived from B cells, with the remaining 10% deriving from T cells.
Lymphoproliferative disorders account for up to 21% of all Cancer post transplant in comparison to approx. 4.5% in the healthy non transplant group.
PTLD is common in 1st 1 yr post transplant ,commonly EBV +VE PTLD while EBV -VE that comprises 20-40% of all PTLD occurs after 1 yr with a second peak at 10 years.
Histomorphological description categorizes PTLD into four groups.
1-Non-destructive; includes plasmacytic hyperplasia, infectious mononucleosis-like cells, and florid follicular hyperplasia. Most EBV-associated cases are early PTLD.
2-Polymorphic; B-cell maturation stages with T cells, EBV-associated in >90% instances.
3-Monomorphic; 60–80% of PTLD are DLBCL, Burkitt lymphoma, plasma cell myeloma, or plasmacytoma. Indolent B-cell lymphomas and T-cell neoplasms are diagnosed less often. EBV-negative monomorphic PTLD.
4-Classical Hodgkin Lymphoma: This is classical Hodgkin lymphoma and usually (>90%) associated with EBV.
Diagnosis and staging:
1-Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
2-Staging with a CT is recommended in all patients where PET-CT is not available (1A).
3-Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Essential pre-treatment baseline evaluation for all patients diagnosed with PTLD:
1-full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH).
2-Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres .
3-Bone marrow biopsy is indicated and some selected patients it may not be clinically
needed or appropriate .
4-Echocardiography where appropriate and potentially when cardiotoxic agents are being used .
5-Fertility-preserving treatments, such as sperm cryopreservation for male and referral to a fertility specialist in female patients, should be considered for eligible patients .
6-Details should include; date of transplant, organ type and immunosuppresion regimen .
7-all patients require assessment of the function of the transplanted organ, ideally directed by the transplant physician .
8-All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at
diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response .
9-Where available, PET-CT scan should be utilised for staging over CT scan .
Multidisciplinary approach to care:
1-All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
2-All diagnostic material should be reviewed by a haematopathologist (1A).
Treatment of PTLD
1- Immunosuppression reduction:
Withdrawal of azathioprine and MMF and reducing CNIs by 30–50% while maintaining or reducing corticosteroids in all patients whenever possible under the advice of the transplant physician with graft function monitoring (1B).
Patients receiving RIS alone should be assessed for disease response at 2–4 weeks to see if they need additional treatment (1B).
2- Rituximab +/- chemotherapy:
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
-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 (1B).
-Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
-Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
-Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
3- Radiotherapy:
Used incorporation with chemotherapy in some sort of PTLDs.
may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse, and localised extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
4- Antivirals, intravenous immunoglobulin and interferon-alpha treatment:
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
5- Therapy for relapsed or refractory PTLD:
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Adoptive immunotherapy is a permissive modality of treatment in some R/R PTLD.
Extra-nodal marginal zone lymphoma – PTLD:
EBV-positive MALT lymphoma may respond well to RIS, Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option.
Radiotherapy is an effective treatment.
Post-transplant lymphoproliferative disease affecting the central nervous system:
Intrathecal chemotherapy and whole-brain radiotherapy.
Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate with rituximab.
Supportive care:
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Recommendations:
All patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Re-transplantation:
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
but as by Prof. Dr Ahmed Halwa better to wait a 2 year for Re-Transplant
SUMMARISE THE ARTICLE.
FRONTLINE MGT OF PTLD IN ADULT SOT RECIPIENTS -BSC GUIDELINES.
Lymphoproliferative disorders account for up to 21% of all Ca post transplant in comparison to approx. 4.5% in the healthy non transplant group.
PTLD is common in 1st 1 yr post transplant ,this is mostly EBV +VE PTLD while EBV -VE that comprises 20-40% of all PTLD occurs after 1 yr with a second peak at 10 years.
PTLD is classified as; Non destructive, Polymorphic, Monomorphic and Classical Hodgkin’s Lymphoma.
DIAGNOSIS & STAGING.
An excision biopsy is recommended to get a histological diagnosis.
Where available, a PET Scan is used for staging it into the various Ann Arbor categories. In absence of a PET scan, a CT scan can be used for staging prior to treatment.
Baseline pre treatment workups need to be done ; FHG,UECS,LFTS,HIV,HEP B,HEP C serologies, LDH,CMV/EBV DNA etc A csf analysis is indicated in those with CNS symptoms. ECHO should be done in those at risk of cardiovascular dx prior to initiating Chemo.
MANAGEMENT
An MDT approach with a transplant physician,hematologost,oncologist,pathologist,radiologist,psychiatrist and nutritionist should be involved in discussing the individual pt prior to starting treatment.
Reduction of Immunosuppressive Medication.
For those with low risk, non bulky disease, RIS should be done and response gauged in2-4 weeks, if CR, no other therapy indicated, we monitor the patient for any rejection, while for those with PR, we either monitor for a further 2-4 weeks or consider adding Rituximab.
Recommendation is to stop antimetabolites and decrease CNIs by 30-50% and maintain/reduce steroids when possible and again monitor for rejection.
RTX +/- Chemo.
This is 1st line for monomorphic CD20+VE B cell PTLD.
After RIS ,if in remission, maintain, if RIS failed, consider 4 weekly 375 mg/m2 or IV RTX, if CR proceed to 4×3 weekly 375mg/m2 IV RTX, if no CR, give CHOP-21.PCP prophylaxis should be considered while on chemo and infection monitored.
For patients unable to tolerate the above, single agent RTX, steroids, oral etoposide and alkylating agents can be considered.
Polymorphic CD20+VE B Cell PTLD.
This is treated as monomorphic or Hodgkin’s lymphoma if an over lap occurs.
NB – Response to treatment should be assessed by a CT Scan if symptoms progress and at the end of treatment.
Radiotherapy.
Candidates include;
a. Pt with limited dx in combination with SX/RIS.
b. Pts with extra nodal dx ;orbit, CNS etc not eligible for chemo.
c. Rare PTLD; nasal NK/T cell lymphoma.
.Antivirals/IVIG and interferon alpha.
Use recommended within a clinical trial.
Refractory PTLD.
Salvage therapy with autologous stem cell transplant or enrollment into a clinical trial should be discussed with the patient. Refractory carries a poor prognosis.
Adoptive immunotherapy.
Autologous /allogenic CTL to be considered in those with EBV +VE PTLD.
Burkitt lymphoma like PTLD.
R CHOP +RIS to be considered.
Dose adjusted EPOCH R with CNS prophylaxis is another option in specific patients.
Plasmablastic and plasma cell myeloma PTLD.
Treated as plasmacytoid dyscrasia in healthy population.
T Cell lymphoma PTLD.
This is treated using the same algorithm as those in the general population.
HL PTLD
ABVD +/- DXT +RIS in those with normal cardiac and lung function.
BEACOPP/Escalated BEACOPP or BEACOPDac to be considered in those with high risk disease.
Extra nodal marginal zone lymphoma PTLD
Main site is gastric for MALT lymphoma.
EBV+VE MALT -RIS +/- RTX.
DXT to be adopted as per healthy pts guidelines with extra nodal marginal zone lymphoma.
PTLD affecting the CNS.
Estimated to affect 10-20% of PTLD. Typically monomorphic,high grade B cell Lymphoma that are EBV +VE.
Treatment options;
-RIS
-DXT
-Chemo with CNS penetration -high dose methotrexate. RTX may be added to chemo.
Supportive care.
G-CSF to prevent infection in those with high risk of febrile neutropenia.
Antibiotics, antivirals and antifungals prophylaxis esp if treatment associate d with a low white cell count.
Septrin to be considered in those with a hx of PCP.
A hepatologist should be involved in managing those with Hep B and C infection.
Re transplantation.
This can be evaluated after 1 yr control of PTLD. A minimum of 1 yr should lapse before evaluation.
II. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline
Summarise this article
Introduction
Post-transplant lymphoproliferative disease (PTLD) is a common malignancy following solid organ transplantation (SOT) and is associate with a significant cancer-related mortality.
The incidence of PTLD varies with the level of immunosuppression, type of transplant and patient’s age. Lymphoproliferative disorders are more common in SOT recipients compared to immunocompetent people (21% vs 5%).
Most PTLD cases are EBV-positive and occur within the first-year post-transplant. On the other hand, EBV-negative PTLD accounts for 20-40% of the cases and mostly occur after the first-year post-transplant with a second peak after ten years.
PTLD is most common among multiorgan and intestinal transplants (20%) while the lowest incidence is reported among kidney transplants (0.8-2.5%).
Four histopathological categories have been described i.e., Non-destructive, Polymorhic, Monomorphic and Classical Hodgkin lymphoma type
Diagnosis and staging
Patients with PTLD require baseline investigations as indicated, these include: – CBC, UEC, LFT, LDH, uric acid, viral screen (HIV, HBV, HCV, EBV, CMV), bone marrow biopsy.
For staging purposes, staging CT scans (neck, chest, abdomen, pelvis) or a PET-CT scan can be done.
Additional investigations in patients with CNS involvement include: – brain MRI or CT scan and a diagnostic lumbar puncture.
A biopsy (surgical excisional or incisional or core needle biopsy) is essential to establish the diagnosis.
Multidisciplinary approach to care
A multidisciplinary team composed of the transplant physicians, radiologists, hematopathologists, hemato- and radio- oncologists should all be engaged in patient care.
Prognostic scoring
Currently there is no universally approved prognostic scoring system for PTLD. However, a number of adverse risk factors have been recognized i.e., older age, EBV-negative status, graft involvement, monomorphic histologic type, elevated LDH, low serum albumin, CNS or bone marrow involvement, poor performance status.
Management of PTLD
Unfortunately, there are no RCTs to guide on management of PTLD.
Reduction of immunosuppression
Reduction in immunosuppression (RIS) helps to partially restore the patient’s T-cell function. This approach is adequate for low-risk patients i.e., patients with early lesions, low-stage and non-bulky disease.
Following RIS, response to treatment should be reassessed in 2-4weeks.
· Patients who achieve complete remission following RIS should be closely monitored for rejection given the reduction in immunosuppression.
· Patients who achieve partial remission, can be monitored and assessed again in another 2-4weeks or can be considered for rituximab ± chemotherapy
There is no specific guidance on RIS but there are recommendations i.e., stop MMF and azathioprine, reduce CNI dose by 30-50% but maintain or reduce the corticosteroid dose while monitoring the graft function.
Rituximab ± chemotherapy
o CD20+ PTLD patients who do not respond to RIS should be offered rituximab monotherapy i.e., 4 cycles of weekly standard-dose rituximab.
o If they achieve complete remission (CR) or complete metabolic remission (CMR), they should be offered four further 3-weekly cycles of rituximab.
o Patients who fail to achieve CR after 4 cycles of weekly standard-dose rituximab or patients who deteriorate clinically during these 4 cycles should be offered 4 cycles of R-CHOP-21.
o Patients with clinically aggressive lymphoma with compromise of critical organs should receive R-CHOP-21 automatically.
o A cardiac and renal function assessment should be done for all SOT patients.
o PET-CT scan should be done to assess response to treatment where available.
Radiotherapy
The role of radiotherapy in treatment of PTLD is not well defined.
Radiotherapy can be considered in the following instances: –
o Limited-stage disease with concurrent RIS
o Extra-nodal sites e.g., orbit
o Isolated CNS relapse
o Localized extra-nodal marginal zone lymphomas of the MALT type
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
These agents are not recommended outside clinical trials.
Therapy for relapsed or refractory PTLD
There is no data to guide treatment.
R-CHOP can be considered in patients who do not respond to rituximab.
Patients who do not respond to R-CHOP or who relapse post R-CHOP have poor outcomes since autologous stem cell transplantation (ASCT) remains a challenge among SOT patients. In such cases, intensive second-line chemotherapy should be considered followed by ASCT if the patient achieves a good remission.
Adoptive immunotherapy
In this therapy, EBV-specific cytotoxic T-lymphocytes (CTLs) use either the patients’s own cells are used to generate autologous EBV-directed CTLs or a bank of partially HLA-matched EBV specific CTLs to generate a T-cell immune-mediated response to the abnormal B cells.
EBV-directed CTLs (autologous or allogeneic) should be offered to patients with relapsed or refractory EBV-positive PTLD.
Burkitt lymphoma-like PTLD
Rituximab monotherapy has been found to be inadequate.
R-CHOP in addition to RIS is a viable option.
Assessment for CNS involvement should be done at baseline and CNS prophylaxis considered.
Plasmablastic and plasma-cell myeloma PTLD
There is no data to guide treatment. However, Treatment offered is similar to that for plasmacytoid dyscrasia disease in addition to RIS.
T-cell lymphoma PTLD
This form of PTLD is rare, occurs later after SOT and is associated with poor outcomes.
There is paucity of data to guide treatment, but RIS and anthracycline based chemotherapy can be considered in patients with adequate cardiac function.
Hodgkin lymphoma PTLD (HL-PTLD)
Classical HL-PTLD is rare, occurs late post-SOT, unfortunately there is no data to guide treatment.
RIS in addition to standard combination chemotherapy i.e., ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) ± radiotherapy is considered a safe and efficacious option in HL-PTLD patients with normal pulmonary and cardiac function.
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,
procarbazine, prednisolone) can be used with caution in high-risk patients due to the hematological and infection-related toxicities associated with this regimen.
Extra-nodal marginal zone lymphoma PTLD
SOT increases the risk of extra-nodal marginal zone lymphoma. The most predominant site of MALT lymphoma is gastric. There are no specific treatment guidelines but RIS, rituximab monotherapy and radiotherapy have been found to be effective in selected cases.
Post-transplant lymphoproliferative disease affecting the central nervous system
CNS-PTLD accounts for 10-20% of PTLD cases and is associated with a poor prognosis.
Tissue biopsy provides the definitive diagnosis, it helps rule out opportunistic infections which present with similar findings on MRI.
Optimal therapy for CNS-PTLD remains unknown, but the possible treatment options include: –
o RIS alongside radiotherapy
o RIS, whole-brain radiotherapy and intrathecal chemotherapy
o RIS with concurrent chemotherapy in patients not fit for radiotherapy
o Systemic chemotherapy with CNS penetration i.e., high-dose methotrexate in selected cases
o EBV-specific CTLs in EBV-positive CNS-PTLD patients where available
Supportive care
Primary prophylaxis with G-CSF is recommended in PTLD patients treated with combination immunochemotherapy since this treatment is associated with significant treatment related mortality.
Prophylaxis with antibiotics, antivirals (e.g., acyclovir), antifungals (e.g., fluconazole) and G-CSF should be considered in PTLD patients at risk of febrile neutropenia.
Co-trimoxazole should be offered in all PTLD patients.
Surveillance for CMV should continue.
Liver function tests should be monitored in patients with past hepatitis B or hepatitis C infection. Hepatitis B viral load should be considered as well.
Initiation of HAART in HIV patients has been shown to make chemotherapy more tolerable.
Re-transplantation
Risk of PTLD recurrence after re-transplantation is low. The timing of re-transplantation depends on the organ and the clinical need. A minimum of one year is acceptable before re-transplantation can be considered. However, a longer period might be needed i.e., at least 2 to 5 years after PTLD clearance. This gives the immune system adequate time to recover to increases the probability of a successful re-transplant.
PTLD:
Is a common post-transplant malignancy second to skin cancer
Result from lymphoid proliferation associated with immunosuppression most are EBV
Positive, 20_40percent EBV negatives .lung multi organ transplant more associated with PTLD. , renal
Transplant is least affected other organ like pancreases, heart liver Transplantation also affected with PTLD.
Diagnosis:
Staging should be recorded using the Ann Arbor classification or the Lugano classification which is the recommended classification for staging following Positron Emission Tomography–Computed Tomography (PET-CT) in 18F-fluorodeoxyglucose -avid (FDG-avid) nodal lymphomas.
Complete hematology, chemistry panel, virology screening, echocardiogram, plus minus BM biopsy. Fertility-preserving treatment.
Classification:
Non-destructive, Polymorphic, Monomorphic and Classical Hodgkin Lymphoma.
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haematopathologist.
Prognostic scoring:
International Prognostic Index the IPI was statistically significant, with low IPI risk (0–2 points) exhibiting a superior, OS compared to high IPI risk (≥3 points) at three years (OS 78% vs 54%, respectively, P = 0.0003).27 Thus, the IPI is a pragmatic choice of up-front score to use.
Management of PTLD:
Reduction of immunosuppression:
Low-risk patients which have early lesions, low-stage disease and non-bulky disease.
Response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond.
If a complete remission (CR) is obtained, then no other therapy may be required in patients with low risk factors.
Close monitoring for rejection of the SOT.
Patients that achieve a PR by RIS alone can either be monitored or reassessed within a further 2–4 weeks or further rituximab-based treatment.
Recommendations
Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function.
Rituximab +/# chemotherapy:
A standard of care in patients with polymorphic PTLD, or monomorphic DLBCL-like PTLD, who are unresponsive to initial RIS.
Sequential therapy:
of four cycles of weekly intravenous rituximab at standard dose (375 mg/m2 ) followed by four cycles of standard-dose CHOP-21 chemotherapy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF). This approach resulted in a median OS of 6.6 years and a clear plateau on the PFS curve.
Patients with a low risk of disease progression are ALSO defined as those who achieve a CR after the first four courses of rituximab monotherapy and those with an IPI of 0–2 who achieve a g. This strategy increases the number of PTLD patients who only require rituximab monotherapy and is likely to reduce grade 3–4 leucopenia, infection and subsequently the TRM, but retaining a similar OS.
In case of clinical signs of disease progression at any time during rituximab monotherapy or before interim staging, restaging should be performed prematurely, and RCHOP-21 should be considered to commence immediately if disease progression is confirmed.43–45 Response to treatment can be assessed by CT; however, even though the role of interim PET-CT is not yet established it can be considered a more sensitive tool for interim response assess.
Radiotherapy:
The role of radiotherapy as a component of treatment for PTLD is undefined.
Radiotherapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localized extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
In rare forms of PTLD, radiotherapy tends to be incorporated with the chemotherapy regimens such as in nasal natural killer/T-cell lymphoma.
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
Therapy for relapsed or refractory PTLD:
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD. Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Adoptive immunotherapy:
EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV positive PTLD whilst avoiding the risk of graft rejection.
Burkitt lymphoma-like PTLD
R-CHOP with concurrent RIS could be considered a reasonable option for Burkitt-like PTLD.
Dose-adjusted EPOCH-R with appropriate CNS prophylaxis may also represent a clinically appropriate option in selected patients.
Plasmablastic and plasma-cell myeloma PTLD:
Recommend a standardized approach and therefore it is reasonable to treat as for the plasmacytoid dyscrasia disease.
T-cell lymphoma PTLD:
Combine RIS with anthracycline-based chemotherapy.
Hodgkin lymphoma PTLD:
Rare PTLD.
Treatment standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function
Extra-nodal marginal zone lymphoma – PTLD
Site of involvement of MALT lymphoma is gastric, although isolated cases of colonic and small-bowel involvement are described.
Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option.
Post-transplant lymphoproliferative disease affecting the central nervous system:
Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with.
Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
Supportive care:
Use G-CSF as primary prophylaxis.
Antibiotic, antifungal (e.g. fluconazole) and antiviral (e.g. acyclovir) prophylaxis during therapy.
Prophylaxis with co-trimoxazole for all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia.
Re-transplantation:
A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Post-transplant lymphoproliferative disease represents spectrum of disorders resulting from lymphoid proliferationsthat 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
Diagnosis and staging:
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
· Staging with a CT is recommended in all patients where PET-CT is not available (1A).
Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Multidisciplinary approach to care:
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
· All diagnostic material should be reviewed by a haematopathologist (1A).
Management of PTLD:’
· Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) isrecommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab +/- chemotherapy:
· Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
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 (1B).
Four cycles of R-CHOP-21 immuno chemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ! 3) after four cycles of weekly standard-dose Rituximab or who clinically progress during these four cycles (1B).
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
· Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
· PET-CT should be considered for interim and endof- treatment response assessment where available (1C).
· Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
· In localised disease, radiotherapy may be offered concurrently with RIS (2C).
· Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD:
· Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
· Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Plasmablastic and plasma-cell myeloma PTLD:
·It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
· Treatment of less common forms of PTLD with standard- of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
· Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
·Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care:
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation:
· Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period
may be needed (2C).
Thank you
Article Summary
Post-transplant lymphoproliferative disease results from lymphoid proliferations that occur as a result of immunosuppression post solid organ transplant- SOT . Lymphoproliferative disorders account for 21% of all cancers of SOT recipients. PTLD is a common malignancy after skin cancer. Incidence depends upon to patient age, transplant type and the degree of immunosuppression. Most cases are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated.
Diagnosis and stagin
Accurate diagnosis and staging are important in planning treatment.
Where possible excision biopsy should be done. Staging uses Ann Arbour classification.
Blood tests–
These include Full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH), HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres. In some situation a bone marrow may be required.
Imaging
Staging CT is recommended in all patients. when available a PET-CT should be done.
MDT Approach
All cases should be discussed at a haemato-oncology MDT
there should be an input from the organ transplant physicians
All investigations must be reviewed by haematologist
Categories of PTLD
These include-
Non destructive
Mono Morphic
Polymorphic
Classical Hodgkin lymphoma
Management
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.
Radiotherapy
Radiotherapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localised extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type. Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials
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
CNS PTLD
Intrathecal chemotherapy or radiotherapy can be considered.
Retransplant
This can considered 2 years post complete remission.
Thank you
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT.
PTLD subtypes: Non-destructive, Polymorphic, monomorphic, Hodgkin Lymphoma
Baseline invest:
– FBC, U&E, LFT, LDH, urate, BM, HIV, HCV, HBV, EBV, CMV +/- Bone marrow
– ECHO
– Staging PET scan (better) or CT CAP
– Fertility-preserving treatments for eligible patients
Diagnosis and staging
MDT:
Management of PTLD
1- Reduction of immunosuppression
2- Rituximab +/- chemotherapy
3- Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Therapy for relapsed or refractory PTLD
Post-transplant lymphoproliferative disease affecting the central nervous system
Supportive care: G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation: Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Thank you
Management-of-PTLD-A-British-Society-for-Haematology-Guideline:
PTLD is second most common cause of solid organ transplant after skin cancer.
It’s account 21% of all solid organ transplant.
Incidence of PTLD depend on age and type of transplant and degree of immunosuppressive therapy.
PTLD is associated with EBV and mainly B lymphocytes.
Diagnosis and staging of PTLD:
It’s mainly by PET-CT which are important for staging of PTLD.
MRI and CT brain, orbits and sinus is recommended in patients with CNS lymphoma.
Lumper puncture and CSF analysis is important for cytology and flow cytometry.
Multidisciplinary approach to care:
It’s need care and discussion regarding policy of treatment by transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
Prognostic scoring:
There’s no specific prognostic factors in PTLD. However prognostic factors associated with risk factors as fallowing
Poor performance status
EBV-negative tumour
Graft involvement
Monomorphic histology
Older age
CNS or bone marrow involvement
Raised lactate dehydrogenase (LDH)
Hypoalbuminemia.
Management of PTLD:
Reduction of immunosuppression:
Reduce calcinurine inhibitors to 30-50%, and continue steroid dose but stop azathioprine and MMF.
Start Rituximab and chemotherapy
Rituximab is a monoclonal anti-CD20 antibody against B cell .
Radiotherapy in case of CNS lymphoma.
Antivirals, intravenous immunoglobulin in case of EBV associated with PTLD.
interferon-alpha treatment is not recommended.
R-CHOP used in case of relapse PTLD.
Patients with relapse and refractory PTLD post R-CHOP have a poor long term survival.
So can treat with autologous stem cell transplant.
EBV positive can treat by adoptive immunotherapy ( EBV-specific cytotoxic T-lymphocyte immunotherapy);
Burkitt lymphoma-like PTLD treatment with R-CHOP-like regimen and EPOCH-R.
T-cell lymphoma PTLD:
It’s occur later after solid organ transplant and carry poor outcome.
Hodgkin lymphoma PTLD:
It’s rare and can treat with complications chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy.
Extra-nodal marginal zone lymphoma – PTLD:
treatment with rituximab and radiotherapy .
Post-transplant lymphoproliferative disease affecting the central nervous system: CNS lymphoma
It’s account 10% from PTLD post solid organ transplant .
It’s carrying poor prognosis
It’s treatment with systemic chemotherapy like high-dose methotrexate with rituximab.
Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re- transplantation is low.
Time of re transplant is depend on organ and clinical situations.
Thank you
Summary:
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.
The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, particularly in the first year post SOT. EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.
PTLDs are sub-classified into four histopathological categories as follows:
· Non-destructive: Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia. Most cases are EBV-associated and usually present as early PTLD
· Polymorphic: A spectrum of B-cell maturation stages with admixture of T cells, EBV-associated in >90% cases
· Monomorphic: Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma. Much less commonly indolent B-cell lymphomas, usually mucosa-associated lymphoid tissue lymphoma5,11,12 and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative. Approximately 70% of these lesions are reported to have cytogenetic abnormalities, including trisomy 9 and 11 or both, loss of 17p and rearrangement of 8q24 (MYC)
· Classical Hodgkin Lymphoma: Morphologically this fulfils the conventional criteria for the diagnosis of classical Hodgkin lymphoma and is generally (>90%) associated with EBV
Diagnosis and staging:
Recommendations:
· Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
· Staging with a CT is recommended in all patients where PET-CT is not available (1A).
· Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Multidisciplinary approach to care:
Recommendations:
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
· All diagnostic material should be reviewed by a haematopathologist (1A).
Prognostic scoring:
There is no universally accepted prognostic scoring system specific for PTLD. This is a result of most prognostic scores included varying risk factors, heterogeneous patients or treatments and often being retrospective or single-institution series. However, a number of adverse risk factors have been identified in various prognostic scoring systems including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia.
Management of PTLD:
Reduction of immunosuppression:
Recommendations:
· Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
· Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab +/# chemotherapy:
Recommendations:
· Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
· 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 (1B).
· Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
· Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
· Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
· PET-CT should be considered for interim and endof-treatment response assessment where available (1C).
Radiotherapy:
The role of radiotherapy as a component of treatment for PTLD is undefined. Retrospective, non-randomised heterogeneous case series include patients treated predominantly with RIS and/or chemotherapy, with 7–25% of cases having radiotherapy included in their initial management.
Antivirals, intravenous immunoglobulin and interferon-alpha treatment:
Recommendations:
· Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
· In localised disease, radiotherapy may be offered concurrently with RIS (2C).
· Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD:
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD.
Adoptive immunotherapy:
Recommendations:
· Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
· Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
· Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Burkitt lymphoma-like PTLD:
The largest series of 20 patients with Burkitt-like monomorphic PTLD demonstrated that rituximab monotherapy was inadequate at inducing sustained remission (n = 3). Seventy-three per cent (8/11) of patients receiving an R-CHOP-like regimen [R-CHOP, n = 9; EPOCH-R (EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and rituximab), n = 1; CHOP n = 1] with concurrent RIS attained a CR, which was similar to results obtained with more dose-intensive chemotherapy and concurrent RIS [LLA/LB97 protocol n = 2; CODOX-M/IVAC n = 1; Burkimab regimen n = 3 (5/6) 83% CR].95 These results are supported by a small sub-analysis of seven patients pooled from the PTLD-1 trial and a German PTLD registry.
Plasmablastic and plasma-cell myeloma PTLD:
There is a paucity of data on these subtypes to recommend a standardised approach and therefore it is reasonable to treat as for the plasmacytoid dyscrasia disease in the immunocompetent. RIS should be incorporated in the management algorithm.
T-cell lymphoma PTLD:
Patients with adequate cardiac function is to combine RIS with anthracycline-based chemotherapy. Treatment algorithms used in immunocompetent patients with T-cell lymphoma can be reasonably adopted on T-cell lymphoma PTLD patients.100 There are no published cases describing the use of ASCT in first remission in the setting of PTCLNOS (not otherwise specified) PTLD.
Hodgkin lymphoma PTLD:
Standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function.
Extra-nodal marginal zone lymphoma – PTLD:
The predominant site of involvement of MALT lymphoma is gastric, although isolated cases of colonic and small-bowel involvement are described. Treatment algorithms are heterogeneous and poorly standardised. Occasionally EBV-positive MALT lymphoma occurs in the skin and may respond well to RIS in the first instance. Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option. Radiotherapy is an effective treatment in this setting.
Post-transplant lymphoproliferative disease affecting the central nervous system:
Recommendations:
· It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
· Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
· Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
· Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
· Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care:
Recommendation:
· Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C)
Thank you
Please summarise this article
-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 theimmunocompetent population.
– In adult SOT recipients,mPTLD is a common malignancy after skin cancer and is associated with a significant cancer-related mortality.
– The reported incidence varies according to patient age, transplant type and the degree of immunosuppression.
-The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, particularly in the first year post SOT. EBV-negative cases account for approximately 20–40% of PTLD and usually
occur after the first year of transplantation.
-In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%).
Diagnosis and staging
-Where possible, excision biopsy samples are recommended to enable accurate PTLD sub-classification and to provide sufficient material for subsequent ancillary investigations. Where this is not possible, a core needle biopsy is an
alternative .
-Staging with a CT is recommended in all patients where PET-CT is not available .
-Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma .
Multidisciplinary approach to care
-Patients with PTLD present a multifaceted clinical challenge.
-All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians.
– All diagnostic material should be reviewed by a haematopathologist .
Prognostic scoring
-A number of adverse risk factors have been identified in various prognostic scoring systems including poor performance status, EBV-negative tumour, graft
involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia.
Management of PTLD
Reduction of immunosuppression
Where safe to do so, immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team. RIS aims to partially restore T-cell function.
-Where RIS is being considered as the sole initial treatment, response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond.
Rituximab +/_ chemotherapy
-The commonest form of PTLD has a CD20-positive, B-cell monomorphic histology -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) after four cycles of weekly standard-dose rituximab .
– Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles .
– Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise .
-Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected
-PET-CT should be considered for interim and end of- treatment response assessment where available.
Radiotherapy
-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes .
– In localised disease, radiotherapy may be offered concurrently with RIS .
-Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials .
Therapy for relapsed or refractory PTLD
-Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good
remission is achieved .
-Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD .
-Patients with relapsed/refractory PTLD should be offered clinical trials where available .
PTLD affecting the central nervous system
-The histology of CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive.
-The overall prognosis is generally considered poor.
– It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management .
-Treatment of less common forms of PTLD with standard- of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to
potential toxicity and patient comorbidity .
– Patients with CNS-PTLD should be offered treatment with RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity .
-Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD .
-Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD .
Supportive care
-G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD .
Re-transplantation
-Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period
may be needed .
Thank you
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Please summarise this article
# Introduction:
*This study is an updated guideline and details the recommendations for the front-line management of adult patients with an established diagnosis of (PTLD) after (SOT).
*PTLD describe a range of disorders following lymphoid proliferations that develop as a consequence of immunosuppression post- SOT.
*It is estimates as 21% of all malignancies of SOT, as compared with 4–5% within the immunocompetent community.
* In adult it is a common cancer after skin cancer and is associated with high incidence of death.
*Many cases are arise from B lymphocytes and are (EBV)-associated, especially in the first year post SOT, however the incidence of EBV-negative is 20–40% and develop after the first year of transplantation, with a second peak of incidence occurring at 10 years.
# Diagnosis and staging:
*All diagnostic material should be accompanied by relevant clinical information (date of transplant, IS regimen and organ type.
*Excision biopsy is recommended to enable accurate PTLD sub-classification and to provide sufficient material for subsequent ancillary investigations.
*Staging should be recorded using the Ann Arbor classification or the Lugano classification.
(Where possible a surgical excisional or incisional
Biopsy if not possible, a core needle biopsy is an
alternative).
*Staging with a CT is recommended in all patients where PET-CT is not available.
(Where available a PET-CT should be utilised for staging
in line with the recommendation for FDG-avid lymphoma).
*A management plan should be agreed by (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
*There is no universally accepted prognostic scoring system specific for PTLD but the international
Prognostic Index (IPI) for non-Hodgkin lymphoma can be recommended.
* IPI is based on the baseline parameters age, stage of disease, EGOG performance status, extra-nodal site involvement and LDH.
#Management of PTLD
# Reduction of immunosuppression (RIS)
*RIS aims to partially restore T-cell function.
*The only treatment required for a select group of patients with low-risk patients which have early lesions, low-stage disease and non-bulky disease.
*Evaluate the patients within 2–4 weeks and alternative protocol can be promptly initiated in those patients that fail to respond.
*If a complete remission (CR) is obtained, then no other therapy may be required in patients with low risk factors.
*Close monitoring for rejection.
*Patients that achieve a PR by RIS alone can either be reassessed within a further 2–4 weeks or recommended rituximab-based treatment.
***Reduction of IS by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function.
# Rituximab +/chemotherapy:
*Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
*4 further 3-weekly cycles of rituximab are recommended
in patients who obtain CR or complete metabolic remission (CMR) after 4 cycles of weekly standard-dose rituximab.
*4 cycles of R-CHOP-21 immunochemotherapy are
recommended in patients who fail to obtain CR or
CMR after 4 cycles of weekly standard-dose rituximab or who clinically progress during these four cycles.
*Rituximab plus anthracycline-based therapy is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise.
*Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
* PET-CT should be considered for interim and endof- treatment response assessment where available.
# Radiotherapy Antivirals, intravenous immunoglobulin and interferon-alpha treatment
*Involved-field radiotherapy may be offered for selected
patients with PTLD in line with standard protocols
for specific histological subtypes.
* In localised disease, radiotherapy may be offered concurrently with RIS.
*Treatment with anti-viral agents and/or arginine butyrate,
IVIG and IFNa is not recommended outside clinical trials.
# Therapy for relapsed or refractory PTLD / Adoptive immunotherapy
*Patients that relapse post-R-CHOP should be carefully
selected for intensive second-line chemotherapy followed
by autologous stem cell transplant if a good remission is achieved.
*Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD.
*Patients with relapsed/refractory PTLD should be offered clinical trials where available.
# Post-transplant lymphoproliferative disease affecting the central nervous system
*All patients with the less common forms of PTLD be considered for RIS as part of their initial management .
*Treatment of less common forms of PTLD with standard- of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity.
* Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity.
* Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be
offered in CNS-PTLD.
* Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
# Supportive care :
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD.
# Re-transplantation:
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed .
(In the UK they usually they wait for 2 years after completing clearance before re-transplantation).
Thank you
1.Please summarise this article
Diagnosis:
Staging:
Multidisciplinary approach to care:
Prognostic scoring
Management of PTLD
Reduction of immunosuppression:
Rituximab +/- chemotherapy:
Radiotherapy
Antivirals, intravenous immunoglobulin & interferon-alpha treatment:
Therapy for relapsed or refractory PTLD
Adoptive immunotherapy:
Burkitt lymphoma-like PTLD
Plasmablastic and plasma-cell myeloma PTLD
T-cell lymphoma PTLD
Hodgkin lymphoma PTLD
Extra-nodal marginal zone lymphoma – PTLD
PTLD affecting the CNS:
Supportive care:
Re-transplantation:
Thank you
Please Summarize The Article
Introduction
Lymphoproliferative disorders are approximately 21% of all cancers among solid organ transplantation recipients, and 4-5% within the immunocompetent population. Post-transplantation lymphoproliferative disorders (PTLD) is a common malignancy and is associated with a significant cancer-related mortality. The incidence is dependent on patient age, type of transplant, and the level of immunosuppression.
Diagnosis and staging
To establish a diagnosis, it is recommended to perform a biopsy – either an excisional or incisional, if not possible then a core biopsy may be an alternative. The diagnostic material should accompany a thorough clinical history. The evaluation should allow for staging with a PET-CT or a CT scan. For patients with suspected CNS involvement, it is recommended to perform a MRI and a lumbar puncture for CSF analysis.
A multidisciplinary team that includes transplant physicians, hemato-oncologists, hematopathologists, radiation-oncologists and radiologists should handle all cases, as the patients require a multifaceted approach to their management.
Some of the risk factors that have been identified include poor performance status, EBV-negative tumor, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase and hypoalbuminemia.
Management of PTLD
Reduction of immunosuppression (RIS)
Rituximab and chemotherapy
Radiotherapy
Antivirals, IVIG and interferon-alpha treatment
Therapy for relapsed or refractory PTLD
Patients who have relapsed and refractory PTLD should be selected for second line chemotherapy, and followed by autologous stem cell transplant if a good remission is achieved. The patients should also be offered clinical trials where available.
Burkitt lymphoma-like PTLD
Studies have shown that RIS with R-CHOP should be considered for Burkitt-like lymphoma. CNC examination should be done prior to initiation of treatment, and carefully monitored during treatment. CNS prophylaxis should be considered.
Plasmablastic and plasma-cell myeloma PTLD
There is limited data on the subject and therefore a standardized treatment approach is not available. The disease may be treated as done in immunocompetent patients. RIS should also be incorporated in the management.
T-cell lymphoma PTLD
It is a rare form of PTLD, and is associated with poor outcomes. It is suggested to combine RIS with an anthracycline-based chemotherapy.
Hodgkin lymphoma PTLD
Standard chemotherapy of ABVD, with RIS should be considered for treatment, for patients with normal cardiac and pulmonary function.
Extra-nodal marginal zone lymphoma – PTLD
Rituximab as a monotherapy has been shown to be effective. Radiotherapy can also be added to the management protocol.
PTLD affecting the CNS
Patients with PTLD affecting the CNS should be initiated on RIS, and a combination chemotherapy with rituximab. Local radiotherapy and corticosteroids have also shown to be useful.
Supportive care and re-transplantation
Patients should be carefully monitored for concomitant infections. Antibiotic, antifungal and antiviral prophylactic treatment should be considered. Re-transplantation should be considered in patients after careful clinical assessment, and is dictated by organ type.
Thank you. How long this patient needs to wait after complete clearance of the PTLD?
Thank you Prof
The patient will need to wait for at least 2 to 5 years after clearance of PTLD
Summary of the article
Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
PTLD:Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations that occur as a result of immunosuppression following SOT.
· Account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.
· PTLD has been reported to occur most frequently in the first year following transplantation.
· The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated.
· EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation with a second peak of incidence occurring at 10 years.
· Incidence of PTLD in SOT: recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%) followed by lung transplants (3.0–10%), heart transplants (2.0–8.0%), liver transplants (1.0–5.5%), pancreatic trans- plants (0.5–5.0%) and renal transplant recipients having the lowest incidence of PTLD (0.8–2.5%).
· PTLDs are sub-classified into four histopathological categories: Non-destructive, Polymorphic, Monomorphic and Classical Hodgkin Lymphoma.
PTLD; Diagnosis and staging
1. Relevant clinical information; date of transplant, immune suppression regimen and organ type.
2. CBC, KFT, LFT, LDH and blood sugar.
3. Virology: HIV 1 &2, HBV &HCV, EBV serology, CMV/EBV DNA titres.
4. Bone marrow biopsy may be clinically indicated in some cases.
5. Excision biopsy samples to enable accurate PTLD sub-classification.
6. Staging should be recorded using the Ann Arbor classification or the Lugano classification following Positron Emission Tomography–Computed Tomography (PET-CT).
7. MRI or CT imaging of the brain, orbits and sinuses is recommended for patients with suspected central nervous system (CNS) or craniofacial disease.
8. Diagnostic lumbar puncture for cerebrospinal fluid (CSF) analysis, including cytology and flow cytometry, is recommended for patients with suspected CNS involvement.
PTLD;Multidisciplinary approach to care
· A management plan should be agreed by a core multidisciplinary team (MDT) which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD managemen with input from the organ transplant physicians (1A).
· All diagnostic material should be reviewed by a haematopathologist(1A).
PTLD; Prognostic scoring
· No universally accepted prognostic scoring system specific for PTLD.
· Adverse risk factors: poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia.
PTLD; Management
1. Reduction of immunosuppression
· immediate reduction in immunosuppression (RIS) by 25% in limited diseases and up to 50% in extensive disease. Response should be assessed within 2–4 weeks, If a complete remission (CR) is obtained, then no other therapy may be required.
· Patients that achieve a PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks or further rituximab-based treatment.
· Consider stopping AZA/MMF. Maintain prednisolone 7.5/10 mg/day.
· Failure of RIS to be followed by sequential treatment with rituximab and subsequently by CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy in adult B-cell PTLD.
2. Rituximab +/- chemotherapy
· RTX is the front-line therapy for monomorphic CD20-positive B-cell PTLD. Rituximab at standard dose (375 mg/m2) followed by four cycles of standard-dose CHOP-21 chemotherapy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF).
· Based on data from PTLD-1and PTLD-1/3, patients with a low risk of disease progression achieved a CR after the first four courses of rituximab monotherapy.
· Dose-attenuated treatment or alternative less toxic treatment regimens (such as single-agent rituximab, corticosteroids, oral etoposide and alkylating agents) can be considered in selected patients.
· Polymorphic CD20-positive B-cell PTLD, to be treated with the same algorithm as monomorphic CD20-positive B-cell PTLD as described above. Rarely, polymorphic PTLD can have an overlap with Hodgkin Lymphoma PTLD and thus the management would be as in Hodgkin Lymphoma PTLD.
· Recommendations:
a) Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
b) 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 (1B).
c) Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville £ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
d) Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
e) Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B). PET-CT should be considered for interim and end- of-treatment response assessment where available (1C).
3. Radiotherapy:
· Radio- therapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localized extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
· Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
· In localised disease, radiotherapy may be offered con- currently with RIS (2C).
4. Antivirals, intravenous immunoglobulin and interferon-alpha treatment.
· Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
5. Therapy for relapsed or refractory PTLD (R/R PTLD)
· Patients with R/R PTLD post R-CHOP have a poor long- term survival.
· conventional salvage approaches with consolidation autologous stem cell transplantation (ASCT) are challenging to deliver in SOT patients.
· Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
6. Adoptive immunotherapy
· EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV- positive PTLD whilst avoiding the risk of graft rejection.
· Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD(1C)
· Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Burkitt lymphoma-like PTLD
· Rituximab monotherapy was inadequate at inducing sustained remission.
· R-CHOP with concurrent RIS could be considered a reasonable option for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immune-competent patient.
· Dose-adjusted EPOCH-R with appropriate CNS prophylaxis may also represent a clinically appropriate option in selected patients aiming to achieve curative therapy.
Plasmablastic and plasma-cell myeloma PTLD
· There is a paucity of data on these subtypes.
· it is reasonable to treat as for the plasmacytoid dyscrasia disease in the immunocompetent.
· RIS should be incorporated in the management algorithm.
T-cell lymphoma PTLD
· Peripheral T-cell lymphomas (PTCL) are a rare form of PTLD.
· A reasonable approach in patients with adequate cardiac function is to combine RIS with anthracycline-based chemotherapy.
Hodgkin lymphoma PTLD
· Classical Hodgkin lymphoma-type PTLD (HL-PTLD) is rare.
· A standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function.
· BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone), Escalated BEACOPP or BEA- COPDac (dacarbazine substituted for procarbazine) should only be considered and used with caution in patients with particularly high-risk disease given the known associated haematological and infection-related toxicities with these regimen(s).
Extra-nodal marginal zone lymphoma – PTLD
· Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option.
· Radiotherapy is an effective treatment in this setting.
PTLD affecting the CNS:
· Overall prognosis is poor.
· No optimal therapy for CNS-PTLD has been established.
· Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
· RIS is routinely performed, usually alongside radiotherapy (ORR of 75%).
· RIS, intrathecal chemotherapy and whole-brain radiotherapy yielded an ORR of 75% and OS of 62% at five years.
· Intensive, systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate (HD- MTX) with rituximab, is the standard for immunocompetent primary CNS lymphoma.
· Prockop et al. demonstrated responses with donor and ‘third-party’ (Tabelecluecel) EBV-specific CTLs in patients with EBV-positive CNS-PTLD in patients following haemopoietic stem cell transplant or SOT.
· Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
· Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
PTLD; Supportive care and Re-transplantation
· G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
· Re-transplantation may be considered after successful control of PTLD as the risk of recurrence of PTLD after re-trans- plantation is low.
· Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be consid- ered before re-transplantation, but a longer period may be needed (2C).
Thank you
This article shed light on the management of post-transplant lymphoproliferative disease, detailing its diagnosis and treatment.
PTLD:
Its lymphoid tissue proliferation provoked by immunocompromised status post transplantation.it accounts for 21% of all cancer incidence is solid organ transplantation.
It occurred predominantly in the first post-transplant year, however, several other papers pointed towards its equal prevalence after the first-year post transplantation.
EBV:
considered the major etiologic factor in triggering tumoral process. B lymphocytes are principal cells of PTLD. 20-40 % are EBV negative PTLD, reported usually after the first year.
PTLD prevalence in different organs transplantation:
In adult population its more prevalent in multiorgan transplant patient, then Intestinal transplant, lung transplant, cardiac and least in kidney transplant recipients.
Types:
4 subtypes are recognized:
1]Non-destructive, Plasmacytic , associated with EBV.
2]Polymorphic, B cells mature admix with t lymphocytes. EBV associated.
3]Monomorphic, resemble lymphoma subtypes. can be EBV negative.
4]Classical Hodgkins lymphoma, EBV related.
Recommendation for diagnosis:
1]Excisional or incisional diagnosis is essential in diagnosis. otherwise, core needle biopsy.
2] CT for staging where PET-CT is not available.
3] PET-CT is gold standered for staging of PTLD.
Thank you
Management of PTLD:
Management has to be planned by a multidisciplinary team involving transplant physician, oncologist, hemato-oncologist.
the main strategy entails reduction of immunosuppression medication, as it might enhance the immune system to control abnormal proliferation of lymphocytes.
The plan depends on how critical the patients, stage and grade of PTLD is.
As follows:
Reduction in Immunosuppresant RIS
1] In stable patients:
Azathioprine and MMF to be stopped.
CNi dose reduced 50%, continue Cs with 10 mg
2] Critical patient
To stop MMF, and Aza.
reduce CNi by 75%.
For rechecking of PTLD progression within 2-4weeks.
The second line therapy
Rituximab:
375 mg 4 weekly doses.
R-CHOP protocol for 4 weekly cycles.
Introduction:
This article is a guideline regarding management of adult post-transplant recipients diagnosed with PTLD.
PTLD accounts for 21% of all cancers in post-transplant recipients and is common malignancy after skin cancer. Majority of PTLD is in EBV positive recipients, among solid organ transplant recipients, renal transplant patients have the lowest incidence of PTLD (0.8–2.5%).
Diagnosis, Staging and Scoring:
1. Excision biopsy is recommended for accurate PTLD sub-classification and for providing sufficient material for subsequent investigations.
2. Staging should be recorded using the Ann Arbor classification or the Lugano classification.
3. Staging with a CT is recommended in all patients where PET-CT is not available.
4. A management plan should be agreed by a multidisciplinary team (MDT), including a transplant physician, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists.
5. International Prognostic Index (IPI) is recommended prognostic score.
Management of PTLD:
Reduction of immunosuppression (RIS):
1. RIS partially restores T-cell function, and may be the only treatment required for low-risk patients who have early lesions, low-stage disease and non-bulky disease.
2. Monitor for rejection.
3. Response should be assessed within 2–4 weeks and if complete remission (CR) is obtained, then no other therapy is needed.
4. Patients who achieve partial remission can be further monitored for 2-4 weeks or Rituximab can be considered.
5. American guidelines on RIS :
a. Limited disease Reduction by 25% of all immunosuppression
b. Extensive disease — not critically ill: Reduction of CNIs by 50% Consider stopping azathioprine/MMF Maintain prednisolone 7.5/10 mg/day
c. Extensive disease — critically ill: Stop all agents except for maintaining prednisolone 7.5/10 mg/day.
Rituximab +/- chemotherapy:
1. Front-line therapy for monomorphic CD20-positive B-cell PTLD.
2. Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab.
3. Four cycles of R-CHOP-21, (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 days alongside mandatory granulocyte colony-stimulating factor (G-CSF), immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab.
Radiotherapy, antivirals, IVIG:
1. The role of radiotherapy as a component of treatment for PTLD is undefined.
2. A retrospective analysis suggested that adults with limited-stage disease, irrespective of the histological subtype, can obtain CRs after surgical resection or radiotherapy, usually with concurrent RIS.
3. Treatment with anti-viral medication, IVIG and interferon is not recommended outside clinical trials.
Treatment of relapse or refractory PTLD:
Adaptive immunotherapy, in EBV positive PTLD which did not respond to RIS, Rituximab or chemotherapy.
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.
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SUMMARY
Introduction
One of the falls out of necessary immunosuppression in solid organ transplantation is the development of lymphoproliferative disease which is the second most common malignancy after skin can in these groups of people.
It has been shown to account for 21% of all cancers of solid organ transplant recipients as compared to 4-5% seen in immunocompetent individuals and EBV has been linked with a strong association with its occurrence. The highest incidence is seen in lung transplants while the least is found in kidney transplants.
Diagnosis and staging
Classification
PTLD type
THE MULTIDISCIPLINARY APPROACH TO CARE
Recommendation
The identified adverse risk factor in different prognostic scoring
Management of PTLD
Therapy for relapsed PTLD
Recommendation for other forms of PTLD
Conclusion
The success achieved in new immunosuppressive therapy has also come with attendant problems like PTLD which has also a strong association with EBV. There are various forms of histological classifications of PTLD with different methods of therapy and some of them are novel. Re- transplantation is possible even even a graft is lost to the disease, but average of 2 years is needed for this to be done,
Thank you
Please summarise this article
British guidelines for PTLD management:
Introduction:
Post-transplant lymphoproliferative diseases are a spectrum of disorders resulting from lymphoid proliferations by immunosuppressive medications used post SOT. Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.
PTLD is the second most common malignancy after skin cancer with a significant mortality.
PTLDs are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, in the first year post SOT. EBV-negative cases account for 20–40% of PTLD usually occurs after the first year of transplantation, with a second peak of incidence occurring at 10 years post SOT.
In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%) followed by lung transplants (3–10%), heart transplants (2–8%), liver transplants (1–5.5%), pancreatic transplants (0.5–5%) and renal transplant recipients having the lowest incidence of PTLD (0.8–2.5%).
Diagnosis and staging:
– Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
– Staging with a CT is recommended in all patients where PET-CT is not available (1A). “
– Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Multidisciplinary approach to care:
– All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A). “
– All diagnostic material should be reviewed by a haematopathologist (1A).
Prognostic scoring:
– The Ghobrial prognostic score allocated one point for ECOG (Eastern Cooperative Oncology Group) > 2, but its utility was limited due to a majority of patient having monomorphic disease (96%) and only 16% having graft involvement.
– International Prognostic Index (IPI) for non-Hodgkin lymphoma.
– Risk factors in various prognostic scoring systems are: poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia.
Management of PTLD:
1. Reduction of immunosuppression:
– Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
– Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
2. Rituximab +/# chemotherapy:
– Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
– 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 (1B).
– Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
– Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
– Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
3. Radiotherapy:
– Used incorporation with chemotherapy in some sort of PTLDs.
– may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse, and localised extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type.
4. Antivirals, intravenous immunoglobulin and interferon-alpha treatment:
– Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
5. Therapy for relapsed or refractory PTLD:
– Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
– Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
– Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
– Adoptive immunotherapy is a permissive modality of treatment in some R/R PTLD.
Burkitt lymphoma-like PTLD:
· R-CHOP with concurrent RIS could be considered a reasonable option for Burkitt-like PTLD. However, dose-adjusted EPOCH-R with appropriate CNS prophylaxis may also represent a clinically appropriate option in selected patients aiming to achieve curative therapy.
Plasmablastic and plasma-cell myeloma PTLD:
· Treat as for the plasmacytoid dyscrasia disease in the immunocompetent patients.
T-cell lymphoma PTLD:
· Combined RIS with anthracycline-based chemotherapy, in patients with good cardiac function.
Hodgkin lymphoma PTLD:
· Combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy may represent a safe and efficacious option alongside RIS in HL-PTLD patients with normal cardiac and pulmonary function.
· BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone), Eescalated BEACOPP or BEACOPDac (dacarbazine substituted for procarbazine) should only be considered and used with caution in patients with particularly high-risk disease.
Extra-nodal marginal zone lymphoma – PTLD:
· EBV-positive MALT lymphoma may respond well to RIS, Rituximab monotherapy has been shown to be effective and can be a reasonable treatment option.
· Radiotherapy is an effective treatment.
Post-transplant lymphoproliferative disease affecting the central nervous system:
· Intrathecal chemotherapy and whole-brain radiotherapy.
· Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate with rituximab.
Recommendations:
– All patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
– Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
– Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
– Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
– Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care:
– G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation:
– Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
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Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Post-transplant lymphoproliferative disease represents a spectrum of disorders resulting from lymphoid proliferations, attributed to immunosuppression post transplantation. It account for 21% of all cancers of SOT recipients, mostly due to B lymphocytes and are Epstein–Barr virus (EBV)-associated.
PTLD has 2 peaks of occurrence, either 1st year (Usually EBV associated) or the second peak of incidence occurring at 10 years (EBV negative ).
Among all SOT, renal transplant recipients having the lowest incidence of PTLD (0.8–2.5%).
Diagnosing and staging
diagnostic material should be accompanied by relevant clinical information including :
· The date of transplant.
· Immune suppression regimen.
· Organ type.
The guidelines recommends a surgical excisional or incisional biopsy or a core needle biopsy is an alternative (1A). Staging either with a CT or a PET-CT (1A).
Multidisciplinary approach to care
MDT approach to be used for All cases , haemato-oncology experience in PTLD management, with input from the organ transplant physicians (1A). and all diagnostic material should be reviewed by a haematopathologist (1A).
Management of PTLD
Reduction of immunosuppression (RIS) is the mainstay, including stopping azathioprine and MMF and reduction of CNIs ( by 30–50%) and corticosteroids, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B)
Rituximab +/# chemotherapy
1. Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B). 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 (1B).
2. Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
3. Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
4. Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
5. PET-CT should be considered for interim and end of-treatment response assessment where available (1C).
Radiotherapy: Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C). while if the disease is localised, radiotherapy may be offered concurrently with RIS (2C).
Therapy for relapsed or refractory PTLD is recommended to offer autologous stem cell transplant and /or adoptive immunotherapy.
Patients with CNS-PTLD should be offered treatment with
1. RIS followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
2. Local radiotherapy +/# corticosteroids (2C).
3. Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Re-transplantation can be offered after minimum of one year, but a longer period may be needed (2C).
Well done
Front-line management of PTLD in adult SOT— A British Society for Haematology Guidelines
PTLD is the second most prevalent malignancy in adult recipients of solid organ transplants, behind skin cancer, and poses a significant mortality risk.
The risk is increased when an EBV-negative recipient receives a transplant from an EBV-positive donor, when there is strong immunosuppression such as ATG induction and tacrolimus-based maintenance therapy, when immunosuppression is at its peak in the first year after transplantation, and when transplanted organs such as the small bowel and heart-lung.
90% of PTLD are EBV-positive and derived from B cells, with the remaining 10% deriving from T cells.
Histomorphological description categorizes PTLD into four groups.
1-Non-destructive; includes plasmacytic hyperplasia, infectious mononucleosis-like cells, and florid follicular hyperplasia. Most EBV-associated cases are early PTLD.
2-Polymorphic; B-cell maturation stages with T cells, EBV-associated in >90% instances.
3-Monomorphic; 60–80% of PTLD are DLBCL, Burkitt lymphoma, plasma cell myeloma, or plasmacytoma. Indolent B-cell lymphomas and T-cell neoplasms are diagnosed less often. EBV-negative monomorphic PTLD.
4-Classical Hodgkin Lymphoma: This is classical Hodgkin lymphoma and usually (>90%) associated with EBV.
Treatment of PTLD
1- Immunosuppression reduction:
The guidelines propose eliminating azathioprine and MMF and reducing CNIs by 30–50% while maintaining or reducing corticosteroids in all patients whenever possible under the advice of the transplant physician with graft function monitoring (1B). Patients receiving RIS alone should be assessed for disease response at 2–4 weeks to see if they need additional treatment (1B).
2-Rituximab/chemotherapy:
The guidelines suggest rituximab monotherapy for CD20-positive PTLD patients who don’t react to RIS (1B). Patients who achieve CR or complete metabolic remission (CMR) (Deauville 3) after four cycles of weekly standard-dose rituximab should get four more three-weekly treatments (1B).
Four cycles of R-CHOP-21 immunochemotherapy are indicated for patients who fail to achieve CR or CMR (with Deauville 3) after four cycles of weekly standard-dose rituximab or clinically advance during these four cycles (1B).
Rituximab plus anthracycline-based therapy (usually R-CHOP-21) is advised with RIS for patients with clinically aggressive lymphoma with serious organ impairment at any time (1B).
All individuals with SOT or suspected renal or cardiac impairment should have formal cardiac and renal function testing (1B).
PET-CT should be evaluated for interim and end-of-treatment response assessment when available (1C).
3-Radiotherapy:
-Selected PTLD patients may receive involved-field radiation according to conventional protocols for certain histological subtypes (2C).
– Radiotherapy may be used with RIS in localized illness (2C).
4-Antivirals, intravenous immunoglobulin, and interferon-alpha treatment are not indicated outside clinical trials (1C).
5- Refractory cases- relapses following the CHOP therapy;
If a good remission is obtained, intense second-line chemotherapy followed by an autologous stem cell transplant.
Use immunotherapy (EBV-specific T cells, EBVSTs in situations of relapse and resistance).
6- Retransplantation: following a full year of remission (with better matched donor to reduce immunosuppression, avoid ATG, minimize use of tacrolimus to the least possible dose)
Well done
Post-transplant lymphoproliferative disease PTLD is the second common cancer posttransplant after skin cancer, and represent 21% of cancers post solid organ transplant SOT.
Its incidence bimodal, one in the first year post transplant and one mode at 10 years post-transplant, also EBV as a causative agent can happen early and EBV negative origin occurs in the late period post-transplant.
In addition, PTLD is common more in multiorgan transplant and intestinal transplant, and least common in renal transplant recipient among all SOT.
Excisional biopsy for diagnosis and staging is important for management; role of Positron Emission Tomography–Computed Tomography (PET-CT) in the staging of PTLD is less well defined when compared to lymphoma.
PTLD can be categorized as: non destructive type, polymorphic, monomorphic, and classical Hodgikin lymphoma.
Investigations needed:
1- CBC, liver enzymes, liver function tests, renal function tests, calcium, LDH, uric acid.
2- Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres.
3- Bone marrow biopsy is indicated and some selected patients it may not be clinically needed or appropriate.
4- Echocardiography
5- Assessment of the function of the transplanted organ
6- All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response Where available, PET-CT scan should be utilized for staging over CT scan.
All cases should be submitted for discussion from MDT essentially include hematologist and oncologist.
No accepted universal prognostic scoring system for PTLD because of varying risk factors, heterogeneity of the patients and treatments.
Management of PTLD:
1- Reduction of immunosuppression RIS:
Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab (1B).
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected.
PET-CT should be considered for interim and endof-treatment response assessment where available (1C).
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
In localised disease, radiotherapy may be offered concurrently with RIS (2C).
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
Local radiotherapy +/# corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Well done
· Diagnosis and stagingEstablishing a tissue diagnosis of PTLD can be challenging and all diagnostic material should be accompanied by relevant clinical information including the date of transplant, immune suppression regimen and organ type.
In addition, PET-CT may have a role in the diagnostic work-up as demonstrated in a retrospective study published by Montes de Jesus et al They reported a sensitivity of 85% and specificity of 90% with a positive predictive value of 83% and a negative predictive value of 92% in PTLD.
Despite the limitations of these PTLD data, a staging PET-CT, where available, should be performed in line with recommendations for FDG-avid lymphomas in the immunocompetent patients.
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Staging with a CT is recommended in all patients where PET-CT is not available(1A).
Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B)
· PTLD type DescriptionNon-destructive Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia.
Most cases are EBV-associated and usually present as early PTLD.
Polymorphic A spectrum of B-cell maturation stages with admixture of T cells, EBV-associated in >90% cases.
Monomorphic Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large.
B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma.
Much less commonly indolent B-cell lymphomas, usually mucosa-associated lymphoid tissue lymphoma[5,11,12] and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative.
70% of these lesions are reported to have cytogenetic abnormalities, including trisomy 9 and 11 or both, loss of 17p and rearrangement of 8q24 (MYC)
· Baseline investigationsElectrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH).
Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres.
All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response.
Details should include; date of transplant, organ type and immunosuppresion regimen.
All patients require assessment of the function of the transplanted organ, ideally directed by the transplant physician.
CMV, cytomegalovirus; CT, computed tomography; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; PET, positron emission tomography; PTLD, post-transplantation lymphoproliferative disease.
It is recommended that the lead MDT should be the lymphoma MDT and where possible, a representative of the transplant team should attend.
MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haematopathologist (1A)
· Prognostic scoringThere is no universally accepted prognostic scoring system specific for PTLD. This is a result of most prognostic scores included varying risk factors, heterogeneous patients or treatments and often being retrospective or single-institution series.
The Ghobrial prognostic score allocated one point for ECOG (Eastern Cooperative Oncology Group) > 2, monomorphic disease and graft involvement to demonstrated significant for overall survival (OS) but its utility was limited due to a majority of patient having monomorphic disease (96%) and only 16% having graft involvement.
28 In addition, another prognostic score, the PTLD Prognostic Index, is a variation of the IPI with baseline factors of age, ECOG performance status and LDH.
· Management of PTLDGiven the rarity of the diagnosis and the histological heterogeneity together with the medical complexity of the patients, there are no data available from randomised trials to inform management.
For the rarer subtypes and in the relapsed/refractory setting, treatment decisions are informed by small case series and case reports.
For the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL), there are robust data from prospective phase II studies that have informed existing treatment algorithms.
For the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL), there are robust data from prospective phase II studies that have informed existing treatment algorithms. 23,24
· Reduction of immunosuppressionWhere safe to do so, immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team.
Where RIS is being considered as the sole initial treatment, response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond.
The response to RIS was assessed early between two and four weeks and failure of RIS was followed by sequential treatment with rituximab and subsequently by CHOP chemotherapy in adult B-cell PTLD.
RIS should be considered in conjunction with other therapies, in patients who have risk factors which include clinically aggressive PTLD Ann Arbor stage ≥III, elevated LDH and more than one extra-nodal site or a high-risk IPI.
Disease response assessment is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond .
· Or withdrawal of all immunosuppressant drugs except for corticosteroidsCNIs, calcineurin inhibitors; MMF, mycophenolate mofetil; PTLD, post-transplantation lymphoproliferative disease; RIS, reduction in immunosuppression; SWOG, Southwest Oncology Group.
ASCT, autologous stem cell transplant; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; G-CSF, granulocyte-colony stimulating factor; IPI, international prognostic index; IV, intravenous; PJP, Pneumocystis jirovecii; PR, partial remission; RIS, reduction of immunosuppresion; PTLD, post-transplantation lymphoproliferative disease; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone.
47% at 27!5 months (R) CHOP, (Rituximab) cyclophosphamide, doxorubicin, vincristine, prednisolone; CR/CRu, complete remission/response/unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival; PR, partial remission; PTLD, post-transplantation lymphoproliferative disease.
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
· Therapy for relapsed or refractory PTLDThere are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD.
76–78 In patients who are unresponsive to rituximab, using R-CHOP is a reasonable and logical approach.
23,24,79 A sequential approach as in front-line therapy can be considered if relapse post rituximab monotherapy occurs late.
Patients with R/R PTLD post R-CHOP have a poor longterm survival with OS < 20% as conventional salvage approaches with consolidation autologous stem cell transplantation (ASCT) are challenging to deliver in SOT patients.
78,79 Extrapolating treatments from R/R DLBCL in immunocompetent patients is reasonable 80–83 but this approach has little evidence in R/R PTLD.
Particular attention should be paid to the toxicities of salvage chemotherapy in relation to the underlying SOT and patient comorbidities.
Patients should be offered enrolment in a clinical trial where available
· Adoptive immunotherapyEBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV-.
Autologous or allogeneic EBV-directed CTLs should be considered in patients with R/R EBV-positive.
89 This is similar to the results demonstrated by Prockop et al where a 54% ORR in 13 PTLD patients who were refractory to rituximab was reported.
Trials using CTL for PTLD are small, but the results appear promising and the recent development of chimaeric antigen receptor (CAR)-T cells reported for B-cell malignancies 91,92 suggests that this technology could have a future role in the treatment of PTLD.
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Peripheral T-cell lymphomas (PTCL) are a rare form of PTLD
They typically occur later after SOT and are often associated with poor outcome.
· Hodgkin lymphoma PTLDClassical Hodgkin lymphoma-type PTLD (HL-PTLD) is rare and data on optimal therapy are lacking.
Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate (HD-MTX) with rituximab, is the standard for immunocompetent primary CNS lymphoma 113,114 but may be challenging to administer safely due to comorbidities, typically renal failure or SOT dysfunction in CNS-PTLD patients.
This approach has been adopted in CNS-PTLD patients with some success.
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
· Supportive careSignificant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection. 42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group.
Significant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection.
42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group.
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered.
116,117 Age is an important risk factor for developing FN which can partly be prevented by G-CSF.
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered. 116,117 Age is an important risk factor for developing FN which can partly be prevented by G-CSF. 116,117
· FindingsEBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years. 6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD.
EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.
6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD.
43–45 Treatment-related mortality (TRM) was reduced to 13% compared to retrospective case series with front-line CHOP therapy which documented TRMs of up to.
Limited disease Reduction by 25% of all immunosuppression not critically ill Reduction of CNIs by 50%.
Reduction of CNIs by 50% and further reduction by 50% if not in complete remission by day 14.
Reduce glucocorticoids by 50%, with a lower limit of prednisone of.
Reduce CNIs by 50% and maintain steriods.
With reports of up to 50% mortality following infection.
With reports of up to 50% mortality following infection. 42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group
· Given the degree of immunosuppression in patients withPTLD, strong consideration should be given to antibiotic, antifungal and antiviral prophylaxis during therapy, if treatment is associated with neutropenia as per local protocols.
Prophylaxis with co-trimoxazole or equivalent should be considered in all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia.
Surveillance for CMV infections should continue in patients with PTLD with guidance from the transplant physician or team.
Patients with past hepatitis B or C infection should be managed in conjunction with a hepatologist.
118 Regular monitoring of liver function is required through treatment, and monitoring of hepatitis B viral load should be considered as per the guidance outlined by NICE CG165 118 or as directed by the hepatologist.
Patients with HIV should be managed under joint care with their HIV physician
Well done
II. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Summary
Diagnosis and staging
Multidisciplinary approach to care
Prognostic scoring
Management of PTLD
Reduction of immunosuppression
Rituximab +/# chemotherapy
Polymorphic CD20-positive B-cell PTLD
Radiotherapy
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Therapy for relapsed or refractory PTLD
Adoptive immunotherapy
Burkitt lymphoma-like PTLD
Plasmablastic and plasma-cell myeloma PTLD
T-cell lymphoma PTLD
Hodgkin lymphoma PTLD
Extra-nodal marginal zone lymphoma – PTLD
Post-transplant lymphoproliferative disease (CNS-PTLD)
Supportive care
Re-transplantation
Well done
PTLDs are sub-classified into four histopathological categories as;
—————————————————————————————–
1-Non-destructive;
Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia. Most cases are EBV-associated and usually present as early PTLD.
2-Polymorphic;
A spectrum of B-cell maturation stages with admixture of T cells, EBV -associated in >90% cases.
3-Monomorphic;
Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma . Much less commonly indolent B-cell lymphomas, usually mucosa -associated lymphoid tissue lymphoma and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative.
4-Classical Hodgkin Lymphoma ;
Morphologically this fulfils the conventional criteria for the diagnosis of classical Hodgkin lymphoma and is generally (>90%) associated with EBV .
Diagnosis and staging;
—————————————————————————
The guidelines recommend the following ;
1-Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
2-Staging with a CT is recommended in all patients where PET-CT is not available (1A).
3-Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B).
Essential pre-treatment baseline evaluation for all patients diagnosed with PTLD;
——————————————————————————————————–
1-full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH).
2-Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres .
3-Bone marrow biopsy is indicated and some selected patients it may not be clinically
needed or appropriate .
4-Echocardiography where appropriate and potentially when cardiotoxic agents are being used .
5-Fertility-preserving treatments, such as sperm cryopreservation for male and referral to a fertility specialist in female patients, should be considered for eligible patients .
6-Details should include; date of transplant, organ type and immunosuppresion regimen .
7-all patients require assessment of the function of the transplanted organ, ideally directed by the transplant physician .
8-All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at
diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response .
9-Where available, PET-CT scan should be utilised for staging over CT scan .
Multidisciplinary approach to care;
—————————————————————-
The guidelines recommend the following ;
1-All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
2-All diagnostic material should be reviewed by a haematopathologist (1A).
Prognostic scoring ;
——————————————————–
a number of adverse risk factors have been identified in various prognostic scoring systems including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised lactate dehydrogenase (LDH) and hypoalbuminaemia .
Management of PTLD;
———————————————–
1-Reduction of immunosuppression ;
The guidelines recommend the following ;
1-Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, unde rthe guidance of the transplant physician with surveillance of graft function (1B).
2-Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
2-Rituximab +/- chemotherapy ;
The guidelines recommend ;
1- Rituximab monotherapy;
is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
2- 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 (1B).
3-Four cycles of R-CHOP-21 immunochemotherapy ;
Are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
4-Rituximab plus anthracycline-based therapy (typically
R-CHOP-21);
is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
5-Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
6-PET-CT should be considered for interim and end- of-treatment response assessment where available (1C).
3-Radiotherapy;
The guidelines ;
1-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
2- In localised disease, radiotherapy may be offered concurrently with RIS (2C).
4-Antivirals, intravenous immunoglobulin and interferon-alpha treatment ;
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C).
Therapy for relapsed or refractory PTLD;
——————————————————————-
The guidelines recommend ;
1-Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Adoptive immunotherapy;
——————————————————-
The guidelines recommend ;
1-Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
2-Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
The less common PTLD ;
———————————————————-
1-Burkitt lymphoma-like PTLD
2-Plasmablastic and plasma-cell myeloma PTLD
3-T-cell lymphoma PTLD
4-Hodgkin lymphoma PTLD
5-Extra-nodal marginal zone lymphoma – PTLD
The guidelines recommend ;
1-It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C).
2-Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Post-transplant lymphoproliferative disease affecting the central nervous system;
———————————————————————————————
The guidelines recommend ;
1-Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
2- Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
3- Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care ;
————————————————–
The guidelines recommend ;
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B).
Re-transplantation;
——————————————
The guidelines recommend ;
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
Well done
PTLD represents a spectrum of lymphoid proliferations disorders in immunosuppressed SOT recipient. It accounts for 21% of cancers and associated with a significant mortality. The highest incidence occur in the first year after transplantation. However, late occurrence is prevalent.
The majority are B lymphocytes and EBV associated. EBV-negative PTLD account for 20–40%, occur usually after the first year.
The highest incidence occurs in multiorgan, intestinal and intrathoracic transplants. Renal transplants have the lowest incidence.
Diagnosis and staging
Excision biopsy is recommended to provide sufficient material and enable accurate sub-classification. incisional or core needle biopsy are alternatives.
Staging PET-CT, where available, CT where PET-CT is not available
MRI or CT of the brain, orbits and sinuses is recommended for suspected CNS or craniofacial disease along with CSF analysis for cytology and flow cytometry.
Multidisciplinary approach to care
All PTLD cases should be discussed at a haemato-oncology MDT, with input from transplant physicians, pathologist and radiologist.
Prognostic scoring
There is no universally accepted scoring system specific for PTLD, however adverse risk factors include:
Poor performance status
EBV-negative tumour
Graft involvement
Monomorphic histology
Older age
CNS or bone marrow involvement
Raised LDH and hypalbuminaemia
Management of PTLD
No data available from randomised trials to inform management.
Reduction of immunosuppression
Reduction in immunosuppression by stopping antimetabolite and reducing CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended whenever possible with surveillance of graft function
Response should be assessed at 2–4 weeks. Rituximab +/# chemotherapy can be initiated if no response.
Rituximab +/ – chemotherapy
If no response to RIS, Rituximab should be considered in CD20-positive PTLD.
For patients who obtain CR or complete metabolic remission after four cycles of weekly rituximab, consider further four cycles three-weekly .
For patients who fail to obtain clinical or metabolic remission after four cycles or who progress during treatment, consider Four cycles of R-CHOP-21
R-CHOP-21 with RIS for should be considered in aggressive disease with critical organ compromise.
Assess cardiac and renal function in all patients. Interim and end of-treatment PET to assess response
Radiotherapy
Radiotherapy may be considered in localized disease and certain histological subtypes
Antiviral
No evidence to support anti-viral, arginine butyrate, IVIG or IFNa.
Relapse/Refractory disease
Second-line chemotherapy should be considered in selected cases with relapse following standard chemotherapy.
In EBV-positive PTLD, EBV-specific CTLs should be considered where available.
Patients should be offered clinical trials where available.
Other Type of Lymphoma
RIF should be offered to all patients; Further therapies may be offered based on comorbidities.
CNS PTLD
RIS should be offered to all patient, Chemotherapy+/- rituximab if patient is fit, otherwise radiotherapy +/- steroids with RIS can be considered.
EBV-specific CTL can be considered for EBV-positive cases.
Supportive treatment
PJP prophylaxis should be offered to all patients with G-CSF for those receiving chemotherapy.
Re-transplantation
A minimum of one year wait before re-transplantation, longer time may be needed.
That is an excellent summary and very well structured reply. I wish you could give the heading ‘Introduction’ to first paragraph). Headings and sub-headings make it easier to read.
What is your analysis of level of evidence of this study?
Front-line management of PTLD in adult SOT— A British Society for Haematology Guideline
Summary:
· PTLD is 2nd most common malignancy after SOT in adults (21% of cases), (after skin cancer) with significant mortality.
· The risk is increased with EBV negative recipient receiving from EBV +ve donor, strong immunosuppression as ATG induction, TAC based maintenance therapy, peak in 1st year post transplant (max immunosuppression stage), and long time after transplantation, certain organ transplantation as intestine and heart-lung transplantation.
· 90 % of cases are EBV +VE and of B cell origin.
· Diagnosis and staging:
o Tissue biopsy is the golden standard for definitive diagnosis and histopathology determination whether (none destructive, monomorphic or polymorphic, classic Hodgkin disease).
o Excisional /incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
· Basic investigations are required before commencing ttt:
o as CBC, electrolytes, serum uric acid, ca, LDH, liver and kidney function.
o PCR for EBV, CMV, HIV and serology for HBV, HCV.
o BMA and echo as indicated.
· CT neck, chest, abdomen and pelvis for initial staging and to monitor response to ttt thereafter. BET scan for staging if available.
· Staging with a CT is recommended in all patients where PET-CT is not available.
· Patients with suspected CNS involvement, CT and MRI brain with CSF analysis (cytology and flowcytometry).
Management plan:
· Multidisciplinary team (transplant team, oncologist, radiologist, pathologist, psychiatry).
· Poor prognostic factors: as old age, monomorphic histology, EBV -ve, CNS, BM and multiple sites involvement, elevated LDH nad hypalbuminemia.
· Treatment includes many steps:
1. Reduction of immunosuppression (RIS) (sufficient alone in low-risk patients which have early lesions, low-stage disease and non-bulky disease):
· Assess response after 2-4 weeks.
· Close monitor the graft function and surveillance for rejection.
· If no at least partial remission, Rituximab should be started.
· No consensus about how to reduce immunosuppression, mostly we sop antiproliferative (MMF and azathioprine), reduce CNI by 50% and keep steroid 7.5-10 mg/day.
2. Rituximab ± sequential chemotherapy (CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone);
· After failed RIS alone after 2-4 weeks.
· Aggressive PTLD Ann Arbor stage III, elevated LDH and > one extra-nodal site or a high-risk IPI.
· Complete stoppage of IS is reasonable in kidney transplantation (as return to dialysis is still an option, unlike heart and lung transplantation).
· 4 cycles of weekly IV rituximab at standard dose (375 mg/m2) then assess response as some patients will respond to rituximab monotherapy.
· Cases with no response (no complete remission or worsening with rituximab) should be followed by 4 cycles of standard-dose CHOP chemotherapy (50 mg/m2 doxorubicin; 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 50 mg/m2 prednisolone) every 21 day.
· Mandatory granulocyte colony-stimulating factor (G-CSF) and chemoprophylaxis against pneumocystis Jirovecii.
· Treatment related mortality (TRM) as cardiotoxicity (by doxorubicin) and severe myelosuppression by cyclophosphamide, that makes it more judicious to use selective agents in particular patients (not all chemotherapeutic agents).
· Response to treatment can be assessed by CT; however, PET-CT is more sensitive tool for response assessment and should be utilised where available.
3. Radiotherapy:
· In rare forms of PTLD, tends to be incorporated with the chemotherapy as in nasal natural killer/T-cell lymphoma. Treatment regimen tends to follow lymphoma protocols.
· Local disease in the orbit.
4. Anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
5. Refractory cases (relapsed after CHOP protocol);
· intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
· Adoptive immunotherapy as (EBV specific T lymphocytes), EBVSTs in relapsed and refractory cases).
6. Retransplantation: after 1 year of complete remission (with better matched donor to reduce immunosuppression, avoid ATG, minimize use of tacrolimus to the least possible dose)
You have used too much of bold in the middle part of your write-up. Typing in bold or in capitals amounts to shouting. Is one year wait enough? What is the current practice in your department or in your region?
· Diagnosis and staging
Establishing a tissue diagnosis of PTLD can be challenging and all diagnostic material should be accompanied by relevant clinical information including the date of transplant, immune suppression regimen and organ type.
In addition, PET-CT may have a role in the diagnostic work-up as demonstrated in a retrospective study published by Montes de Jesus et al They reported a sensitivity of 85% and specificity of 90% with a positive predictive value of 83% and a negative predictive value of 92% in PTLD.
Despite the limitations of these PTLD data, a staging PET-CT, where available, should be performed in line with recommendations for FDG-avid lymphomas in the immunocompetent patients.
Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
Staging with a CT is recommended in all patients where PET-CT is not available(1A).
Where available a PET-CT should be utilised for staging in line with the recommendation for FDG-avid lymphoma (1B)
· PTLD type Description
Non-destructive Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia.
Most cases are EBV-associated and usually present as early PTLD.
Polymorphic A spectrum of B-cell maturation stages with admixture of T cells, EBV-associated in >90% cases.
Monomorphic Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large.
B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma.
Much less commonly indolent B-cell lymphomas, usually mucosa-associated lymphoid tissue lymphoma[5,11,12] and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative.
70% of these lesions are reported to have cytogenetic abnormalities, including trisomy 9 and 11 or both, loss of 17p and rearrangement of 8q24 (MYC)
· Baseline investigations
Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH).
Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titres.
All patients should have a staging CT- scan of neck, chest, abdomen and pelvis at diagnosis to inform the treatment decisions and to act as a baseline for the assessment of response.
Details should include; date of transplant, organ type and immunosuppresion regimen.
All patients require assessment of the function of the transplanted organ, ideally directed by the transplant physician.
CMV, cytomegalovirus; CT, computed tomography; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; PET, positron emission tomography; PTLD, post-transplantation lymphoproliferative disease.
It is recommended that the lead MDT should be the lymphoma MDT and where possible, a representative of the transplant team should attend.
MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
All diagnostic material should be reviewed by a haematopathologist (1A)
· Prognostic scoring
There is no universally accepted prognostic scoring system specific for PTLD. This is a result of most prognostic scores included varying risk factors, heterogeneous patients or treatments and often being retrospective or single-institution series.
The Ghobrial prognostic score allocated one point for ECOG (Eastern Cooperative Oncology Group) > 2, monomorphic disease and graft involvement to demonstrated significant for overall survival (OS) but its utility was limited due to a majority of patient having monomorphic disease (96%) and only 16% having graft involvement.
28 In addition, another prognostic score, the PTLD Prognostic Index, is a variation of the IPI with baseline factors of age, ECOG performance status and LDH.
· Management of PTLD
Given the rarity of the diagnosis and the histological heterogeneity together with the medical complexity of the patients, there are no data available from randomised trials to inform management.
For the rarer subtypes and in the relapsed/refractory setting, treatment decisions are informed by small case series and case reports.
For the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL), there are robust data from prospective phase II studies that have informed existing treatment algorithms.
For the commonest monomorphic subtype, diffuse large B-cell lymphoma (DLBCL), there are robust data from prospective phase II studies that have informed existing treatment algorithms. 23,24
· Reduction of immunosuppression
Where safe to do so, immediate reduction in immunosuppression (RIS) should be instituted under the direction of the transplant team.
Where RIS is being considered as the sole initial treatment, response should be assessed within 2–4 weeks so that alternative strategies can be promptly initiated in those patients that fail to respond.
The response to RIS was assessed early between two and four weeks and failure of RIS was followed by sequential treatment with rituximab and subsequently by CHOP chemotherapy in adult B-cell PTLD.
RIS should be considered in conjunction with other therapies, in patients who have risk factors which include clinically aggressive PTLD Ann Arbor stage ≥III, elevated LDH and more than one extra-nodal site or a high-risk IPI.
Disease response assessment is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond .
· Or withdrawal of all immunosuppressant drugs except for corticosteroids
CNIs, calcineurin inhibitors; MMF, mycophenolate mofetil; PTLD, post-transplantation lymphoproliferative disease; RIS, reduction in immunosuppression; SWOG, Southwest Oncology Group.
ASCT, autologous stem cell transplant; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; G-CSF, granulocyte-colony stimulating factor; IPI, international prognostic index; IV, intravenous; PJP, Pneumocystis jirovecii; PR, partial remission; RIS, reduction of immunosuppresion; PTLD, post-transplantation lymphoproliferative disease; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone.
47% at 27!5 months (R) CHOP, (Rituximab) cyclophosphamide, doxorubicin, vincristine, prednisolone; CR/CRu, complete remission/response/unconfirmed complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival; PR, partial remission; PTLD, post-transplantation lymphoproliferative disease.
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials.
· Therapy for relapsed or refractory PTLD
There are no prospective data to guide the treatment of patients with refractory or relapsed (R/R) PTLD.
76–78 In patients who are unresponsive to rituximab, using R-CHOP is a reasonable and logical approach.
23,24,79 A sequential approach as in front-line therapy can be considered if relapse post rituximab monotherapy occurs late.
Patients with R/R PTLD post R-CHOP have a poor longterm survival with OS < 20% as conventional salvage approaches with consolidation autologous stem cell transplantation (ASCT) are challenging to deliver in SOT patients.
78,79 Extrapolating treatments from R/R DLBCL in immunocompetent patients is reasonable 80–83 but this approach has little evidence in R/R PTLD.
Particular attention should be paid to the toxicities of salvage chemotherapy in relation to the underlying SOT and patient comorbidities.
Patients should be offered enrolment in a clinical trial where available
· Adoptive immunotherapy
EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy potentially offers another approach in the treatment of EBV-.
Autologous or allogeneic EBV-directed CTLs should be considered in patients with R/R EBV-positive.
89 This is similar to the results demonstrated by Prockop et al where a 54% ORR in 13 PTLD patients who were refractory to rituximab was reported.
Trials using CTL for PTLD are small, but the results appear promising and the recent development of chimaeric antigen receptor (CAR)-T cells reported for B-cell malignancies 91,92 suggests that this technology could have a future role in the treatment of PTLD.
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
Peripheral T-cell lymphomas (PTCL) are a rare form of PTLD
They typically occur later after SOT and are often associated with poor outcome.
· Hodgkin lymphoma PTLD
Classical Hodgkin lymphoma-type PTLD (HL-PTLD) is rare and data on optimal therapy are lacking.
Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate (HD-MTX) with rituximab, is the standard for immunocompetent primary CNS lymphoma 113,114 but may be challenging to administer safely due to comorbidities, typically renal failure or SOT dysfunction in CNS-PTLD patients.
This approach has been adopted in CNS-PTLD patients with some success.
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD.
· Supportive care
Significant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection. 42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group.
Significant TRM has been described in patients with PTLD treated with combination immunochemotherapy, with reports of up to 50% mortality following infection.
42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group.
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered.
116,117 Age is an important risk factor for developing FN which can partly be prevented by G-CSF.
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered. 116,117 Age is an important risk factor for developing FN which can partly be prevented by G-CSF. 116,117
· Findings
EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years. 6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD.
EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.
6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD.
43–45 Treatment-related mortality (TRM) was reduced to 13% compared to retrospective case series with front-line CHOP therapy which documented TRMs of up to.
Limited disease Reduction by 25% of all immunosuppression not critically ill Reduction of CNIs by 50%.
Reduction of CNIs by 50% and further reduction by 50% if not in complete remission by day 14.
Reduce glucocorticoids by 50%, with a lower limit of prednisone of.
Reduce CNIs by 50% and maintain steriods.
With reports of up to 50% mortality following infection.
With reports of up to 50% mortality following infection. 42,53 It is appropriate to use G-CSF as primary prophylaxis in this patient group
· Given the degree of immunosuppression in patients withPTLD, strong consideration should be given to antibiotic, antifungal and antiviral prophylaxis during therapy, if treatment is associated with neutropenia as per local protocols.
Prophylaxis with co-trimoxazole or equivalent should be considered in all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia.
Surveillance for CMV infections should continue in patients with PTLD with guidance from the transplant physician or team.
Patients with past hepatitis B or C infection should be managed in conjunction with a hepatologist.
118 Regular monitoring of liver function is required through treatment, and monitoring of hepatitis B viral load should be considered as per the guidance outlined by NICE CG165 118 or as directed by the hepatologist.
Patients with HIV should be managed under joint care with their HIV physician
Front-line management of the post-transplantation lymphoproliferative disorder in adult solid organ recipient patients — A British Society for Haematology Guideline
Introduction:
this document is an updated guideline and details the recommendations for the front-line management of adult patients with an established diagnosis of post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation (SOT).
Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.
PTLD is a common malignancy after skin cancer and is associated with a significant cancer-related mortality
The majority of cases in the western world are derived from B lymphocytes and are Epstein–Barr virus (EBV)-associated, particularly in the first year post-SOT. EBV-negative cases account for approximately 20–40% of PTLD and usually occur after the first year of transplantation, with a second peak of incidence occurring at 10 years.6,7 In the adult population, recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%) followed by lung transplants, heart, liver transplants, pancreatic transplants, and renal transplant recipients having the lowest incidence of PTLD (up to 2.5%).
Diagnosis and staging:
>Recommendations: – Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A).
– Staging with a CT is recommended in all patients where PET-CT is not available (1A).
– Where available a PET-CT should be utilized for staging in line with the recommendation for FDG-avid lymphoma (1B).
> Categories of PTLD:
– Non-destructive Encompasses plasmacytic hyperplasia, lymphocytes representing infectious mononucleosis-like changes and florid follicular hyperplasia. Most cases are EBV-associated and usually present as early PTLD
– Polymorphic A spectrum of B-cell maturation stages with admixture of T cells, EBV-associated in >90% cases
– Monomorphic Classified according to the lymphoma sub-type they resemble, comprising 60–80% of PTLD; diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, plasma cell myeloma, plasmacytoma. Much less commonly indolent B-cell lymphomas, usually mucosa-associated lymphoid tissue lymphoma and T-cell neoplasms are diagnosed Monomorphic PTLD can be EBV-negative. Approximately 70% of these lesions are reported to have cytogenetic abnormalities, including trisomy 9 and 11 or both, loss of 17p and rearrangement of 8q24 (MYC)
– Classical Hodgkin Lymphoma Morphologically this fulfils the conventional criteria for the diagnosis of classical Hodgkin lymphoma and is generally (>90%) associated with EBV
>baseline investigations:
– Full blood count, Electrolytes, Renal function, Glucose, Liver enzymes, Urate, Lactate dehydrogenase (LDH) Virology: HIV type 1 & 2, Hepatitis B and C and EBV serology, CMV/EBV DNA titers
– Bone marrow biopsy is indicated and for some selected patients it may not be clinically needed or appropriate
> All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
> All diagnostic material should be reviewed by a hematopathologist(1A).
Management of PTLD:
Recommendations:
1st line – Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B).
– Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B).
> if an Extensive disease or critically ill, stop all agents except for maintaining prednisolone 7.5/10 mg/day.
2nd line -Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B).
-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 (1B). ” Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B).
-Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B).
– Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B).
– PET-CT should be considered for interim and end-of-treatment response assessment where available (1C).
3rd line-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C).
– In localized disease, radiotherapy may be offered concurrently with RIS (2C).
– Treatment with anti-viral agents and/or arginine butyrate, IVIG, and IFN alpha is not recommended outside clinical trials (1C)
Adoptive immunotherapy– Patients who relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B).
– Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C).
– Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C).
Post-transplant lymphoproliferative disease affecting the central nervous system
-It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C)
–Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C).
– Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C).
–Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C).
– Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C).
Supportive care
Prophylactic administration of G-CSF if the risk of febrile neutropenia (FN) is >20% for all planned cycles of treatment should be considered
strong consideration should be given to antibiotic, antifungal (e.g. fluconazole) and antiviral (e.g. acyclovir) prophylaxis during therapy, particularly if treatment is associated with neutropenia as per local protocols. Prophylaxis with co-trimoxazole or equivalent should be considered in all patients and especially in those with a past history of Pneumocystis jirovecii pneumonia (PJP). Surveillance for CMV infections should continue in patients with PTLD with guidance from the transplant physician or team.
Re-transplantation
-Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C).
What do you mean by ‘a longer period may be needed’?
You have used too much of bold, italics and underline at the same time in your write-up just before ‘management’ heading.
Is one year wait enough? What is the current practice in your department or in your region?
The article deals with British Society of Hematology guidelines for management of post transplant lymphoproliferative disorder (PTLD) in adult sold organ transplant (SOT) patients.
Introduction:
PTLD consists of 21% of all cancers in SOT recipients, derived mainly by B cells, and could be either Epstein-Barr virus (EBV) associated (60-80% within first year post-transplant) or EBV-negative (20-40% occurring after first year and later at 10 year post-transplant). PTLD incidence is most common in multiorgan and intestinal transplant with least incidence in renal transplants.
4 histopathological categories of PTLD include non-destructive, polymorphic, monomorphic, and classical Hodgkin’s lymphoma.
Diagnosis and Staging: A biopsy (excisional or incisional) is recommended for diagnosing PTLD. Staging with a computed tomogram (CT) of neck chest, abdomen and pelvis is recommended and PET-CT (positron emission tomography – CT) should be utilized, if available. Once diagnosed, patients should undergo detailed baseline evaluation including detailed history, current medication regimen details, and lab tests including full blood count, electrolytes, renal function and liver function tests, lactate dehydrogenase (LDH), and virology (hepatitis B, Hepatitis C, HIV, cytomegalovirus – CMV, EBV DNA tires, EBV serology). Echocardiography and fertility preserving treatments should be done as per clinical status of the patient. Cardiac and renal function assessment is required in patients. PET-CT should be used for interim and end-of treatment assessment, if available.
Management of PTLD: It should involve a multidisciplinary approach including transplant physician, hemato-oncologist, hematopathologist, radiologist and radiation-oncologist. Treatment involves reduction of immunosuppression (RIS), rituximab, chemotherapy and other measures.
B cell PTLD
RIS: For early lesion, low-stage and non-bulky disease, RSI in form of stopping antimetabolite, reducing calcineurin inhibitor dose by 30-50%, and continuing steroids is done. The patient is monitored for next 2-4 weeks and no other treatment id required if complete remission achieved.
Riruximab: In case of partial remission/ no response to RIS in CD20-positive B cell PTLD, or aggressive Ann Arbor stage III or IV, elevated LDH, or extra-nodal site or high-risk IPI (international prognostic index), 4 weekly cycles of injection Rituximab 375 mg/m2 are given. In case complete remission is achieved, 4 more cycles of rituximab are given 3 weekly.
Chemotherapy: In case complete remission is not achieved with rituximab alone, or if the disease progressed, chemotherapy in form of R-CHOP 21 (Doxorubicin, cyclophosphamide, vincristine, and prednisolone) every 3 weeks for 4 cycles should be given. It should be accompanied by GCSF (Granulocyte colony stimulating factor) and pneumocystis jirovecii prophylaxis.
Radiotherapy: It can be used for treating PTLD involving orbit, isolated central nervous system (CNS), or localized extra-nodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT). In nasal natural killer/ T-cell lymphoma, radiotherapy and chemotherapy can be combined.
Antivirals, Intravenous immunoglobulin (IVIG), interferon anlpha and arginine butyrate are not recommended outside clinical trials.
Relapse/ refractory PTLD: sequential approach for intensive second-line chemotherapy followed by autologous stem cell transplant (if a good remission is achieved) can be used for relapse. Enrolment in clinical trials should be offered for refractory patients.
Adoptive immunotherapy: EBV specific cytotoxic T lymphocyte (CTL) can be used in relapsed/ refractory EBV positive PTLD.
Burkitt lymphoma like PTLD: R-CHOP with RIS, or EPOCH-R (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and rituximab) can be used.
Plasmablastic and plasma-cell myeloma PTLD: RIS with treatment as for plasmacytoid dyscrasia disease.
T-cell lymphoma PTLD: Treatment involves RIS and chemotherapy.
Hodgkin lymphoma PTLD: RIS with chemotherapy – ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy will be required.
Extranodal marginal zone lymphoma PTLD: RIS with rituximab with or without radiotherapy.
CNS PTLD: RIS, intrathecal chemotherapy (with or without rituximab) and whole-brain radiotherapy can be used. Local radiotherapy with or without corticosteroids can be used. EBV-specific CTLs can also been used, if available.
Re-transplantation: Risk of recurrence is low, hence retransplant can be offered after minimum 1 year of remission, but a longer period is needed. Avoid antithymocyte globulin induction in re-transplant.
WHat do you mean by ‘a longer period may be needed’?
Is one year wait enough? What is the current practice in your department or in your region?
Thank you Professor.
A longer period means waiting upto 2 years.
We have never undertaken any patient with PTLD for re-transplant. I have based my comment on the article on PTLD.
Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46. doi: 10.5500/wjt.v10.i2.29. PMID: 32226769; PMCID: PMC7093305.
Front-line management of the post-transplantation lymphoproliferative disorder in adult solid organ recipient patients- A British Society for hematology Guideline.
Summary:
In solid organ transplant, the PTLD is more common second to skin cancer, and represent 21% of all cancers, compared to 4-5% in the immunocompetent population.
PTLD associated with significant mortality.
Occur as early as within one year and as late as 10 years, and mostly derived from B-lymphocytes, and EBV associated.
Incidence is rated as follows:
Histological diagnosis:
Base-line investigation:
Recommendations:
Management of PTLD:
Recommendation:
Recommendation:
Radiotherapy:
Retrospective analysis suggests that adults with the limited-stage disease, whatever histological subtype, can remit completely after surgical resection, or radiotherapy, usually with RIS.
Antiviral, IVIG, and INF-alpha:
No demonstrative data to suggest a benefit of use.
Recommendation:
Therapy for relapse or refractory PTLD:
Adoptive immunotherapy:
EBV-CT-lymphocyte immunotherapy offers another approach to the treatment of EBV-positive PTLD, utilizing either the recipient’s own cells or HLA-matched ones.
Recommendation:
Burkitt lymphoma-like PTLD:
T-cell lymphoma PTLD:
Hodgkin lymphoma PTLD:
HL-PTLD regimen includes combination chemotherapy with ABVD with or without radiotherapy along with RIS.
Central nervous system affection PTLD:
Recommendation:
That is an excellent summary and very well structured reply.
You have used too much of bold, italics and underline at the same time in your write-up. Typing in bold or capitals amounts to shouting!
What is your analysis of level of evidence of this study?
Introduction
Lymphoproliferative disorders is prevelant in recioient ofSolid organ transplantation (SOT )account for 21% of all cancers SOT recipients, as compared with 4–5% within the immunocompetent population and they are associated with a significant cancer-related mortality.The reported incidence varies according to patient age, transplant type and the degree of immunosuppression being highest in intestinal transplant { up to 20 % )and lowest in renal transplant ( 0.8-2.5%). most of PTLD cases are associated with EPV and derived from B lymphocyte lineage
Diagnosis and staging
Diagnosis :In order to diagnose a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
If not possible , a core needle biopsy is an alternative
Staging with PET-CT is recommended
if not available a CT is recommended in all patients
management
MDT including hematologist, haematopathologist, nephrologist and oncologist
immunosuppression modulation by
· stopping antimetabolites (azathioprine and MMF) and
· reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids
· this is indicated for all patient with close observation of the graft function
· response to be evaluated from 2- 4 weeks for complete remission ( CR) or not to take decision for 2nd line introduction
if there is no CR
for patients who are CD20 positve ” Rituximab monotherapy is recommended as 375 mg/m2 weekly for 4 weeks with 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 ”
if there is failure to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles Four cycles of R-CHOP-21 immunochemotherapy are recommended (1B).
For aggressive lymphoma or critical organ affection both immunosuppression reduction with ” Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended .
· consider chemotherapy side effects and graft function
if there is relapse after CHOP consider intensive therapy like second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved
in patients with EBV positive PTLD consider EBV specific cytotoxic T lymphocytes
for less common form of PTLD including : Burkitt lymphoma-like PTLD, Plasmablastic and plasma-cell myeloma PTLD, T-cell lymphoma PTLD, Hodgkin lymphoma PTLD and Extra-nodal marginal zone lymphoma – PTLD should underwent reduction of IS in addition to same line of management of non transplanted patients
· for PT:D affecting central nervous system : according to clinical presentation , either RIS followed by combination of RTx with chemotherapy or use both at same time in clinically relevant cases
Supportive care
Antibiotic
Antifungal
G- CSF
Prophylaxis for PJP by using cotrimoxazole
Surveillance for CMV, HBv viral load
Seeking consultation for related specialties during treatment
Retransplantation
Wait for 1 year or more according to evaluation
Is one year wait enough? What do you mean by ‘or more’? What is the current practice in your department or in your region?
Summary of recommendations of the British society of hematology:
1- Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis. core needle biopsy is an alternative.
2- Staging using CT scan if PECT-CT is not available
3- When available, PET-CT scan is used for staging in line with the recommendation of FDG-avid lymphoma.
4- PET-CT should be considered for interim and end of treatment response assessment where available
1- All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians.
2- Reduction of immunotherapy (RIS):
3- NON-responder to RIS:
3- Other treatment modalities:
4- Therapy for refractory or relapsing PTLD:
5- Less common forms of PTLD (Burkitt lymphoma, plasma cell lymphoma, T cell lymphoma, HL):
6- Supportive therapy:
7- Re-transplantation:
I wish you could type heading in bold or underline or in italics. That would make it easier to read. WHat do you mean by ‘a longer period may be needed’?
Is one year wait enough? What is the current practice in your department or in your region?
I- it should be clear that it is not my own word, it is the recommendations of the British society of hematology.
II- I don not remember that we did re-transplant or patient with previous lymphoma
But according to the review published by Dr. Halawa:
Time to re-transplant: Approximately two years of time should elapse after successful PTLD management.
ref:
1- Abbas F, El Kossi M, Shaheen IS, Sharma A, Halawa A. Post-transplantation lymphoproliferative disorders: Current concepts and future therapeutic approaches. World J Transplant. 2020 Feb 28;10(2):29-46.
Please summarise this article
This is an updated British society for haematology guidelines (2021) for the front-line management of adult patients with an established diagnosis PTLD following SOT
PTLD account for 21% of all cancers of SOT recipients (4–5% in the immunocompetent)
In the adults, multiorgan and intestinal transplants have the highest incidence of PTLD (20%)
Histopathological categories of PTLD
1. Non-destructive
2. Polymorphic
3. Monomorphic
4. Classical Hodgkin Lymphoma
Diagnosis and staging
A comprehensive pre-treatment evaluation is required
A tissue diagnosis accompanied by clinical information including the date of transplant, immune suppression regimen and organ type
Staging should be recorded using the Ann Arbor classification or the Lugano classification which is the recommended classification for staging following PET-CT in 18F-fluorodeoxyglucose -avid (FDG-avid) nodal lymphomas
PET-CT in the staging of PTLD is less well defined when compared to lymphoma in the immunocompetent
MRI or CT imaging of the brain, orbits and sinuses is recommended for patients with suspected central CNS or craniofacial disease
Diagnostic LP for CSF analysis, including cytology and flow cytometry, is recommended for patients with suspected CNS involvement
Surgical excisional or incisional biopsy is recommended where possible for diagnosis. Where this is not possible, a core needle biopsy is an alternative (1A)
Where PET-CT is not available, staging with a CT is recommended in all patients, (1A)
A staging PET-CT, where available, should be performed in line with recommendations for FDG-avid lymphomas in the immunocompetent patients (1B)
Multidisciplinary approach to care
A management plan should be agreed by a MDT which should include transplant physicians, haemato-oncologists, haematopathologists, radiation-oncologists and radiologists (in line with the 2016 NICE guideline (NG47), ‘Haematological cancers: improving outcomes)
Consider the patient’s general health, the histological subtypes, clinical stage, the SOT function, the degree of immunosuppression, and the modalities of therapy available
All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A)
All diagnostic material should be reviewed by a haematopathologist (1A)
Prognostic scoring
There is no universally accepted prognostic scoring system specific for PTLD
Poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH and hypoalbuminaemia
IPI score for non-Hodgkin lymphoma: age, stage of disease, EGOG performance status, extra-nodal site involvement and LDH. Low (0, 1, 2 points) and high is (3, 4, 5 points). Has a significant effect on overall survival (OS) and treatment-related mortality, but did not have an effect on progression-free survival (PFS)
A low IPI risk (0–2 points) exhibiting a superior OS compared to high IPI risk (≥3 points) at three years (OS 78% vs 54%, respectively)
The PTLD Prognostic Index: a variation of the IPI (age, ECOG performance status and LDH)
The IPI is a pragmatic choice of up-front score to use
Management of PTLD
Reduction of immunosuppression (RIS)
For low-risk patients early lesions, low-stage disease and non-bulky disease
Response should be assessed within 2–4 weeks.
Close monitoring for rejection is crucial in these patients who are in complete remission and maintained at RIS
PR by RIS alone can either be monitored and reassessed within a further 2–4 weeks or further rituximab-based treatment may be considered
RIS should be considered in conjunction with other therapies, in patients who have risk factors (clinically aggressive PTLD Ann Arbor stage ≥III, elevated LDH and more than one extra-nodal site or a high-risk IPI)
RIS by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function (1B)
Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond (1B)
Rituximab +/-chemotherapy
Front-line therapy for monomorphic CD20-positive B-cell PTLD
RIS and if denotes a complete remission, watch and wait
If no response to RIS, 4 weekly 375 mg m2 rituximab iv. If CR or CMR occurred, 4*3-weekly 375 mg m2 rituximab iv. If no CR or CMR, 4 cycles of CHOP-21
Polymorphic CD20-positive B-cell PTLD
Treated with the same as monomorphic CD20-positive B-cell PTLD
Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy (1B)
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 (1B)
Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR (with Deauville ≤ 3) after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles (1B)
Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise (1B)
Formal assessment of cardiac and renal function should be undertaken in all patients with SOT or in patients where renal or cardiac impairment is suspected (1B)
Radiotherapy
Radiotherapy may be considered for some extra-nodal sites, such as the orbit, isolated CNS relapse and is an effective therapy in localised extra-nodal marginal zone lymphomas of the MALT type
Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes (2C)
In localised disease, radiotherapy may be offered concurrently with RIS (2C)
Antivirals, intravenous immunoglobulin and interferon-alpha treatment
Treatment with anti-viral agents and/or arginine butyrate, IVIG and IFNa is not recommended outside clinical trials (1C)
Relapsed or refractory PTLD therapy (R/R)
No data to guide management
Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved (2B)
Patients with relapsed/refractory PTLD should be offered clinical trials where available (1C)
Adoptive immunotherapy
Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD (1C)
An overall response rate (ORR) was 52% in 33 patients who had failed initial therapy
Burkitt lymphoma-like PTLD
R-CHOP with concurrent RIS could be considered for Burkitt-like PTLD (as in diffuse large B-cell lymphoma in the immunocompetent patient)
The CNS should always be assessed for overt or occult involvement at baseline and CNS prophylaxis should be strongly considered
Plasmablastic and plasma-cell myeloma PTLD
No data; treat as for the plasmacytoid dyscrasia disease in the immunocompetent
T-cell lymphoma PTLD (PTCL)
Rare, occur later and are often associated with poor outcome
RIS with anthracycline-based chemotherapy (in patients with adequate cardiac function)
Hodgkin lymphoma PTLD
It is Rare. Standard combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy
Extra-nodal marginal zone lymphoma – PTLD
The predominant site of involvement of MALT lymphoma is gastric (skin, colonic and small-bowel are rare)
Treatment options include RIS, rituximab and radiotherapy
PTLD affecting the CNS
The risk of CNS lymphoma is between 10 and 20% of PTLD
Typically monomorphic, high grade B-cell lymphoma and all are EBV-positive
Usually multifocal and detectable by MRI but tissue biopsy is recommended given that opportunistic infections may present with similar radiological findings
The overall prognosis is poor
Treatment is RIS, radiotherapy and intrathecal chemotherapy
Systemic chemotherapy with CNS penetration, such as regimes including high-dose methotrexate (HDMTX) with rituximab, is the standard for immunocompetent primary CNS lymphoma (challenging here)
Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity (1C)
Local radiotherapy +/-corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD (2C)
Where available EBV-specific CTL can be considered for EBV-positive CNS-PTLD (1C)
It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management (1C)
Treatment of less common forms of PTLD with standard-of-care therapies as per the algorithms outside the PTLD setting may be offered with caution due to potential toxicity and patient comorbidity (2C)
Supportive care
G-CSF is recommended for patients receiving chemotherapy and PJP prophylaxis should be offered to all patients with diagnosis of PTLD (1B)
Re-transplantation
Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed (2C)
That is a very detailed summary and very well structured reply.
I wish you could type sub-heading under the heading of Diagnosis and Staging in bold or underline or in italics. That would make it easier to read.
Is one year wait enough? What is the current practice in your department or in your region?
Thank you Prof. Ajay
2 years
INTRODUCTION;.
-Lymphoproliferative disorders account for 21% of all cancers of SOT recipients, as compared with 4–5% within the immunocompetent population.
-PTLD is a common malignancy after skin cancer and is associated with a significant cancer-related mortality.
-Recipients of multiorgan and intestinal transplants have the highest incidence of PTLD (up to 20%).
DIAGNOSIS;.
–Where possible a surgical excisional or incisional biopsy is recommended to establish a diagnosis.
-Where this is not possible, a core needle biopsy is an alternative.
-Staging with a CT is recommended in all patients where PET-CT is not available.
-End-of-treatment PET-CT appears to have moderate sensitivity (71%) and specificity (73%) for predicting relapse but a higher negative predictive value of 92%.
MANAGEMENT OF PTLD;.
-Immediate reduction in immunosuppression (RIS).
-Close monitoring for rejection.
-Reduction in immunosuppression by stopping azathioprine and MMF and reduction of CNIs by 30–50% whilst maintaining or reducing corticosteroids, is recommended in all patients whenever possible, under the guidance of the transplant physician with surveillance of graft function.
-Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment can be initiated in those that fail to respond.
-Rituximab monotherapy is recommended for patients with CD20-positive PTLD who fail to respond adequately to RIS as initial therapy.
-Four further three-weekly cycles of rituximab are recommended in patients who obtain CR or complete metabolic remission (CMR) after four cycles of weekly standard-dose rituximab.
-Four cycles of R-CHOP-21 immunochemotherapy are recommended in patients who fail to obtain CR or CMR after four cycles of weekly standard-dose rituximab or who clinically progress during these four cycles.
–Rituximab plus anthracycline-based therapy (typically R-CHOP-21) is recommended with RIS for patients at any time following diagnosis with clinically aggressive lymphoma with critical organ compromise.
-Involved-field radiotherapy may be offered for selected patients with PTLD in line with standard protocols for specific histological subtypes.
-Patients that relapse post-R-CHOP should be carefully selected for intensive second-line chemotherapy followed by autologous stem cell transplant if a good remission is achieved.
-Treatment of PTLD with EBV-specific CTLs should be considered where available with R/R EBV-positive PTLD.
-Patients with relapsed/refractory PTLD should be offered clinical trials where available.
-It is recommended that all patients with the less common forms of PTLD be considered for RIS as part of their initial management.
-Patients with CNS-PTLD should be offered treatment with RIS (it may not always be possible to wait for response to initial RIS before embarking on secondary therapy) followed by combination chemotherapy with rituximab in suitable patients depending on adequate organ function and comorbidity.
-Local radiotherapy +/- corticosteroids with RIS where fitness and comorbidity are limiting factors may be offered in CNS-PTLD.
–G-CSF is recommended for patients receiving chemotherapy.
–PJP prophylaxis should be offered to all patients with diagnosis of PTLD.
–Re-transplantation is dictated by clinical need and organ type. A minimum of one year may be considered before re-transplantation, but a longer period may be needed.
That is a very detailed summary and very well structured reply.
Is one year wait enough? What is the current practice in your department or in your region?
Thanks so much Prof,Ajay
-The ideal time gap between PTLD remission and listing for retransplantation is not clear.
-The British Transplantation Society guidelines recommend a period of at least 1 year from the control of PTLD to retransplantation to minimize the risk of PTLD recurrence,
-In our Practice;patient may underwent for a second kidney transplantataion surgery after 2-3 years from having achieved complete remission of PTLD.and after clearance from Hematology & Oncology.
Introduction
PTLD is the second most common malignancy after skin cancer in solid organ recipients. It accounts for 21% of all malignancy in solid organ recipients in comparison to 4-5% in general population. Its incidence depends on the patient’s age, type of organ transplanted and level of immunosuppression. Majority of the cases are B cell derived associated with EBV and occur in the first year post-transplant. However EBV negative PTLD though rare can occur after 1 year post-transplant and a second peak seen 10 years post.
Diagnosis and staging
Excisional biopsy required where possible to make a diagnosis, core biopsy may be done in instances an excision biopsy not feasible.
Staging should be done via the Ann Arbor or Lugano staging.
Where possible a PET scan should be done for staging for it is able to detect sites that could be missed with a CT scan.
CT scan neck, chest, abdomen and pelvis should be done at diagnosis to determine treatment and for a possible baseline to determine response to treatment.
Patients with possible CNS involvement require MRI/CT brain, sinuses and orbit, a lumbar puncture with CSF analysis for flow cytometry and cytology should also be done.
Prognosis
No universally accepted scoring system.
Poor prognostic factors include:
Treatment
Multidisciplinary approach.
1.Reduced immunosuppression.
Only required treatment in low risk patients (early lesions, non-bulky and low stage disease). Asses in 2-4 weeks. Those who have achieved complete remission no need for further treatment. Partial remission can wait further for another 2-4 weeks or can add rituximab.
How to reduce varies per guidelines. American guidelines recommended 25% reduction for limited disease of all immunosuppression. Extensive disease and not critically ill 50% reduction of CNI, withdrawal of antimetabolite and maintenance of steroids at 7.5-10mg/day. Extensive disease and critically ill withdrawal of all and maintaining only on steroids 7.5-10mg/day.
European guidelines have almost similar recommendation.
Close monitoring of the graft to avoid rejection.
2.Rituximab
Front line for monomorphic CD20+ B cell PTLD which is the component form.
Patients unresponsive to reduced immunosuppression should receive 4 weekly cycles of Rituximab.
Patients who achieve complete remission are considered low risk and should receive further 3 weekly doses of rituximab.
Patients who fail to achieve remission are considered high risk and switched to 4 cycles R-CHOP with mandatory PJP prophylaxis and G-CSF.
3.Radiotherapy
Role undefined.
Maybe considered for localised monomorphic or Hodgkins lymphoma combined with reduced immunosuppression.
Maybe considered for extra-nodal sites eg the orbits and exclusive CNS relapse.
Effective treatment for MALT.
Rare forms of PTLD can be incorporated with chemotherapy.
Dose and fractional regimen are like those of normal lymphoma.
4.Other treatments
There is paucity of data on the use of antivirals, intravenous immunoglobulin and intravenous alpha interferon.
Treatment for relapsed or refractory
Patients who relapse after R-CHOP have a poor longterm survival.
They should be offered second line chemotherapy followed by autologous stem cell transplantation where feasible.
There is a role of adaptive immunotherapy where donor EBV specific cytotoxic T lymphocytes are infused in the recipient; where they induce a T cell mediated immune response to the abnormal B cells.
Supportive care
Due to high rate of treatment related mortality supportive care should be offered to all patients on immunochemotherapy.
Prophylaxis with G-CSF should be offered if the patient is at risk of febrile neutropenia.
Other prophylactic treatments include antibiotics, antiviral and antifungals.
Co-trimoxazole for PJP prophylaxis should be offered to all.
Patients with HIV/HCV/HIV should be closely monitored.
Re-transplantation.
Risk of recurrence is low after successful control of PTLD.
Timing depends on clinical need and the organ type.
Minimum wait period of 1 year should be considered however longer wait period maybe required.
That is a very detailed summary and very well structured reply.
Is one year wait enough? What is the current practice in your department or in your region?
Thank you.
In my region prevalence of PTLD is low thus not much experience.
One year maybe a short duration, maybe a wait period of 2 years would be adequate.
Is one year wait enough? What is the current practice in your department or in your region?
Introduction:
PTLD is the second most common post transplant malignancy, and it associated with significant cancer related mortality. Its incidence differs according patient`s age, transplant type & intensity of immunosuppression. Most PTLD cases associated with EBV infection, which is prevalent in first year post transplantation. About 20-40% of PTLD case are not associated with EBV infection with peak incidence after 10 years post transplantation.
PTLD incidence higher in multi-organ transplant(20%) followed by lung transplant(3-10%), heart transplant(2-8%), liver transplant(1-5.5%), pancreatic transplant(0.5-5%) and renal transplant(0.8-2.5%).
PTLD subtypes include: non destructive, polymorphic, monomorphic & classical Hodgkin lymphoma.
Diagnosis:
Adverse risk factors in prognostic scoring system:
PTLD treatment:
3.Radiotherapy: May be considered for some extra nodal sites (orbit), isolated CNS relapse & MALToma.
4.Antiviral, IVIG & INT-alpha treatment: not recommended outside clinical trials.
Treatment of relapsed PTLD:
Treatment of less common PTLD forms:
Thank you. We usually wait for 2 years after completing clearance before retransplantation
Introduction:
Diagnosis and staging:
o Relevant clinical information; the date of transplant, IS regimen and organ type.
o Tissue biopsy ( preferred excisional) are recommended to enable accurate PTLD sub-classification.
o Comprehensive pre-treatment evaluation.
o Accurate staging and response assessments are crucial for patient management.
o Staging using PET-CT and if not available CT
o Using Ann Arbor classification.
o If CNS- involvement suspected: consider brain/ orbit and sinuses CT or MRI with CSF analysis.
-PTLDs are sub-classified histopathological into; Non-destructive, Polymorphic, Monomorphic and Classical Hodgkin Lymphoma
Management of PTLD:
Multidisciplinary approach to care
· All cases should be discussed at a haemato-oncology MDT meeting with experience in PTLD management, with input from the organ transplant physicians (1A).
Reduction of immunosuppression RIS:
– Stopping azathioprine and MMF
– Reduction of CNIs by 30–50%
– Maintaining or reducing corticosteroids, is recommended in all patients whenever possible.
· Close monitoring for rejection.
· Early disease response assessment (at 2–4 weeks) by CT.
– If patient achieve CR; keep monitoring.
– If PR achieved or in those that fail to respond; further treatment needed.
· For high risk individuals RIS in conjunction with other therapies.
Rituximab +/# chemotherapy
Front-line therapy for monomorphic CD20-positive B-cell PTLD: The commonest form
Polymorphic CD20-positive B-cell PTLD:
Radiotherapy:
Antivirals, IVIG and interferon-alpha treatment: Data are limited and is not recommended outside clinical trials.
Therapy for relapsed or refractory R/R PTLD:
Adoptive immunotherapy:
EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy:
Burkitt lymphoma-like PTLD
Plasmablastic and plasma-cell myeloma PTLD;
T-cell lymphoma PTLD
Hodgkin lymphoma PTLD:
Extra-nodal marginal zone lymphoma – PTLD
PTLD affecting the CNS.
Supportive care:
Re-transplantation
Thank you. We usually wait for 2 years after completing clearance before retransplantation
Introduction
Lymphoproliferative disorders represent 21% of all cancers of SOT recipients.
Post-transplant lymphoproliferative disease occur due to lymphoid proliferations caused by immunosuppression after SOT.
PTLD commonly occurs after skin cancer with high mortality rate ,it can develop early or late after transplantation but it’s highest incidence of occurrence is with multiorgan or intestinal transplantation ,followed by lung transplant ,then heart transplant ,then liver transplant then pancreatic transplant then the smallest incidence is with renal transplant.
PTLD is derived from B lymphocyte and is associated with EBV
Diagnosis and staging
PTLD is divided into 4 histopathological categories which are non destructive, poly morphic ,monomorphic and classical Hodgkin lymphoma.
Diagnosis is difficult and staging requires using the Ann Arbor classification or the Lugano classification for staging lymphomas although using PETCT for PTLD staging is less well defined in comparison to lymphoma.
In fact PETCT has beneficial role in PTLD diagnosing , staging ,detecting new involved sites and post treatment relapse to some extent.
For cases with possible CNS involvement MRI ,CT imaging and CSF analysis will be needed.
-Surgical excisional or incisional biopsy is needed for diagnosis (alternative core needle biopsy) and PET CT is needed (alternative is CT ) for staging
Multidisciplinary care
(MDT) need to involve transplant physicians, haemato-oncologists, haematopathologists,
radiation-oncologists and radiologists.
Prognostic scoring
There is not a standardised prognostic scoring for PTLD ,however some ominous risk factors were acknowledged involving including poor performance status, EBV-negative tumour, graft involvement, monomorphic histology, older age, CNS or bone marrow involvement, raised LDH and hypoalbuminaemia.
PTLD management
Reduction of Immunosuppression(RIS)
Can be done if applicable under transplant team supervision, representing the only therapy for low risk early stage disease, along with follow up for 2-4 weeks because in case of failure to reach complete remission , alternative treatment can be started in addition to close monitoring of rejection.
Cases who reached partial remission with RIS can either followed and be reassessed within 2-4 weeks or rituximab based therapy can be started.
There are American, SWOG and European Renal Guidelines for RIS.
It is recommended to RIS by stopping azathioprine and MMF ,decreasing CNIs to 30–50% and maintaining or reducing corticosteroids also early disease assessment is adviced for cases on RIS onlt in order to start alternative treatment soon if RIS alone failed.
Rituximab +/- chemotherapy
– Monomorphic CD20-positive B-cell PTLD which is the most common PTLD forum.
Rituximab is used for treatment of polymorphic PTLD, or monomorphic DLBCL-like PTLD, unresponsive to initial RIS.
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wasnot achieved —4 cycles of CHOP21
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If RIS failed —-4 weekly IV Rituximab will be given —-If CR
was achieved—4X 3weekly IV Rituximab
A trial that used sequential 4 cycles of weekly IV Rituximab, followed by four cycles of standard-dose CHOP-21 chemotherapy every 21 days with GCSF and prophylaxis against PJP demonstrated better outcomes than using Rituximab alone also TRM was less in R-CHOP21 group compared to CHOP21 group.
At the same time some patients can not tolerate the combination therapy so attenuated or less toxic regimens can be tailored for them.
Special considerations are needed to be taken in each individual case as cardiac transplant recipents with vasculopathy can experience preserved LV EF HF
– Polymorphic CD20-positive B-cell PTLD treatment algorithms similar to monomorphic due to paucity of data on polymorphic
It includes IV Rituximab of 4 weekly standard cycle as monotherapy for cases who did not respond to RIS initially followed by 4 more 3 weekly cycles for cases with CMR while cases who did not reach remission can receive 4 cycles of RCHOP21.
Along with cardiac and renal assessment for SOT recipients.
PETCT is needed for evaluation of treatment response.
Radiotherapy
A study proposed that adults with early-stage disease, apart from the histological subtype, can achieve CRs after surgical resection or radiotherapy, usually with concurrent RIS.
Radiotherapy can be applied for some extra-nodal sites, as the orbit, isolated CNS relapse and for localised extra-nodal marginal zone lymphomas of the MALT.
Radiotherapy with chemotherapy regimens can be used in nasal NK/T-cell lymphoma
Antivirals, IVIG and interferon-alpha treatment
are not adviced outside clinical trials
Therapy for relapsed or refractory PTLD
R/R PTLD cases post R-CHOP have poor prognosis, extrapolating treatments from R/R DLBCL in
immunocompetent patients can be offered, but with little evidence in R/R PTLD.
Adoptive immunotherapy
EBV positive PTLD and R/R EBV-positive PTLD can be treated by EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy without graft rejection risk and the outcomes were acceptable.
These T lymphocytes are either autologous or extracted from a bank of partially matched HLA EBV-specific CTLs.
Chimeric antigen receptor (CAR)-T cells used for B-cell malignancies suggests it’s possible
role in the treatment of PTLD.
Burkitt lymphoma-like PTLD
Rituximab monotherapy cannot induce remission
R-CHOP with concurrent RIS can be used for Burkitt-like PTLD as in diffuse large B-cell lymphoma in the immunocompetent patient ,Dose-adjusted EPOCH-R with CNS prophylaxis can be suitable in selected patients.
Plasmablastic and plasma-cell myeloma PTLD
No sufficient data is available therefore RIS along with plasmacytoid dyscrasia disease in the immunocompetent cases can be used
T-cell lymphoma PTLD
It is a rare forum ,that occurs late post SOT , it has a poor prognosis .
RIS with anthracycline-based chemotherapy was proposed for therapy .
Immunocompetent patients with T-cell lymphoma treatment algorithm can be applied.
Hodgkin lymphoma PTLD
It is rare with no much data available, it is supposed to occur late after SOT.
HL-PTLD patients with normal cardiac and pulmonary function can be treated by standard combination chemotherapy with ABVD(doxorubicin, bleomycin, vinblastine, dacarbazine) with or without radiotherapy alongside RIS .
BEACOPP , Eescalated BEACOPP or BEACOPDac is an option in patients with high-risk disease but toxicities must be considered.
Extra-nodal marginal zone lymphoma – PTLD
It’s risk increase with SOT.
Stomach is the most common site to be affected in MALT lymphoma, also colonic and small bowel involvement were dteceted.
EBV-positive MALT lymphoma occurs in the skin and can respond to RIS.
Rituximab monotherapy or Radiotherapy in certain cases are other options.
CNS involvement in PTLD
CNS-PTLD is typically monomorphic, highgrade B-cell lymphoma and all are EBV-positive.
It is multifocal as detected by MRI and tissue biopsy can be needed.
Median OS is 33–47 months.
RIS with intrathecal chemo and whole brain radiotherapy ,outcomes were acceptable.
Systemic chemotherapy with CNS penetration is the standard for primary CNS lymphoma in immunocompetent.
Rituximab with RIS can be used in patients unfit for chemotherapy.
EBV-specific CTLs can be used in patients with EBV-positive CNS-PTLD post HSCT or SOT
Supportive care
G-CSF as primary prophylaxis can be useful in patients with PTLD having high TRM.
Antibiotic ,antiviral and antifungal treatment can be considered for cases with neutropenia
PJP prophylaxis in all PTLD cases
CMV surveillance is adviced, patients with HBV ,HCV or HIV need to be treated .
Retransplant
Can be considered after PTLD control as it’s recurrence rate is low post transplant.
One year gap is considered as a minimum period before re-transplantation varing according to the organ and clinical need.
Thank you. We usually wait for 2 years after completing clearance before retransplantation
Introduction:
Diagnosis and staging:
Multidisciplinary approach to care:
Management of PTLD:
-Low risk patients, early and non-bulky disease
-Review within 2 to 4weeks to check for response, if CR no further action
-Close monitoring for rejection
-PR, monitor for another 2 to4 weeks or consider rituximab
-Indicated for monomorphic CD20 +ve PTLD
-Rituximab (4 cycles) follow by CHOP 21 ( 4 cycle every 21 days) = PTLD-1
-Rituximab monotherapy in low-risk patient = PTLD-2
-Limited data
-Treated the same as monomorphic CD20 +ve PTLD
-Rarely treated as HL
Other forms of PTLD with limited data on treatment:
Supportive therapy:
Re-transplantation:
Thank you. We usually wait for 2 years after completing clearance before retransplantation
Welcome prof
Introduction:
This updated guideline talks about the first treatment for adults with post-transplant lymphoproliferative disease (PTLD) after solid organ transplantation (SOT).
Lymphoid proliferations caused by immunosuppression after SOT cause post-transplant lymphoproliferative illness.
SOT patients’ malignancies are 21% lymphoproliferative, compared to 4–5% in immunocompetent people.
After skin cancer, PTLD is a prevalent malignancy in adult SOT patients and is linked to high cancer mortality.
Diagnosis and staging:
Tissue diagnosis of PTLD is difficult and requires clinical information, including transplant date, immune suppression treatment, and organ type. Excisional biopsy samples are best for PTLD sub-classification and auxiliary studies.
If not, a core needle biopsy may be done (1A).
Categories of PTLD:
Non-destructive: Includes plasmacytic hyperplasia, infectious mononucleosis-like lymphocytes, and florid follicular hyperplasia. EBV-associated early PTLD patients predominate.
polymorphic: B-cell maturation stages with T cells, EBV-associated in >90% instances.
monomorphic: DLBCL, Burkitt lymphoma, plasma cell myeloma, plasmacytoma, 60–80% of PTLD. Indolent B-cell lymphomas and T-cell neoplasms are rarer. EBV-negative monomorphic PTLD. 70% of these lesions had trisomies 9 and 11 or both.
Classical Hodgkin lymphoma: This meets the morphological criteria for classical Hodgkin lymphoma, and EBV is usually (>90%) the cause.
Management of PTLD:
Reduction of immunosuppression: The clinical picture and illness severity determine the American guidelines’ approach.
Lines of Treatment:
Re-transplantation:
Clinical necessity and organ type determine re-transplantation. Before re-transplantation, one year is recommended, although longer may be required (2C).
Thank you. We usually wait for 2 years after completing clearance before retransplantation
o Form a MDT which includes –
Transplant physicians
haemato -oncologist
haematopathologist
Radiologist
Radiation oncologist
o For diagnosis –
surgical excisional Or incisional biopsy recommended.
alternatinge is Core needle biopsy.
If PET CT is not available then staging with a CT is recommended.
If available PET CT should be done for staging
o All biopsy samples to be revised by haemato pathologist.
o All cases to be discussed at haemato oncology MDT meeting.
Adverse risk factors in PTLD
Raised LDH
Hypoalbuminemia
cNS or bone marrow involvement
older age
mono morphic histology
graft involvement
EBV negative tumour
poor performance status.
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o Other scoring systems –
Ghobrial prognostic score
International Prognostic Index
PTLD prognostic index
Management of PTLD
o Reduction of immunosuppression
may be sufficient in patients with low risk disease.
Assess response within 2-4 weeks of reducing immuno suppression.
Whether CR | PR acheived
Watch out for rejection
Strategy to reduce immunosuppression
Stop anti metabolites
Decrease CNI by 30-50%
Maintain Or reduce steroids
In presence of-
clinically aggressive disease Ann Arbor stage > III
Elevated LDH
high risk IPI
more than one extranodal site
Use other strategy with reduction of immunosuppression.
Rituximab + / – chemotherapy
If unresponsive to RIS
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4 cycles of weekly intravenous rituximab at 375mg/ m2 followed by 4 cycle of standard dose CHOP – 21 chemotherapy.
50 mg/m2 doxorubicin
750 mg/m2 cyclophosphamide
1.4 mg /m2 vincristine
50 mg/m2 prednisolone.
every 21 days
along with G – CSF
In the PTLD 1/3 trial
first R IS
fails
4 cycles of Rituximab
interim CT at Day 50
if CR – low risk, then Further 4 cycles of 3 weekly Rituximab and then stop.
if no CR acheived or if progression present, then high risk, 4 cycles of R- CHOP 21.
along with G-CSF and PCP prophylaxis.
Low risk further redefined in PTLD -2
who acheive a CR with first 4 cycles of Rituximab monotherapy.
those who acheina PR and IPI of 0-2.
PET- CT to be done for inthim staging and end of treatment response if available.
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Radio therapy –
with RIS in localised monomorphic type DLBCL and Hodgkin lymphoma PTLD with RIS +/ – on taximats in DLBCL if patient not eligible For intensive chemotherapy.
Orbit PTLD
isolated CNs relapse
localised MALT
No role of-
Antivirals
intravenous immunoglobulin
Retractory PTLD
Poor prognosis
Adoptive immuno therapy
in those who relapse post R-CHOP
intensive second line chemotherapy to be given. if remission acheived then do autologous stem cell transplant.
Burkit lymphoma like PTLD
R I S with R- CHOP
Assess CNs
T cell lymphoma PTLD
RIS plus anthracycline based chemotherapy.
Hodgkin lymphoma PTLD
RIS plus ABVD chemotherapy ( Doxorubicin, b leomycin,
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Vinblastine,dacarbarine ) with or without radio therapy.
Extra nodal marginal zone lymphoma – PTLD
Rituximab monotherapy
CNS PTLD
RIS, In tracranial chemotherapy, and whole brain radiotherapy.
Supporting Care
G-CSF
Antibiotic, antifungal, antiviral Prophylaxis
Re transplantation
Minimum 12-24 months before re transplant considered.
Recurrence rare
I wish you could type the heading of first para as Introduction. Under this main heading, I wish you could type sub-headings in bold or underline or in italics. That would make it easier to read.
Your write-up looks like lecture notes. .
What is your analysis of level of evidence of this study?