IV. Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence based treatment protocol for CD 20 positive B cell PTLD
They demonstrated improved median overall survival and lower treatment related mortality compared to the previous smaller rituximab monotherapy trials.
The PTLD 1 sequential treatment confirmed the safety of rituximab followed by CHOP 21and established response to rituximab induction
The subsequent trial of risk stratified sequential treatment considered rituximab consolidation for patients in complete remission and R and CHOP21 for whom not in complete remission
Patients and methods
Prospective multicenter phase II trial tested modified risk stratification in adult SOT recipients with CD 20 positive PTLD based on the principles established in the PTLD 1 trials : sequential treatment and risk stratification, patients are classified into three groups low risk group, high risk group and very high risk group
After rituximab monotherapy induction, patients of complete remission as well as those in partial remission with IPI less than 3 at diagnosis( low risk ) continued with rituximab monotherapy and thus chemotherapy free.Most others ( high risk ) received R-CHOP21 . Thoracic SOT recipients who progressed( very high risk) received alternating R-CHOP21 and modified R-DHAOx
The primary endpoint was event free survival in the low risk group
The PTLD 1 trials provided historical controls
Rituximab was applied SC
Of 60 patients enrolled, 21 were low risk,28 high risk and 9 very high risk
Results
Overall response was 94%.
2 year Kaplan-Meier estimates of time progression and overall were 78% and 68% similar to the PTLD 1 trials. Treatment related mortality was 7%
In the low risk group, 2 year EFS ( event free survival) was 66% versus 52% the historical comparator that received CHOP. 2 year overall survival in the low risk group was 100%, 18% in high risk group and 0% in very high risk group
Phase 2 in PTLD 2 trial prospective, multicentre, open-label phase II trial enrolled treatment-
nave adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020.
They divided patients to 3 groups:
Low risk :Rituximab mono therapy
High risk :RcHOP-21
Very high risk :RCHOP-21 and modified R-DHAOX
Conclusion:
The overall response rate to rituximab monotherapy 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
This is phase 2 of the PTLD2 trial.It is a prospective, multicentre, open-label study of organ recipients who have CD20-positive PTLD at 15 centers in Germany over 5 years. It had involved 60 patients. It had tested modified risk-stratification.
Patients were divided into :
1- Low risk : 21 patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis. They were provided with rituximab monotherapy alone.
2- high-risk 28 patients who received R-CHOP-21.
3- very-high-risk :9 patients who are thoracic SOT recipients who received alternating R-CHOP-21 and modified R-DHAOx.
the primary endpoint was event-free survival (EFS) in the low-risk group.2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68%. In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP. 2-year OS in the low-risk group was 100%.
The level of evidence is 1 as it is 1
Q1:
Introduction:
PTLD-2 was an open label, multicenter and prospective trial conducted in patients with CD20+ PTLD who had not good response to IS reduction, with more than 2 cm lesion, BM involvement, ECOGroup performance status of ≤2.
Exclusion criteria: CNS involvement, pregnancy or breast feeding, HIV or other active infections and uncontrolled heart disease.
Method:
After initially treatment with rituximab (first dose IV and 3 doses SQ weekly), these patients had interim staging to evaluate their response to treatment on day 40-50 and were divided to the following groups:
Low-risk: patients in CR or in PR but with less than 3 IPI at diagnosis: continued with 4 doses of SQ rituximab every 3 week.
High- risk: patients without CR or PR with≥3 IPI without CHOP every 3 weeks.
Very high- risk: patients with thoracic organ TX who were unresponsive to rituximab. These patients received six alternative courses of R-CHOP or R-DHAO every 3 weeks. These patients were compared with the historical control of PTLD-1 trial. PTLD-1 trial: patients received 4 cycles of CHOP-21 (every 3 weeks).
Primary endpoint was event free survival (EFS) in the low risk patients. Events were infections grade 3-4from day 50 to 143, discontinuation of treatment, disease progression and death.
Results:
During 2.8 years, 60 patients were followed. Two of them died and 58 were analyzed. About 45 percent respond to RTX. They (58 patients) were divided into three groups: low- risk:21, high- risk:28 and very high- risk: 9 patients. At the end only 21, 22 and 5 of them were analyzed.
Low-risk group 100% responded to RXT vs 18% and zero percent in high and very high- risk group, respectively.
At final staging, overall response was 94% with CR of 46%. Two year Kaplan-Meyer estimates of time to progression and overall survival were 78% and 68%, similar to PTLD-1 trials. Treatment related mortality was 7%. In low-risk group, 2 year EFS was 66% vs 52% in the historical control. Two-year overall survival in the low-risk group was 100%. Results with R-CHOP-21 in high-risk group was like the previous study. The treatment of very high-risk patients was disappointing.
Limitations were: high rate of lung TX, small sample size, high rate of Burkitt and Burkitt-like and high grade B cell lymphoma type PTLD.
Q2: The level of evidence provided by this article is level 1 (RCT).
Level 1 evidence
-This prospective phase II trial enrolled treatment of naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020 Treatment
-Rituximab 1400 mg SC then 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). 48 patients (21, 22, and 5 in groups A, B, C respectively) were analyzed (48 from 58 patients recruited at the beginning). 100% response to rituximab in low risk group, 18% response to rituximab in high risk group. 0% response to rituximab in very-high risk group. 2-year overall survival was 68%, 2-year event free survival was 66% in low risk group. Very high-risk group patients had higher risk of infections and AKI. Conclusion :
The overall response rate to rituximab monotherapy 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Two phase II trials conducted by the German PTLD study group and European PTLD Network established a protocol for the treatment of CD20-positive B-cell PTLD in adults.The PTLD-1 sequential treatment demonstrated the safety and efficacy of four cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy and established rituximab induction response as a prognostic factor.
The hypothesis of this study was that patients with thoracic SOT and disease progression during rituximab induction would benefit from intensified immunochemotherapy.
Six cycles of alternating R-CHOP and modified R-DHAOx every three weeks were selected for this extremely high-risk cohort, the latter based on its efficacy and low renal toxicity. The dose of Rituximab selected was 1400 mg SC.
Methods
This is a prospective, multicenter, open-label phase II trial that enrolled treatment-naive adult SOT recipients with CD20-positive PTLD at 15 centres in Germany between February 3, 2015 and July 13, 2020.
Additional inclusion criteria included an inadequate response to initial immunosuppression reduction (with or without antiviral therapy), measurable disease larger than 2 cm in diameter (and/or bone marrow involvement), and an Eastern Cooperative Oncology Group (ECOG) performance status of 2.
Principal exclusion criteria included involvement of the central nervous system, pregnancy or lactation, and concurrent diseases that precluded the administration of study therapy, including severe uncontrolled heart disease, HIV infection, and other severe active infections.
Using in-situ hybridization for EBER transcripts, the Epstein–Barr virus association was confirmed.
Rituximab (1400 mg SC; initial application 375 mg/m2 IV) is administered on days 1, 8, 15, and 22, followed by interim staging (days 40–50). (Low-risk group) continued with four cycles of rituximab administered every three weeks. The majority of other patients (high-risk group) received four RSC-CHOP-21 cycles.
In the case of clinical indications of disease progression before interim staging, restaging was performed prematurely and treatment in the high-risk or very-high-risk groups was initiated immediately if progression was confirmed.
Thoracic SOT recipients who progressed while receiving rituximab (extremely high-risk group) were administered six cycles of alternating RSC-CHOP and modified RSC-DHAOx at three-week intervals.
After chemotherapy, chemoprophylaxis for Pneumocystis jirovecii and treatment with granulocyte-colony stimulating factor were administered.
A month after the last cycle of treatment, the final evaluation of response was conducted.
Patients underwent follow-up exams every three months for the first two years, and then annually thereafter.
Results
60 patients were observed for a mean duration of 2.80 years. One patient died prior to treatment, while the other died during rituximab induction but unrelated to it.
26 of 58 patients (45%) responded to rituximab monotherapy induction, and 5 of 58 patients (9%) attained a complete response.
Five patients in complete response (CR) and sixteen patients in partial response (PR) with IPI 3 at baseline were assigned to, received, and were evaluated after rituximab monotherapy consolidation in the low-risk group.
Due to PR with IPI 3 (five patients), stable disease (ten patients), or progressive disease (thirteen non-thoracic transplant recipients), 28 patients were assigned to the high-risk group.
Two lung transplant recipients did not begin treatment with R-CHOP-21 due to deteriorating transplant function and tuberculosis, respectively. This resulted in 26/28 patients receiving treatment.
Four patients discontinued treatment: one after one cycle of trial treatment and three due to infections (two of which were fatal: liver abscesses and febrile neutropenia complicated by a stroke, respectively).
22/28 patients were evaluable at the final staging stage.
Outcome and toxicity: The final stage response rate was 94% overall.
22/59 reported G3/4 leukopenia.
25/59 reported infection with G3/4.
Most infection episode was (pneumonia,9), (febrile neutropenia,8), (sepsis,6), (and Varicella Zoster,3).
Other adverse effects include anaemia, thrombocytopenia, acute respiratory failure, and gastrointestinal haemorrhage.
8/59 individuals develop a rituximab-infusion reaction.
Discussion
Similar ORR, TTP, OS, and PFS were observed in comparison to the preceding PTLD-1 ST and RSST trials.
36% of patients in the low-risk cohort were treated with rituximab monotherapy consolidation and were therefore chemotherapy-free; 76% of these patients would have received R-CHOP consolidation under the previous PTLD-1 RSST protocol.
OS and PFS were substantially different between the three risk groups, whereas DR, a measure of remission quality, was quite comparable. Similar ORR, TTP, OS, and PFS were observed in comparison to the preceding PTLD-1 ST and RSST trials.
The 2-year EFS in the low-risk group was numerically, but not statistically, preferable to the predetermined comparison group.
The trial’s primary objective was not attained, and the original trial hypothesis is therefore rejected.
Alternative treatment methods are required for this extremely high-risk subgroup.
There were no significant differences in ORR between intravenous and subcutaneous administration of rituximab, nor gender-specific differences.
Level I (multi-center randomized controlled trial)
This is a prospective, multicentre, open-label phase II trial handling treatment of
SOT adult recipients diagnosed with CD20-positive PTLD at 15
centres in Germany from February 3rd 2015 until July 13th 2020. Inclusion criteria :
1- Insufficient response to immunosuppression reduction (with or without antiviral therapy)
2- Measurable disease > 2 cm in diameter (and/or bone marrow involvement)
3- Eastern Cooperative Oncology Group (ECOG) performance status “2. Exclusion criteria :
1- central nervous system involvement
2- pregnancy or nursing
3- concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections. Treatment plan :
After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free.
Others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx. The primary endpoint
event-free survival (EFS) in the low-risk group.
Rituximab was applied subcutaneously. Results
60 patients in this study , 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 .
In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP . 2-year OS in the low-risk group was 100%.
Results with RCHOP- 21 in high-risk patients confirmed previous results.
Immuno-chemotherapy intensification in very-high-risk patients was
disappointing.
level 1
Please summarize this article: This is a multi-center prospective open label trial (PTLD-2 trial).
Inclusion criteria: 1-CD20 +ve PTLD with weak response to immune-suppression reduction 2-measurable disease 2cm or above in diameter. 3-BM involvement. 4-ECOG performance status below or equals to 2.
Exclusion criteria: 1-CNS involvement. 2-Pregnancy or breast feeding. 3-HIV infection. 4-Other active infections. 5-Uncontrolled heart disease.
Methods: 60 patients were included from 2015 to 2020. 2 patients died. 58 patients were followed up for median 2.8 years. All patients were treated with 4 doses of Rituximab as per protocol then those patients were divided at day 40-50 into 3 groups according to the risk: A- 21 low risk patients: complete or partial remission, IPI risk factors include age above 60, ECOG status 2 or above, Ann-Arbor stage 3 or above, high LDH and more than one extra-nodal disease. No chemotherapy was given. B- 28 high risk patients: treated with CHOP every 3 weeks. C- 9 very high-risk patients: thoracic SOT recipients with progressive disease despite rituximab treatment. They received 6 cycles of alternating chemotherapy R-CHOP and R-DHAOx. D- Control group: historical controls of PTLD-1 trial.
Aim: Primary end-point: event free survival in low risk group including infection, disease progression, death and treatment discontinuation. Results: 48 patients (21, 22, and 5 in groups A, B, C respectively) were analyzed (48 from 58 patients recruited at the beginning). 100% response to rituximab in low risk group, 18% response to rituximab in high risk group. 0% response to rituximab in very-high risk group. 2-year overall survival was 68%, 2-year event free survival was 66% in low risk group. Very high-risk group patients had higher risk of hemato-toxicity, infections and AKI. Leucopenia was found in 37%. Infections were found in 42% Limitations of the study: 1- Small number of patients. 2- It is not a multi-national trial. 3- Over representation of lung transplant recipients who carry poor prognosis. 4- Higher percentage of rare PTLD forms Conclusion: De-escalation of therapy with rituximab is effective is low risk group patients. Poor outcomes in very high-risk group even with intensified immune-chemotherapy.
What is the level of evidence provided by this article? Level I (multi-center randomized controlled trial)
INTRODUCTION
Post-transplant lymphoproliferative disorders (PTLD) are compli- cations of immunosuppression after solid organ transplantation (SOT). Their epidemiology, pathogenesis, classification, presenta- tion and treatment have previously been reviewed in depth
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence-based
treatment protocol for CD20-positive B-cell PTLD in adults [6]. They demonstrated improved median overall survival (OS) compared to preceding smaller rituximab monotherapy trials and lower treatment-related mortality (TRM) compared to prior retrospective case series of first-line chemotherapy
METHODS Study design and patients
This prospective, multicentre, open-label phase II trial enrolled treatment- naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020. Additional inclusion criteria were an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measur- able disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Main exclusion criteria were central nervous system involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Treatment plan
Treatment consisted of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). Response to treatment at interim and final staging was determined according to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging
Statistical analysis
Analysis was by intention to treat (ITT) unless otherwise specified. The per- protocol (PP) population included all patients treated according to protocol with a minimum number of two treatment cycles and sufficient information to determine remission status. For the calculation of the overall response to full treatment, subjects non-evaluable for response (i.e. subjects suffering TRM before final staging without evidence for PD) were not included in the denominator. The primary endpoint was EFS in the low-risk group. Events were infections grade III/IV from day 50 to day 143, treatment discontinua- tion for any reason, disease progression and death. The pre-specified comparator group included 25 patients in CR or PR with <3 initial IPI risk factors after rituximab IV induction who were treated with CHOP consolidation in the PTLD-1 ST trial
Treatment
One patient died before the start of treatment, another during, but unrelated to rituximab induction .58 patients could be evaluated for response to rituximab induction, 48 of which had received all four scheduled applications. The ten patients that did not receive the four scheduled applications all had disease progression during treatment: three after the first application, two after two doses and four after three doses. In summary, 26/58 patients (45%, 95% CI 33–58) responded to rituximab mono- therapy induction and 5/58 (9%, 95% CI 3–19) achieved a CR.
Outcome and toxicity by treatment group
The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group. Time-to event outcomes RD, TTP, OS and PFS for each risk group are plotted in Supplementary
In the low-risk group, ORR at final staging was 95% (20/21 patients; CR 11/21, 52%). One patient suffered disease progression. Median RD was not reached; the 2-year KM estimate was 89% (95% CI
The primary endpoint of this trial, the 2-year EFS KM estimate in the low-risk group, was 66% .This was 14% higher than in the pre-specified comparator group (52% )
DISCUSSION
Rarity and disease heterogeneity are the reasons evidence for PTLD treatment is still based on phase II clinical trial data. The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients unresponsive to initial immunosuppression reduction. With a median OS of 6.6 years and a clear plateau on the PFS curve it compared favourably to earlier rituximab monotherapy trials. The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) successfully tested a response-adapted treatment strategy based on response to rituximab monotherapy induction. Exposure of patients to chemotherapy was limited and long-term outcomes maintained. It is considered a 1st-line standard in the treatment of PTLD
During the conduct of the PTLD-2 trial, two other prospective multicentre phase II trials evaluated ibrutinib and brentuximab vedotin, respectively, in the treatment of PTLD. Ibrutinib was added to risk-stratified sequential treatment in induction and consolidation (n = 39). It did not result in a sufficiently high CR rate to warrant further investigation, while the OS and PFS outcomes were very similar to those reported in the PTLD-1 RSST trial
A small trial of brentuximab vedotin given concurrently with rituximab for patients with de novo immunosuppression- associated CD30-positive and/or EBV-positive lymphomas included 12 PTLD after solid organ transplantation
Study design and patients -This prospective, multicentre, open-label phase II trial enrolled treatmentnaïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020. Additional inclusion criteria were an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. .. PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification.
Treatment plan -Treatment – consisted of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50)
After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx.
The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Outcome and toxicity by treatment group–
The overall response rate(ORR) to rituximab monotherapy at interim staging was 100%in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group. In the low-risk group, ORR at final staging was 95% (20/21 patients; CR 11/21, 52%).In the high-risk group, ORR at final staging was 100% (22/22; CR 9/22 [41%).Toxicity was low; 7/21 (33%) patients suffered a single episode each of grade 3/4 infections (pneumonia in 4/7, none fatal) – three of these were outside the time interval defined for EFS. There was no TRM (0/21, 0%). Only three further adverse events grade 3/4 were reported.
Chemotherapy in thehigh-risk groupwas associated with significant toxicity: 13/26 (50%) patients suffered grade 3/4 infections. Most frequent was febrile neutropenia. Haematotoxicity was common (leukopenia grade 3/4 in 16/ 26 [62%]), as was acute renal failure (4/26, 15%), gastrointestinal bleeding (3/26, 12%) and tumour lysis syndrome (2/26, 8%). TRM was 2/26 (8%).
In the very-high-risk group, 5/9 patients could be evaluated for response at final staging. 3/5 (60%) responded with two patients (40%) in CR.Toxicity in the very-high-risk group was substantial: 5/8 (63%) patients suffered grade 3/4 infections (two cases fatal, TRM 2/8 [25%]). Haematotoxicity was very common (leukopenia grade 3/4 in 6/8 [75%]), as was acute renal failure (4/8, 50%). Ten additional single cases of adverse events grade 3/4 were reported among these eight patients and included gastrointestinal bleeding, gastrointestinal perforation, multi-organ failure and cerebral bleeding. The highest rate of haematotoxicity, infections and mortality occurred after the first application of chemotherapy (RSCCHOP) rather than subsequent cycles (either RSC-CHOP or RSCDHAO
population: Inclusion: Adult SOT recipients diagnosed with CD20-positive PTLD, insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Main exclusion criteria: CNS involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections. Intervention: After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx Outcome: event-free survival (EFS) in the low-risk group
Results: Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing Strength: Good design and follow up, it is good phase II trial with potential options for more stronger evidenceopulation: Inclusion: Adult SOT recipients diagnosed with CD20-positive PTLD, insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Main exclusion criteria: CNS involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections. Intervention: After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx Outcome: event-free survival (EFS) in the low-risk group
Results: Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing Strength: Good design and follow up, it is good phase II trial with potential options for more stronger evidence
INTRODUCTION:
PTLD is an immunosuppression related malignancy with high morbidity in transplant recipients. The preceding PTLD-I trial showed that stepwise therapy with rituximab followed by CHOPD-21 was effective and had lower adverse effect profile.
This is prospective, multicenter, open-label phase II trial tested modified risk stratified sequential treatment of CD20-positive PTLD in adults after SOT. METHODS:
Study design and patients, treatment plan and statistical analysis. Treatment Plan:
Rituximab (1400 mg SC; initial application.375 mg/m2 IV) was administered on days 1, 8, 15, and 22 as part of the treatment. The interim staging was then performed (day.40–50).
PTLD-adapted response criteria for malignant lymphomas were used to assess treatment response at intermediate and final stages. Results:
45% patients achieved response to Rituximab and 9% achieved complete remission with rituximab after 4 doses as part of induction therapy. 21 low risk cases were assigned to rituximab consolidation therapy (4 additional doses), 28 were allotted to high risk for R-CHOP and 9 were allotted to very high risk for therapy with R-CHOP & R-DHAOx. Overall response was 94% with 46% achieving complete remission. Most severe adverse effects were related to infections (42% overall, 33% in low risk and 46% in high risk category), leukopenia (37%), Anemia (24%), thrombocytopenia (22%), AKI (15%), GI bleed (7%). Overall response rate was 100% in both low risk and high risk arms but treatment related toxicities were higher in the high-risk category. In the very high risk category 3/5 (60%) responded with 2 achieving complete remission. DISCUSSION:
marked variability in disease subtypes and rarity of disease are factor which have limited deeper insight into this disease. PTLD-I aimed at standardizing chemotherapy protocol for PTLD. PTLD-II aimed at step wise approach based on modified risk stratification with a target to reduce chemotherapy related adverse effects. Level of evidence is 1
Please summarise this article INTRODUCTION: The PTLD-2 trial is a multicenter phase II trial with treatment protocols based on modified risk stratification and step up therapy treatment protocol based on risk category. PTLD is an immunosuppression related malignancy with high morbidity in transplant recipients. The preceding PTLD-I trial showed that stepwise therapy with rituximab followed by CHOPD-21 was effective and had lower adverse effect profile. RESEARCH QUESTION: The question raised was whether Rituximab alone could be sufficient to achieve remission in low risk cases after risk stratification. The hypothesis was that in low risk cases subcutaneous rituximab alone would be as effective as R-CHOP-21 with lower rate of severe infections. METHODS: Open label multicenter phase II trial, 14 centers in total over 5 years with 60 patients enrolled in total. TREATMENT PLAN: 4 doses of Rituximab followed by staging of disease. Low risk cases were given further 4 doses of Rituximab, whereas high risk cases were switched to R-CHOP (as per PTLD-I trial). Very high risk cases received 6 cycles of alternating R-CHOP and R-DHAOx. PCPC prophylaxis and G-CSF administration was mandatory. Disease activity was assessed at 1 month after final dose and patients were kept on regular follow up. RESULTS: 45% patients achieved response to Rituximab and 9% achieved complete remission with rituximab after 4 doses as part of induction therapy. 21 low risk cases were assigned to rituximab consolidation therapy (4 additional doses), 28 were allotted to high risk for R-CHOP and 9 were allotted to very high risk for therapy with R-CHOP & R-DHAOx. Overall response was 94% with 46% achieving complete remission. Most severe adverse effects were related to infections (42% overall, 33% in low risk and 46% in high risk category), leukopenia (37%), Anemia (24%), thrombocytopenia (22%), AKI (15%), GI bleed (7%). Overall response rate was 100% in both low risk and high risk arms but treatment related toxicities were higher in the high risk category. In the very high risk category 3/5 (60%) responded with 2 achieving complete remission. DISCUSSION: marked variability in disease subtypes and rarity of disease are factor which have limited deeper insight into this disease. PTLD-I aimed at standardizing chemotherapy protocol for PTLD. PTLD-II aimed at step wise approach based on modified risk stratification with a target to reduce chemotherapy related adverse effects. STRENGTHS OF STUDY: Multicenter, open label trial with predefined risk stratification and treatment protocols. Use of CT rather than PET scan for interval staging. LIMITATIONS OF STUDY: Lower number of patients and patients in Germany alone. What is the level of evidence provided by this article?
Level 1 for open label multi-center trial.
INTRODUCTION:
Post renal transplantation,potent immunosuppression may be complicated by post-transplant lymphoproliferative diseases (PTLD) .
This article reviews the epidemiology, aetiology, classification, presentation, and therapy.
Study design and patients:
This is prospective, multicentre, open-label phase II trial tested modified risk strati fied sequential treatment of CD20-positive PTLD in adults after SOT .
Treatment plan:
Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). (Low-risk group) continued with four three-weekly courses of rituximab. Most other patients (high-risk group) received four cycles of RSC-CHOP-21.
Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals. Outcome and toxicity:
The overall response rate at final staging was 94% . DISCUSSION:
Rarity and disease heterogeneity are the reasons evidence for PTLD treatment is still based on phase II clinical trial data.
The PTLD-1 trial show a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patient sun responsive to initial immunosuppression reduction. By this regimen Exposure of patients to chemotherapy was limited and long-term outcomes maintained. It is considered a 1st-line standard in the treatment of PTLD.
This study observed similar ORR, TTP, OS and PFS compared to the preceding PTLD-1 ST and RSST trials.
2-year EFS in the low-risk group was numerically, but not statistically, superior to a pre-specified comparator group from the PTLD-1 ST trial treated with CHOP consolidation.
Patient allocation to the very-high-risk group of the PTLD-2 protocol was based on two previously identified risk factors for poor outcome: progressive disease under rituximab induction and thoracic organ transplant.
This trial utilized rituximab in its formulation for subcutaneous injection. In a pre-specified inter-trial comparison, we did not detect significant differences in ORR between rituximab SC and IV, nor a sex-specific difference.
Limitations of this trial included
– small size
– and lack of international recruitment due to funding constraints ( over-representation of lung transplant recipients , high proportion of Burkitt, Burkitt-like lymphoma with 11q aberration and high-grade B-cell lymphoma PTLD .
This article is based on subcutaneous Rituximab treatment in PTLD post solid organ transplantation. Immunochemotherapy intensification was studied in high and low risk groups.
Discussion
PTLD is rare and highly heterogenous. Phase I trial included four courses of weekly Rituximab followed by four cycles of CHOP 21 for patients who were unresponsive to initial immunosuppression induction. This study is based on a phase II trial which tested modified sequential treatment of CD20 positive PTLD in adults after SOT. Rituximab was used in its formulation for subcutaneous treatment. No difference in subcutaneous and IV administration was detected. No sex specific differences were found.
Progressive disease have been found following Rituximab induction. This is a disappointing result. Further studies need to be made in this regard.
Other drugs that were employed in comparison were ibrutinib and brentuximab vedotin in the treatment of PTLD. The former was added to induction therapy and did not result in making a significant impact. Brentuximab vedotin given concurrently with Rituximab for patients with de novo immunosuppression associated EBV lymphomas found a small percentage of development of PTLD in the patients post transplant.
Conclusion
Rituximab given subcutaneously may have reduced rates of CR.
After solid organ transplantation, immunosuppression can lead to problems called post-transplant lymphoproliferative diseases (PTLD) (SOT).
In-depth reviews of their epidemiology, aetiology, classification, presentation, and therapy have already been done.
METHODS:
Study design and patients:
· This prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centers in Germany from February 3rd, 2015 until July 13th, 2020.
· Central nervous system involvement, pregnancy, or concurrent diseases that made it impossible to provide study treatment were the main exclusion criteria.
TREATMENT PLAN:
· Rituximab (1400 mg SC; initial application.375 mg/m2 IV) was administered on days 1, 8, 15, and 22 as part of the treatment. The interim staging was then performed (day.40–50).
· PTLD-adapted response criteria for malignant lymphomas were used to assess treatment response at intermediate and final stages.
RESULTS:
Patients
· 60 patients were treated with the medication; the median follow-up period was 2.8 years; 26/58 patients responded to rituximab monotherapy induction; and 5/58 (9%, 95% CI 3-19) patients attained a CR after beginning the medication.
· The six patients who had BCL and PTLD of the MYC-rearrangement type were not treated in the low-risk or very-high-risk groups
· Twenty-six of the 21 patients who were assigned to the low-risk group continued to receive therapy; four patients discontinued due to infections and declining transplant function. Outcome and toxicity
At the final stage, the response rate was 94% overall (45/48, 95% CI 83-98). The Kaplan-Meier (KM) estimate of RD over a two-year period was 81% (95% CI 68-94). TTP was 78% and OS was 68% in the 60 patients in the population that was intended to be treated (5.1 years). The toxicity of treatment
· Pneumonia (9).
· Febrile neutropenia (8).
· Sepsis (6).
· reactivation of varicella zoster, (3)
· Infections of grade 3/4 were observed in 25/59 cases (42%, 95% CI 31-55).
· Rituximab IV infusion-related responses occurred in 8/59 patients (14%, 95% CI 7-25; all grade 1 or 2) and local drug reactions in 4/59 individuals.
· Anaemia, thrombocytopenia, acute renal failure and gastrointestinal bleeding were another common grade 3/4 adverse effects. Outcome and toxicity by treatment group
· In the low-risk group, the overall response rate (ORR) to rituximab monotherapy was 100 percent.
· From day 50 to day 143, there were 4 grade 3/4 infections associated with EFS episodes (19% vs. 32% for the comparison group).
· Both the TTP and PFS projections for the next two and three years were 85%.
· The ORR at the final stage in the high-risk group was 100% (22/22; CR 9/22 [41%]).
· The 2- and 3-year KM estimate was 79% (95% CI 59-98), however, the median RD was not met.
· 13/26 participants in this group of patients experienced grade 3/4 infections after receiving chemotherapy.
· At the final stage, the response in 5/9 patients in the very-high-risk group could be assessed. 2/5 (or 40%) of respondents had two patients in CR.
· 1.2 years was the median RD. The TTP estimate at 2 years was 33%.
· There were no appreciable changes in ORR, TTP, or OS between rituximab SC and the earlier treatment regimens in terms of response rates and time-to-event outcomes.
· EBV-association and sex subgroup analyses that were pre-specified did not find any appreciable differences between the two therapies.
Prognostic factors:
· The three risk groups in this regimen had very varied OS and PFS, but not TTP or DR (n = 58, p 0.001).
· Baseline IPI was a standalone predictive factor for both TTP and OS in a multivariate study.
Discussion:
· The PTLD-1 study established sequential therapy with four rounds of weekly rituximab followed by four cycles of CHOP-21 for patients, creating a new benchmark in CD20-positive B-cell PTLD.
· It contrasted favorably to past rituximab monotherapy studies, with a median OS of 6.6 years and a distinct plateau on the PFS curve.
· Why Patients in the low-risk group of the R-CHOP study received rituximab monotherapy instead of chemotherapy; 76% of these patients would have been treated according to the previous PTLD-1st ST and RSST protocol.
· OS and PFS in the three risk groups were considerably different, although DR, a gauge of how well patients recovered, was relatively comparable.
· The low-risk group’s 2-year EFS was numerically, but not statistically, superior to that of a pre-determined comparison group from the.
· Treatment of the PTLD-1 ST trial with CHOP consolidation.
· Because the experiment’s main objective was not achieved, the initial trial hypothesis was disproved.
· To guarantee that the procedure could be utilized globally, the PTLD-2 trial used therapy stratification based on response to treatment at intermediate staging based on CT imaging rather than positron emission tomography (PET).
· It has been demonstrated that in PTLD, PET identifies individuals at low risk of relapsing and provides clinically useful information.
· It is doubtful that PET-based interim staging would have found more low-risk patients.
· Only 5/58 patients, who had a PR at interim staging and an IPI of 3, were deemed to be high-risk.
· In multivariate analysis, the risk factor no longer has a favorable prognostic value for TTP.
· The poor prognosis in this subset of individuals with Epstein-Barr virus illness is not improved by immuno-chemotherapy (EBV-associated PTLD).
· Other therapy modalities are necessary for this population of patients with an exceedingly high risk.
· Outcomes (ORR, TTP, and OS) were nearly identical irrespective of EBV association, in contrast to the differences in genomic profiles between CD20-positive and CD8-positive patients. The rate of grade 3/4 infections was high (42%) in patients treated with immunochemotherapy for DLBCL, but there were no cases of pneumocystis jirovecii under strict antibiotic prophylaxis.
· This is consistent with findings published for the same drug in follicular lymphoma and in combination with CHOP in DLBCL. We did not discover any variations in ORR between rituximab SC and IV, nor a sex-specific difference.
· However, it’s possible that rituximab SC has somewhat lower CR rates following four weekly cycles of monotherapy.
What is the level of evidence provided by this article:
Level I
Summary
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence-based treatment protocol for CD20-positive B-cell PTLD in adults.The PTLD-1 sequential treatment demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy and established response to rituximab induction as a prognostic factor.
This trial hypothesized that patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified immunochemotherapy.
Six cycles of alternating R-CHOP and modified R-DHAOx every three weeks were chosen for this very-high-risk group, the latter based on efficacy and low renal toxicity. Rituximab at a dose of 1400 mg SC was chosen.
Methods
This is a prospective, multicenter, open-label phase II trial enrolled treatment naive adult SOT recipients diagnosed with CD20-positive PTLD at 15 centers in Germany from February 3rd 2015 until July 13th 2020.
Additional inclusion criteria were an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Main exclusion criteria were central nervous system involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Epstein–Barr virus association was confirmed by in-situ hybridization for EBER transcripts.
Treatment plan:
Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). (Low-risk group) continued with four three-weekly courses of rituximab. Most other patients (high-risk group) received four cycles of RSC-CHOP-21.
Case of clinical signs of disease progression prior to interim staging, restaging was performed prematurely and treatment in the high-risk or very-high-risk groups started immediately if disease progression was confirmed.
Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals.
Pneumocystis jirovecii chemoprophylaxis and treatment with granulocyte-colony stimulating factor after chemotherapy were given.
The final response assessment was performed one month after the last cycle of therapy.
Patients completed follow-up examinations every three months for two years, and annually thereafter.
Result:
60 patients were followed for median time of 2.8 years. One patient died before treatment, other one died during but unrelated to rituximab induction.
26/58 patients (45%) responded to rituximab monotherapy induction and 5/58 (9%) achieved a CR.
21 patients – five in CR and sixteen in PR with baseline IPI < 3 – were allocated to, received, and were evaluated after rituximab monotherapy consolidation in the low-riskgroup.
28 patients were allocated to the high-risk group due to PR with IPI ≥ 3 (five patients), stable disease (10 patients) or progressive disease (13 non-thoracic transplant recipients.
26/28 went on to receive treatment with R-CHOP-21 as two lung transplant recipients did not start treatment due to deteriorating transplant function and tuberculosis, respectively.
Four patients discontinued treatment: One withdrew from trial treatment after one cycle and three patients stopped study treatment due to infections (fatal in two cases: liver abscesses and febrile neutropenia complicated by stroke, respectively).
22/28 patients could be evaluated at final staging.
Outcome and toxicity:
The overall response rate at final stage was 94%.
22/59 reported G3/4 leukopenia.
25/59 reported G3/4 infection.
Most infection episode was (pneumonia,9), (febrile neutropenia,8), (sepsis,6), (and Varicella Zoster,3).
Other adverse events include anemia, thrombocytopenia, ARF, GI hemorrhage.
8/59 develop rituximab-infusion reaction.
Discussion
There was similar ORR, TTP, OS and PFS compared to the preceding PTLD-1 ST and RSST trials.
36% of patients were treated with rituximab monotherapy consolidation and thus chemotherapy-free in the low-risk group – 76% of them would have received R-CHOP consolidation using the preceding PTLD-1 RSST protocol.
OS and PFS were significantly different in the three risk groups – however, DR as a measure of the quality of remissions was very similar. Observed similar ORR, TTP, OS and PFS compared to the preceding PTLD-1 ST and RSST trials.
The 2-year EFS in the low-risk group was numerically, but not statistically, superior to a pre-specified comparator group from the.
The primary end point of the trial was not met, and the original trial hypothesis is rejected.
Alternative treatment strategies are needed for this very-high-risk subgroup.
There was no significant differences in ORR between rituximab SC and IV, nor a sex-specific difference.
Limitations of this trial:
Small size.
Lack of international recruitment due to funding constraints.
Level of evidence : Level 1 prospective open-label phase II trial
PTLD 2 TRIAL
RISK MODIFICATION IN PTLD was achieved in PTLD1 trail
this modification is tested in PTLD 2 TRIAL
PTLD-1 TRIAL FEATURES
RESPONSE TO RITUXIMAB IS PROGNOSTIC FACTOR
RTX monotherapy consolidation for low risk patient
RTX and CHOP for high risk patient
thoracic organ transplant is poor prognostic factor in RTX non responder
so, thoracic SOT and disease progression under rituximab induction may be get benefit from
intensified immunochemotherapy
PTLD 2 TRIAL
open label
phase 2
inclusion – post solid organ transplant with CD 20 positive PTLD in Germany
multicentric
non response to reduction in IS
EXCLUSION – PREGNANCY , HIV ,CNS LESION , inability to atke study drugs
all tissue reviewed by 2 pathologist
WHO classification used
EBV transcript tested
study design
RTX 1400 mg sc on day 1,8,15 and 22
assessment at 40-50 days by ct scan
LOW RISK- patient with CR , patient with PR and less than 3 IPI,>60 yrs , >2 LDH , >stage III __
4 THREE WEEKLY RTX
HIGH RISK – all other
4 CYCLES OF RCHOP
median follow up 2.8 yrs
The primary endpoint was Event Free Survival ( no progression , stoppage of therapy , death or infection III/IV ) in the low-risk group.
these patient were compared with 25 patient from PTDL1 trial wherein CHOP was given to them
58 PATIENTS EVALUATED
48 PATIENT RECIEVED ALL 4 DOSES OF RTX
21 IN LOW RISK GRPOUP,
28 IN HIGH RSK GROUP , 22/28 COULD BE EVALUATED AT FINAAL STAGE
5 HAS CR
21 HAD PR
CONCLUSION
rituximab monotherapy consolidation in an expanded low-rise group including patients with <3 IPI risk factors in PR after
rituximab induction is a safe and feasible alternative to CHOP
consolidation.
Post-transplant lymphoproliferative disorders (PTLD) is a common malignancy following solid organ transplantatio. PTLD-2 trial hypothesized that; rituximab monotherapy consolidation may be better in low risk group may be better than CHOP consolidation in comparable patients of PTLD1 trial. Patients with severe thoracic SOT might be a candidate for aggressive therapy (6 cycles of R-CHOP and modified R-DHAOx with reduced dose of cytarabine and steroids)
Method:
Prospective, multi-center open labelled study. Include patients diagnosed with CD4+ve PTLD from 15 centers in Germany. The study start at Feb. 3rd 2015 to July 13th 2020.Included patients were naive adult SOT recipients, patients with insufficient response to RIS, measurable disease>2 cm with or without bone marrow involvement & patients with ECOG performance status<2. Excluded patients include patients with CNS involvement, pregnancy or nursing, patients with contraindication for treatment as heart disease or infections.
Treatment regime was rituximab (1400mg, 1st dose 375m2 IV) on day 0, 8, 15 & 22. Then intro stage (D40-50). CT image used to assess response to treatment during intermission & final staging. Treatment of low risk patient at diagnosis, patients with CR or partial remission consist of 4 courses (every 3 weeks) of rituximab. Treatment of high risk patients was 4 courses of R-CHOP..Treatment of very high risk patients was 6 cycles of alternating R-CHOP & modified R-DHACX every 3 weeks. Patients with suspicion of disease progression before intermission staging, need re-staging & treated as high risk or very high risk group if disease progression confirmed. PJP prophylaxis & G-CSF is mandatory . Final assessment done 1 month after last cycle of treatment. The patients followed every 3 months for 2 years.
RESULTS:
Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Overall response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 In the low-risk group, 2-year EFS was 66% ( versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with RCHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Discussion:
This prospective, multicenter, phase II trial tested modified risk stratified sequential
treatment of CD20-positive PTLD in adults after SOT. observed similar ORR, TTP, OS
and PFS compared to the preceding PTLD-1 ST and RSST trials Limitations of this trial :
included its small size .
lack of international recruitment due to funding constraints.
This may have resulted in the over-representation of lung transplant recipients who
have a poor prognosis.
What is the level of evidence provided by this article?
1. Please summarise this article INTRODUCTION: (Basis of this trial) This prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification. The PTLD-1 sequential treatment (ST) trial demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy. The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) established rituximab monotherapy consolidation for patients in a complete remission (CR) after rituximab induction and R-CHOP-21 for all non-CR patients. The question raised by this result was whether rituximab monotherapy consolidation might be sufficient treatment for additional PTLD patients?? Further analyses of the initial PTLD-1 ST trial identified the prognostic value of international prognostic index (IPI) risk factors (≥3 vs <3), Thoracic SOT, response to Retuximab. PTLD-2 trial tested modified risk-stratification based on these three risk factors METHODS Study design Prospective, multicentre, open-label phase II trial Period – from February 3rd, 2015 until July 13th, 2020 Patients enrolled from 15 centres in Germany Patients included – Treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD Incomplete response to immunosuppression reduction (RIS) Measurable disease > 2 cm in diameter (and/or bone marrow involvement) ECOG performance status ≤2. Exclusion criteria CNS involvement; pregnancy or nursing concomitant disease precluding administration of therapy (severe uncontrolled heart disease, HIV, severe active infections). TREATMENT PLAN Rituximab 375mg/M2 IV on day-1 followed by Retuximab 1400 mg SC was administered on days 8, 15, and 22 The interim staging with clinical + CT was done on (day 40–50). PTLD-adapted response criteria for malignant lymphomas were used to assess treatment response. Patients in CR as well as those in partial remission (low-risk group) continued with four three-weekly courses of rituximab. Most other patients (high-risk group) received 4 cycles of SC.R-CHOP-21 Thoracic SOT, recipients who progressed under rituximab (very-high-risk group) received six cycles of chemotherapy — RSC-CHOP and RSC-DHAOx alternatively at three-week intervals. Median follow-up for the whole trial cohort, the low and high-risk group was 2.8 years (4.9 years for the very-high-risk group). Statistical analysis: Analysis was by intention to treat (ITT) unless otherwise specified. The primary endpoint was EFS in the low-risk group. Secondary endpoints – overall response rate (ORR), OS, time to progression (TTP), progression-free survival (PFS), response duration (RD) and Tt Related Mortality (TRM) – overall and by risk group Pre-specified subgroup analyses were performed according to EBV-association in males and females RESULTS: – 60 patients enrolled – 58 evaluated for response to Retuximab induction – 48 received all 4 doses – 10 patients had disease progressions, did not receive the four scheduled Retuxi
– 26/58 patients (45%) responded to rituximab monotherapy induction – 5/58 (9%) achieved CR Low-risk group: 21 patients (5 in CR and 16 in PR with baseline IPI < 3)
· received S/C Rituximab consolidation 4 doses on day 50,72,94, 116.
· ORR to rituximab monotherapy was 100%.
High risk group: 28 patients allocated; 26/28 received treatment with R-CHOP-21
· 22/28 patients could be evaluated at final staging. Very high-risk group: 9 thoracic SOT recipients, with disease progression at interim staging
· 5/9 patients could be evaluated at final staging.
· 8/15 lung transplant recipients were stratified to the very-high-risk group. 6 patients who had Burkitt’s Lymphoma and high grade BCL type and MYC-rearrangement type PTLD were allocated to high-risk group (not in low-risk nor very-high-risk groups). Over all Outcome The overall response rate at final staging was 94% (45/48); CR: 46%; The 2-year Kaplan–Meier (KM) estimate of RD was 81% In the ITT population (60 patients) – 2-year KM estimate of TTP was 78%; OS was 68% (5.1 yrs) Treatment related Toxicity: Pneumonia (9), Febrile neutropenia (8), Sepsis (6), Varicella zoster (3) 4 patients had grade 3/4 infection – with EFS episodes (19% vs. 32% for the comparison group). Common grade 3/4 adverse events – anaemia, thrombocytopenia, ARF, GI bleed IV Rituxi infusion-related reactions seen in 8/59 patients (14%); Grade 1/ 2 and local drug reactions in 4/59 Outcome and toxicity by treatment group Low-risk group: ORR to rituximab monotherapy was 100% 4 grade 3/4 infections associated with EFS episodes Both the TTP and PFS projections for the next two and three years were 85%.
High-risk group: ORR at the final stage was 100% (22/22); CR 9/22 [41%]. The 2- and 3-year KM estimate was 79%, however, the median RD was not met. 13/26 patients experienced grade 3/4 infections after chemotherapy. Very-High-risk group: at final stage 5/9 patients could be assessed. 2/5 (or 40%) of respondents had CR. Median RD was 1.2 yrs; TTP estimate at 2 years was 33%.
There were no appreciable changes in ORR, TTP, or OS between rituximab SC and the earlier treatment regimens in terms of response rates and time-to-event outcomes. EBV-association and sex subgroup analyses that were pre-specified did not find any appreciable differences between the two therapies. Prognostic factors 3 risk groups in this regimen had very varied OS and PFS, but not TTP or DR Baseline IPI was a standalone predictive factor for both TTP and OS in a multivariate study. DISCUSSION : The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with 4 cycles of weekly IV rituximab, followed by 4 cycles of CHOP-21 for patients unresponsive to initial RIS. This prospective, multicentre, phase II trial tested modified risk stratified sequential treatment of CD20-positive PTLD in adults after SOT. PTLD-2 trial used treatment stratification based on response to Retuxi and staging based on CT imaging rather than PET, so that the protocol can be applied worldwide, also to compare with the earlier PTLD-1 trial. Patient allocation to “very-high-risk group” was based on 2 previously identified poor risk factors – progressive disease under rituximab induction and thoracic SOT. Intensified immunochemotherapy could not overcome the poor prognosis in the very-high-risk subgroup patients. Although grade 3/4 infections were high (42%), there was no cases of PJP under strict antibiotic prophylaxis.
Complete remission rates after 4 weekly courses of rituximab monotherapy might be slightly lower with rituximab SC Limitations of this trial · small size and lack of international enrolment · Toxicity and efficacy for the PTLD subgroup were not analysed, The evidence available does not encounter the concept of risk stratified sequential treatment as first-line treatment of CD20- positive PTLD in adults after SOT. 1. What is the level of evidence provided by this article Prospective, multicentre, open-label phase II trial – level 1
INTRODUCTION
· The PTLD-1 sequential treatment demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy and established response to rituximab induction as a prognostic factor
· The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) established rituximab monotherapy consolidation for patients in a complete remission (CR) after rituximab induction and R-CHOP-21 for all non-CR patients
· Further analyses of the initial PTLD-1 ST trial identified the prognostic value of international prognostic index (IPI) risk factors (≥3 vs<3) and thoracic SOT in addition to response to rituximab
· The PTLD-2 trial tested modified risk-stratification based on these three clinical risk factors
METHODS Study design and patients Inclusion Criteria
· treatmentnaïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020
· insufficient response to upfront immunosuppression reduction, measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Exclusion criteria
· central nervous system involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Treatment plan
· rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
· Patients in CR as well as those in partial remission (low-risk group) continued with four three-weekly courses of rituximab
· Most other patients (high-risk group) received four cycles of SC.R-CHOP-21
· Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals
· Median follow-up for the whole trial cohort as well as the low- and high-risk groups was 2.8 years (4.9 years for the very-high-risk group).
DISCUSSION
· The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients unresponsive to initial immunosuppression reduction.
· This prospective, multicentre, phase II trial tested modified risk stratified sequential treatment of CD20-positive PTLD in adults after SOT.
· The PTLD-2 study used treatment stratification based on response to treatment at temporary staging based on CT imaging rather than PET to ensure that the protocol can be applyed worldwide and to maintain comparability with the earlier PTLD-1 trials.
· Patient allocation to the very-high-risk group of the PTLD-2 protocol was based on two previously identified risk factors for poor outcome: progressive disease under rituximab induction and thoracic organ transplant
· intensifying immunochemotherapy does not overcome the poor prognosis in the very-high-risk subgroup patients.
· the rate of grade 3/4 infections was high (42%) but there was no cases of pneumocystis jirovecii pneumonia under strict antibiotic prophylaxis.
· Complete remission rates after 4 weekly courses of rituximab monotherapy might be slightly lower with rituximab SC
Limitations of this trial
· small size and lack of international enrolment due to funding limits.
· Toxicity and efficacy for the PTLD subgroup were not analysed,
· The evidence available does not encounter the concept of risk stratified sequential treatment as first-line treatment of CD20- positive PTLD in adults after SOT.
This is a prospective, multi-centre, with level of evidence grade 1.
Please summarise this article Epstein-Barr virus (EBV) is a member of the gamma herpes virus family that is associated with a variety of lymphomas and lymphoproliferative disorders (LPD). It infects more than 90% of the adult population worldwide. have different clinical presentations include asymptomatic infection to symptomatic disease. Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation and hematopoietic stem-cell transplant and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance.
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 treatment
What is the level of evidence provided by this article?
level 1
INTRODUCTION:
After solid organ transplantation, immunosuppression can lead to problems called post-transplant lymphoproliferative diseases (PTLD) (SOT).
In-depth reviews of their epidemiology, etiology, classification, presentation, and therapy have already been done.
METHODS Study design and patients
· This prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centers in Germany from February 3rd, 2015 until July 13th, 2020.
· Central nervous system involvement, pregnancy, or concurrent diseases that made it impossible to provide study treatment were the main exclusion criteria.
TREATMENT PLAN
· Rituximab (1400 mg SC; initial application.375 mg/m2 IV) was administered on days 1, 8, 15, and 22 as part of the treatment. The interim staging was then performed (day.40–50).
· PTLD-adapted response criteria for malignant lymphomas were used to assess treatment response at intermediate and final stages. RESULTS Patients
· 60 patients were treated with the medication; the median follow-up period was 2.8 years; 26/58 patients responded to rituximab monotherapy induction; and 5/58 (9%, 95% CI 3-19) patients attained a CR after beginning the medication.
· The six patients who had BCL and PTLD of the MYC-rearrangement type were not treated in the low-risk or very-high-risk groups
· Twenty-six of the 21 patients who were assigned to the low-risk group continued to receive therapy; four patients discontinued due to infections and declining transplant function.
Outcome and toxicity
At the final stage, the response rate was 94% overall (45/48, 95% CI 83-98). The Kaplan-Meier (KM) estimate of RD over a two-year period was 81% (95% CI 68-94). TTP was 78% and OS was 68% in the 60 patients in the population that was intended to be treated (5.1 years). The toxicity of treatment.
· Pneumonia (9).
· Febrile neutropenia (8).
· Sepsis (6).
· reactivation of varicella zoster, (3)
· Infections of grade 3/4 were observed in 25/59 cases (42%, 95% CI 31-55).
· Rituximab IV infusion-related responses occurred in 8/59 patients (14%, 95% CI 7-25; all grade 1 or 2) and local drug reactions in 4/59 individuals.
· Nanaemia, thrombocytopenia, acute renal failure and gastrointestinal bleeding were another common grade 3/4 adverse effects. Outcome and toxicity by treatment group
· In the low-risk group, the overall response rate (ORR) to rituximab monotherapy was 100 percent.
· From day 50 to day 143, there were 4 grade 3/4 infections associated with EFS episodes (19% vs. 32% for the comparison group).
· Both the TTP and PFS projections for the next two and three years were 85%.
· The ORR at the final stage in the high-risk group was 100% (22/22; CR 9/22 [41%]).
· The 2- and 3-year KM estimate was 79% (95% CI 59-98), however, the median RD was not met.
· 13/26 participants in this group of patients experienced grade 3/4 infections after receiving chemotherapy.
· At the final stage, the response in 5/9 patients in the very-high-risk group could be assessed. 2/5 (or 40%) of respondents had two patients in CR.
· 1.2 years was the median RD. The TTP estimate at 2 years was 33%.
· There were no appreciable changes in ORR, TTP, or OS between rituximab SC and the earlier treatment regimens in terms of response rates and time-to-event outcomes.
· EBV-association and sex subgroup analyses that were pre-specified did not find any appreciable differences between the two therapies.
Prognostic factors
· The three risk groups in this regimen had very varied OS and PFS, but not TTP or DR (n = 58, p 0.001).
· Baseline IPI was a standalone predictive factor for both TTP and OS in a multivariate study.
Discussion
· The PTLD-1 study established sequential therapy with four rounds of weekly rituximab followed by four cycles of CHOP-21 for patients, creating a new benchmark in CD20-positive B-cell PTLD.
· It contrasted favorably to past rituximab monotherapy studies, with a median OS of 6.6 years and a distinct plateau on the PFS curve.
· Why Patients in the low-risk group of the R-CHOP study received rituximab monotherapy instead of chemotherapy; 76% of these patients would have been treated according to the previous PTLD-1st ST and RSST protocol.
· OS and PFS in the three risk groups were considerably different, although DR, a gauge of how well patients recovered, was relatively comparable.
· The low-risk group’s 2-year EFS was numerically, but not statistically, superior to that of a pre-determined comparison group from the.
· Treatment of the PTLD-1 ST trial with CHOP consolidation.
· Because the experiment’s main objective was not achieved, the initial trial hypothesis was disproved.
· To guarantee that the procedure could be utilized globally, the PTLD-2 trial used therapy stratification based on response to treatment at intermediate staging based on CT imaging rather than positron emission tomography (PET).
· It has been demonstrated that in PTLD, PET identifies individuals at low risk of relapsing and provides clinically useful information.
· It is doubtful that PET-based interim staging would have found more low-risk patients.
· Only 5/58 patients, who had a PR at interim staging and an IPI of 3, were deemed to be high-risk.
· In multivariate analysis, the risk factor no longer has a favorable prognostic value for TTP.
· The poor prognosis in this subset of individuals with Epstein-Barr virus illness is not improved by immuno-chemotherapy (EBV-associated PTLD).
· Other therapy modalities are necessary for this population of patients with an exceedingly high risk.
· Outcomes (ORR, TTP, and OS) were nearly identical irrespective of EBV association, in contrast to the differences in genomic profiles between CD20-positive and CD8-positive patients. The rate of grade 3/4 infections was high (42%) in patients treated with immunochemotherapy for DLBCL, but there were no cases of pneumocystis jirovecii under strict antibiotic prophylaxis.
· This is consistent with findings published for the same drug in follicular lymphoma and in combination with CHOP in DLBCL. We did not discover any variations in ORR between rituximab SC and IV, nor a sex-specific difference.
· However, it’s possible that rituximab SC has somewhat lower CR rates following four weekly cycles of monotherapy.
========================================= What is the level of evidence provided by this article?
Introduction: PTLD-1 showed the safety & efficacy of 4 cycles of rituximab (weekly) followed by 4 cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine &prednisolone, every 21 days) with established response to rituximab induction. It showed the efficacy of rituximab as monotherapy for patients in complete remission after rituximab induction & R-CHOP-21 for all non-complete remission. this result raised the that rituximab monotherapy might be sufficient for additional PTLD patients. In the PTLD-2 trial, the key hypothesis was to assume that expanding the low-risk group would be superior to CHOP treatment in comparison to the PTLD-1 trial as regard event-free survival at 2 years by lowering rates of infection with the same efficacy. Study design This prospective, multicentre, open-label phase II trial enrolled treatment[1]naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 202. Additional inclusion criteria were an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. The main exclusion criteria were central nervous system involvement, pregnancy or nursing, and concomitant diseases that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections. Treatment plan – Rituximab 1400 mg SC weekly for four doses & assessment response by CT imaging. – Low risk group: Patient in complete remission & those in partial remission+IPI <3 risk factors( age>60 , ANN arbor stage III or more , ECOG performance status 2 or mre , elevated LDH & >1 extra nodal disease manifestation) four doses of weekly rituximab – High-risk group (most other patients) 4 cycles of R-CHOP-21. – Very high-risk group (thoracic SOT who progressed under rituximab) received 6 cycles of R-CHOP & modified R-DHAOx in a 3-week interval Conclusion: – The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group, and 0% in the very-high-risk group. – the primary endpoint of the trial was not met and the original trial hypothesis(rituximab consolidation results in lower toxicity and similar efficacy) is rejected. – Level of evidence: level 1
PTLD is known complication of immunosuppression post-transplantation,
This study was conducted by German PTLD study group with collaboration of European PTLD Network, this was an evidence based study protocol for CD20- positive B-cell PTLD in adults.
They compared the rituximab monotherapy trails with retrospective case series of first line chemotherapy, they denoted improved median overall survival.
PTLD-1 demonstrated the safety and efficacy of four cycles of rituximab followed by CHOP-21(4 cycle), and established rituximab monotherapy response to rituximab induction as a prognostic factor.
The PTLD-1 trial also identified the prognostic value of IPI risk factor >3 -<3. The primary end point was event free survival (EFS) in the low risk group, the PTLD-1 trial rituximab was given subcutaneously, total of 60 patients enrolled
The key hypotheses was that modified in the PTLD-2 trial demonstrated whether rituximab monotherapy consolidation in an expanded low risk group is superior to CHOP consolidation in comparable patient of the PTLD-1 ST trial by denoting a better event free survival at two years, based on lower rate of ¾ infection and similar efficacy. The lower risk group receiving rituximab was expended compared to the RSST protocol.
Thoracic organ transplant was a prognostic factor, those not responding to rituximab in PTLD-1 group ST trial. So this was hypothesized that patients with thoracic SOT and non-responder with rituximab induction might benefit from intensified immunosuppression, these are given alternating six cycles of R-CHOP and modified R-DHAOx every three weeks.
Rituximab dose was modified to 1400mg SC due to non-inferior pharmacological profile to IV.
Methods;
This was multicenter open label phase II trial done at 15 centeres in Germany from February 2015 to July 2020 and they enrolled the recipient diagnosed with CD20 positive PTLD patients.
The inclusion criteria was non-responders with modified immunosuppression,
Disease >2 cm or bone marrow involvement.
ECOG performance status <2.
Exclusion criteria was CNS involvement,
Pregnant, nursing mother, and concomitant disease like heart failure, other infections.
Treatment plan;
The total number of candidates enrolled were catogerized into three groups,
Low risk,
High risk group,
Very high risk group,
Treatment given alternating six cycles of R-CHOP and modified R-DHAOx every three weeks.
Response to monotherapy was 100% in low risk group.
Rituximab dose was modified to 1400mg SC due to non-inferior pharmacological profile to IV followed by interim staging at day 40-50s.
Patient in CR and in partial remission were considered according to IPI score <3 with risk factors of age >60. ECOG score >2, raised LDH continued with four cycle of SC R-CHOP.
Candidate who were given intensified regimen with thoracic SOT recipient were high risk group (response 18%). Response was 0% in very high risk group.
Similarl to PTLD-1 trial PJP chemoprophylaxis were given.
The primary end point by two years low risk 66%.
Prognostic factor;
Thoracic organ SOT was an independent risk factor.
In high risk group had a highly significant different OS and PFS.
The only baseline score IPI >3 remained an independent prognostic factor for both TTP and OS.
Result;
The overall response rate at the end was 94%, RD 81% at two years.
The total number of candidates enrolled were categorized into three groups, treatment related mortality was around 7%.
With monotherapy the response was, Low risk group- 21 patients- 2 year EFS was 66% and OS was 100%.
High risk group, 28-patients, completed the protocol, overall response rate was 18%, while, Very high risk group- 9- patients was zero percent.
IV. Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicenter phase II PTLD-2 trial
Please summarise this article
Introduction
PTLD is a complication of immunosuppression following SOT. The prospective multicenter Phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20+ PTLD based on two principles established in the PTLD-1 trials i.e., sequential
treatment and risk stratification.
Methods
– prospective, multicenter, open-label phase II trial
– inclusion criteria: –
·treatment naïve adult SOT recipients diagnosed with CD20+ PTLD at 15 centers in Germany between 3rd February 2015 and 13th July 2020
·insufficient response to immunosuppression reduction (± antiviral therapy)
·measurable disease >2cm in diameter (and/ or bone marrow involvement)
·an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
– exclusion criteria: –
·CNS involvement, pregnancy, lactation
·concomitant disease precluding administration of the study drugs e.g., severe uncontrolled heart disease, severe active infections, HIV infection
– the collected tissue samples were reviewed by two expert hematopathologists and classified as per the WHO classification system
– treatment consisted of 4 doses of weekly rituximab followed by interim staging, four 3-weekly courses of rituximab for responders/ low risk group and 4 cycles of R-CHOP-21 for high risk patients
– PCP prophylaxis and G-CSF treatment was offered following chemotherapy
– the PTLD-adapted response criteria was used to assess response to treatment
– follow-up data was evaluated till July 2021
– the primary endpoint was event-free-survival (EFS) in the low-risk group
– PTLD-1 trials provided historical controls
Statistical analysis
– Analysis was by intention to treat (ITT).
– Primary endpoint was EFS in the low-risk group.
– Events included infections, treatment discontinuation, disease progression and death.
– the pre-specified comparator group included 25 patients in either complete (CR) or partial remission (PR).
– Secondary endpoints included overall response rate (ORR), overall survival (OS), time to progression (TTP), progression-free survival (PFS), response duration (RD) and therapy-related mortality (TRM) overall and by risk group.
– Adverse events were documented.
– Pre-specified subgroup analyses were performed according to sex and EBV-association.
– Results from PTLD-1 trials and relevant subgroups based on response to rituximab, IPI and transplanted organ were used for pre-specified historical comparisons of toxicity, survival and efficacy.
Results
Treatment
– 60 patients were enrolled. One patient died before initiation of treatment and another during treatment.
– 58 patients were evaluated for response to rituximab induction, 48 of them received all 4 scheduled doses. The remaining 10 patients had disease progression during treatment.
– 26 patients responded to rituximab monotherapy induction and 5 patients achieved complete remission.
– 21 patients were allocated to the low-risk group, 28 patients were allocated to the high-risk group. 9 were allocated to the very-high risk group.
– 26/28 patients received R-CHOP-21. Two did not receive treatment due to deteriorating transplant function and tuberculosis. Four patients discontinued treatment due to infections hence 22/28 patients were evaluated at final staging.
– 5/9 patients in the very high-risk group were evaluated at the final staging.
– There were differences in the baseline characteristics used for stratification in the different risk groups i.e., transplanted organ, IPI risk factors, rate of early PTLD and rate of EBV association.
Outcome and toxicity
– Overall response rate at final staging was 45/48. Estimates of time to progression and overall survival were 78% and 68% respectively similar to the PTLD-1 trials.
– treatment related mortality (TRM) was 4/59
Outcome and toxicity by treatment group
– Overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
– 2-year event-free survival (EFS) was 66% in the low-risk group vs 52% in the PTLD-1 trial that received CHOP.
– 2-year overall survival was 100% in the low-risk group. The overall response rate at final staging was 100% in the high-risk group.
– There were no significant differences in the overall response rates, time to progression or overall survival.
Prognostic factors
– The overall survival and progression free survival were highly significantly different in the 3 risk groups.
– upon multivariate analysis, only baseline IPI >3 remained an independent prognostic factor for both time to progression and overall survival. Thoracic organ SOT was an independent risk factor for overall survival.
Patients with rituximab monotherapy consolidation in the low-risk groups of PTLD-1 RSST and PTLD-2
– There were no differences in the overall survival or progression free survival.
– The only significant differences were found in the patients who had >3 IPI risk factors and in the presence of individual IPI risk factors i.e., elevated serum LDH activity and extra-nodal disease.
Discussion
This was a prospective, multicenter, phase 2 trial which was testing the modified risk stratified sequential treatment for CD20+ PTLD in adult SOT recipients.
There was no difference in the overall response rate, time to progression and progression free survival compared to the preceding trials i.e., PTLD-1 ST and RSST trials.
Progression free survival and overall survival were significantly different in the three different risk groups i.e., low-risk, high-risk and very-high-risk groups.
The primary end-point of the trial was not met.
Study limitations
– Small size
– Lack of international recruitment
Study strengths
– multicenter
– prospective
Conclusion
In low-risk patients rituximab is a favorable option. It can still be used in high-risk patients but larger studies are needed to look at alternative treatment strategies.
What is the level of evidence provided by this article?
After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21
The PTLD-1 sequential treatment (ST) trial (n = 70) demonstrated fi the safety and ef cacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days) and established response to rituximab induction as a prognostic factor fi .
The subsequent trial of risk-strati ed sequential treatment (PTLD-1 RSST, n = 152) established rituximab monotherapy consolidation for patients in a complete remission (CR) after rituximab induction and R-CHOP-21 (rituximab and CHOP-21) for all non-CR patients .
Finally, rituximab at a dose of 1400 mg SC was chosen based on fi its non-inferior pharmacokinetic pro le compared to 375 mg/m2 intravenously (IV) in immunocompetent patients with follicular lymphoma and reports of rituximab IV serum concentrations during immunochemotherapy correlating with patient sex and clinical response .
Treatment plan
fi Treatment consisted of rituximab (1400 mg SC; rst application 375 mg/m 2 IV) on days 1, 8, 15 and 22, followed by interim staging (day fi 40–50). Response to treatment at interim and nal staging was determined according to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging .
Patients in CR as well as those in partial remission (PR) with <3 international prognostic index (IPI) ≥ risk factors (age > 60 years, Ann Arbor stage III, ECOG performance status ≥ 2, elevated serum lactate dehydrogenase activity [LDH], and more than one extranodal disease manifestation) at diagnosis (low-risk group) continued with four three-weekly courses of rituximab .
Most other patients (high-risk group) received four cycles of RSC -CHOP-21 (for doses see Supplementary Appendix)
Similar to the PTLD-1 trials, pneumocystis jirovecii chemoprophylaxis and treatment with granulocyte-colony stimulating factor after chemotherapy were fi obligatory. The nal response assessment was performed one month after the last cycle of therapy. Patients completed follow-up examinations every three months for two years, and annually thereafter.
Outcome and toxicity by treatment group The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
The prefi speci ed subgroup analyses (EBV-association and sex) detected fi no signi cant differences in ORR, TTP or OS. There were no sexfi speci c differences in the response to rituximab SC compared to fi rituximab IV in a pre-speci ed inter-trial comparison with combined data from the PTLD-1 ST and PTLD-1 RSST trials
The only signi cant differences were ≥ found in the number of patients with 3 IPI risk factors fi (excluded from the PR group by de nition) and in the presence of individual IPI risk factors (‘elevated serum LDH activity’, ‘extranodal disease’). There were no differences in overall survival
treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients unresponsive to initial immunosuppression reduction.
rituximab monotherapy consolidation in an expanded lowrisk group including patients with <3 IPI risk factors in PR after rituximab induction is a safe and feasible alternative to CHOP consolidation.
As in our preceding trials, the rate of grade 3/4 infections was high (42%). However, we observed no cases of pneumocystis jirovecii pneumonia under stringent antibiotic prophylaxis. TRM occurred exclusively in patients treated with immunochemotherapy with an overall rate of 7%, very similar to immunocompetent patients over 60 years treated with R-CHOP immunochemotherapy for DLBCL .
Limitations of this trial included its small size and lack of international recruitment due to funding constraints.
MODIFIED RISK STRATIFIED SEQUENTIAL TX (SC RTX +/- CHEMO) IN B CELL PTLD AFTER SOT;PROSPECTIVE MYLTICENTR PHASE 2 PTLD 2 TRIAL.
INTRODUCTION.
PTLD does occur post transplant from immunity dysfunction from immunosuppressive medications used to aver rejection. European and German PTLD groups had an evidence based TX for CD20+VE pts that showed a fairer median survival compared to smaller RTX monotherapy and less TX related mortality vs retrospective case series of 1st line chemo.
PTLD 1 sequential trial established safety and good outcomes of x4 cycles of RTX followed by x4 cycles of CHOP 21.It recommended RTX monotherapy post induction in pts with CR and R-CHOP 21 for the PR group.
STUDY DESIGN.
-Prospective multicenter open label study.
-Site ; 15 Germany hospitals.
-Study period ; 3/2/2015 -13/7/2020
-Study group-TX naïve adult SOT pts with CD20+VE PTLD.
INCLUSION CRITERIA.
-CD 20+VE PTLD adult SOT.
-Inadequate response to RI +/ ANTIVIRAL THERAPY.
-Quantifiable dx >2 cm diameter + BM involvement.
EXCLUSION CRITERIA.
-CNS involvement.
-Pregnancy /Nursing.
-Concomitant dx that was present before study commenced e.g. RVD +VE status, cardiac dx or any other active infection.
RESULTS.
-Post induction RTX tx pts with no chemo were in CR and PR with IPI3 at diagnosis. The high risk group were given R CHOP 21 with primary result being an event free survival post tx.
-60 pts were involved ;
21 low risk,28 high risk and 9 very high risk.
94 %of pts expected dx advancement(78%) with an overall survival rate of 68% which matched PTLD1 trial results.7% of pts died from tx.
In comparison to previous studies on CHOP,2 yr event free survival period in LR group was 66%(95% CI,45-86) vs 52%(P=0.432)
For RTX monotherapy, response was 100% in LR group,18% in HR group and no response in VHR group.
We had lots of reported toxicities in the HR group on chemo.
No incidences of PCP or PML were reported – pts were on PCP prophylaxes.
STUDY STRENGTHS
-Multicenter study.
STUDY LIMITATIONS.
-Small sample size.
-Limited funding.
-Restricted to one part of the continent and as such its findings cannot be extrapolated to other regions and races.
CONCLUSION.
RTX is safe and good option post induction in LR EBV PTLD pts while in HR groups, more studies are needed on other treatment modalities to better our outcomes post transplant.
Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial Introduction:
Lymphoproliferative Malignancy (PTLD): is the second most common malignancy occurring post solid organ transplant in adults.
It is associated with significant morbidity and mortality with an increased risk of graft loss.
The treatment response has improved after the introduction of rituximab.
The PTLD-1 sequential treatment trial demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 chemotherapy and established response to rituximab induction as a prognostic factor.
The subsequent trial of risk-stratified sequential treatment established rituximab monotherapy consolidation for patients in complete remission after rituximab induction and R-CHOP.
The PTLD-1 trial also identified the prognostic value of IPI risk factors (>3 vs <3)
The PTLD-2 trial therefore tested whether rituximab mono therapy consolidation in an expanded low risk group would be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial by demonstrating an improved event free survival at 2 years, based on a lower rated of grade 3/4 infections and similar efficacy.
Thoracic organ transplant was a prognostic factor for a shorter TTP in rituximab non-responders in the PTLD-1 ST trial.
It was hypothesized that patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified chemotherapy. A dose of 1400 mg of SC rituximab was chosen.
Study design and patient Prospective, multicentre open-label Phase II trial enrolled treatment involving a total of 60 patients
The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Inclusion criteria Adult SOT recipients diagnosed with CD20-positive PTLD within the study year Inadequate response to RI (with or without antiviral therapy) measurable disease >2cm or bone marrow involvement
Exclusion criteria CNS involvement pregnancy or nursing The concomitant disease that precludes the administration of study therapy Diagnostic tissues were collected and stored centrally for review by two hematopathologists and classified based on WHO classification
METHODS:
This prospective, multi-centre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020
Phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification.
This is divided into three groups based on the responses (either CR or PR) to the different treatments:
–low-risk group
–high-risk group
–very high-risk group
-Low-risk: patients in complete remission as well as those in partial remission continued with rituximab monotherapy and thus chemotherapy free
-High-risk: received R-CHOP-21
-Very-high-risk: Thoracic SOT recipients who progressed , received alternating R-CHOP-21 and modified R-DHAO
Chemoprophylaxis for PJP was administered to all the groups as was done for the PTLD-1 trial and the final response to treatment was performed one month after the last cycle of therapy
-Consisted of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
-After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free.
Most others (high-risk) received R-CHOP-21.
Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx
*Outcome: event-free survival (EFS) in the low-risk group
Statistical analysis:
Analysis was by intention to treat (ITT) unless otherwise specified. The per protocol (PP) population included all patients treated according to protocol with a minimum number of two treatment cycles and sufficient information to determine remission status.
Primary outcomes:
-The response rate at interim and final staging. -Treatment hematological toxicity and infections.
Secondery end points:
-Overall response rate (ORR). -Time to progression (TTP). -Treatment related mortality (TRM)- assed by treating physician.. -Response duration(RD) -from complete or partial response at final staging to disease progression. -Progression free survival (PFS) and Overall survival (OS) -from the start of treatment to progression and death from any cause.
Result:
The response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 . In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP (p = 0.432).
TWO -Year OS in the low-risk group was 100%. Results with RCHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Outcome and toxicity:
The overall response rate at final staging was 94% Toxicity of treatment was significant.
The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Patients treated with rituximab monotherapy consolidation in the low-risk groups of PTLD-1 RSST and PTLD-2:
Phase II PTLD-2 trial :
tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials:
The PTLD-1 sequential treatment (ST) trial (n = 70) demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days) and established response to rituximab induction as a prognostic factor
Strength of the study :
-Multicentric
-Standard Staging protocols
-Better follow ups
Limitations:
–Small sample Size
–Less diversity in sample
-Lack of international recruitment
Conclusion :
The Rituximab monotherapy response at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group(may be helpful but still larger studies using other treatment strategies are needed to improve outcome).
Level of Evidence :
A prospective, multi-centre, open-label phase II trial, (level of evidence grade 1).
Post transplant lymph proliferative disorders -PTLD are important complication of immune suppression after solid organ transplant. In this prospective , multicentre, open label, phase 2 trial , included treatment naive SOT recipients who had developed CD 20 PTLD. This involved 15 centres in Germany, from February 2015 to July 2020.
Patient in complete or partial remission were labelled as low risk and were continued on Rituximab without chemotherapy
High risk group – Received R- CHOP- 21
Thoracic SOT recipients which progressed received R- CHOP-21 alternating with modified R-DHAO
The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Results
The response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 . In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP (p = 0.432).
2-year OS in the low-risk group was 100%. Results with RCHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Outcomes
Event free survival in low risk group
Strengths
Multicentric Standard Staging protocols Better follow ups
Limitations Small sample Less diversity in sample
What is the level of evidence provided by this article? Level of evidence 1
Post-transplant lymphoproliferative disorders (PTLD) are complications of immunosuppression after solid organ transplantation (SOT)
METHODS :
This prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020
Phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification.
low-risk: patients in complete remission as well as those in partial remission
continued with rituximab monotherapy and thus chemotherapy free
high-risk: received R-CHOP-21
very-high-risk: Thoracic SOT recipients who progressed , received alternating R-CHOP-21 and modified R-DHAO
Treatment plan:
consisted of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
Statistical analysis
Analysis was by intention to treat (ITT) unless otherwise specified. The per protocol (PP) population included all patients treated according to protocol with a minimum number of two treatment cycles and sufficient information to determine remission status.
RESULTS:
Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Overall response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 In the low-risk group, 2-year EFS was 66% ( versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with RCHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Outcome and toxicity:
The overall response rate at final staging was 94% Toxicity of treatment was significant.
The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Patients treated with rituximab monotherapy consolidation in the low-risk groups of PTLD-1 RSST and PTLD-2:
Phase II PTLD-2 trial : tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials:
The PTLD-1 sequential treatment (ST) trial (n = 70) demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days) and established response to rituximab induction as a prognostic factor
Limitations of this trial included its small size and lack of international recruitment due to funding constraints.
Conclusion :
The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Population: Inclusion: Adult SOT recipients diagnosed with CD20-positive PTLD, insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Main exclusion criteria: CNS involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections. Intervention:After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx Outcome:event-free survival (EFS) in the low-risk group Results: Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing Strength: Good design and follow up, it is good phase II trial with potential options for more stronger evidence
prospective multicenter phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20-positive
*(low-risk) rituximab monotherapy induction, patients in complete remission as well as those in partial remission
**(high-risk) received R-CHOP-21.
***(very-high-risk) Thoracic SOT recipients who progressed received alternating R-CHOP-21 and modified R-DHAOx.. Six cycles of alternating R-CHOP and modified R-DHAOx every three weeks
The R-DHAOx regime was modified due to the high risk of infectious complications in SOT recipients: the cytarabine dose was reduced to 50% and dexamethasone was reduced to
one dose instead of four.
Treatment consisted of rituximab (1400 mg SC; first application375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day40–50). Response to treatment at interim and final staging was determined according to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging Patients in CR
as well as those in partial remission (PR) with <3 international prognostic index (IPI)
risk factors (age > 60 yearselevated serum lactate dehydrogenase activity [LDH], and more than one extranodal disease manifestation) at diagnosis (low-risk group)
pneumocystis jirovecii chemoprophylaxis and treatment with granulocyte-colony stimulating factor after chemotherapy were obligatory.
The final response assessment was performed one month after the last cycle of therapy.
Patients completed follow-up examinations every three months for two years, and annually thereafter
Adverse events
Three patients discontinued treatment after the first cycle of R-CHOP due to infections (two cases of fatal neutropenic sepsis,one case of CMV-encephalitis).
low-risk-group. 8/15 lung transplant recipients were stratified to
Toxicity of treatment was significant. leukopenia was reported in 22/59 patients
infection (up to four). Most common episodes were pneumonia (nine), febrile neutropenia (eight), sepsis (six) and varicellazoster reactivation (three). There were two episodes each of
influenza and fungal pneumonia as well as one case each oftuberculosis and CMV encephalitis,
anaemia, thrombocytopenia, acute renal failure and gastro-intestinal haemorrhage Infusion-related reactionsto rituximab IV occurred in 8/59 patients
The highest rate of haematotoxicity, infections andmortality occurred after the first application of chemotherapy (RSC-CHOP) rather than subsequent cycles (either RSC-CHOP or RSC-DHAOx).
and a pooled analysis of all patients treated with rituximab
monotherapy consolidation in the PTLD-1 RSST and PTLD-2 trials,
The PTLD-2 study used treatment stratification based onresponse to treatment at interim staging based on CT imaging rather than positron emission tomography (PET) to ensure that the protocol can be implemented worldwide and to maintain comparability with the earlier PTLD-1 trials
. 2-What is the level of evidence provided by this article?
well-designed observational studies Cohort prospective study
A comparison cohort.
Introduction:
PTLD is the second most common malignancy occurring post solid organ transplant in adults. It is associated with significant morbidity and mortality with an increased risk of graft loss. The treatment response has improved after the introduction of rituximab. The PTLD-1 sequential treatment trial demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 chemotherapy and established response to rituximab induction as a prognostic factor. The subsequent trial of risk-stratified sequential treatment established rituximab monotherapy consolidation for patients in complete remission after rituximab induction and R-CHOP. The PTLD-1 trial also identified the prognostic value of IPI risk factors (>3 vs <3)
The PTLD-2 trial therefore tested whether rituximab mono therapy consolidation in an expanded low risk group would be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial by demonstrating an improved event free survival at 2 years, based on a lower rated of grade 3/4 infections and similar efficacy. Thoracic organ transplant was a prognostic factor for a shorter TTP in rituximab non-responders in the PTLD-1 ST trial. It was hypothesized that patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified chemotherapy. A dose of 1400 mg of SC rituximab was chosen.
Methodology:
This was a prospective, multi center, open label phase II trial that enrolled treatment naive adult SOT patients diagnosed with CD 20 positive PTLD at 15 centers in Germany. The other additional inclusion criteria were:
Insufficient response to upfront ISS reduction
Measurable disease more than 2 cm
ECOG performance less than or equal to 2
The main exclusion criteria were:
CNS involvement
Pregnancy or nursing
Severe uncontrolled heart disease
HIV infection
Other severe acute infections
Treatment Plan:
Treatment consisted of rituximab 375 mg on days 1, 8, 15, and 22 followed by interim staging between days 40 – 50.
Patients in CR as well as those in partial remission with less than 3 IPI at diagnosis (low risk group) continued with 4 weekly coursed of rituximab
Most others (high risk group) received 4 cycles of SC R-CHOP
Thoracic SOT patients who progressed under rituximab (very high risk group) received intensified chemotherapy
Similar to PTLD 1 trial, PJP chemoprophylaxis and treatment with G-CSF after chemotherapy were obligatory.
Results:
60 patients enrolled in the trial. 2 patients died. 48 out of the 58 patients received all four doses of rituximab induction.
21 patients were classified as low risk and received rituximab monotherapy consolidation.
28 patients were allocated to the high risk group due to partial remission and IPI score of more than 3. 26/28 patients received the R-CHOP 21 therapy while 2 lung transplant recipients did not receive the therapy.
9 thoracic recipients were allocated to the very high risk group \
Outcome and Toxicity:
The overall response rate at final staging was 94%.Median RD was not reached. The 2 year Kapla Meier estimate of RD was 81%. In the ITT analysis, the 2 year KM estimate of TTP was 78%
The 2 year KM estimate for OS was 68%.
Median PFS was 3.8 years with a 2 year KM curve estimate of 56%.
Toxicities of the treatment were significant.
Grade 3/4 leucopenia was reported in 37% of patients while grade 3/4 infections were reported in 42% of patients. 7 patients had more than 1 such infection. Most common episodes were pneumonia, febrile neutropenia, sepsis and VZV reactivation
There were no cases of PJP or PML.
Other frequent grade 3/4 adverse events included anemia, thrombocytopenia, acute renal failure and GI hemorrhage.
Outcome and toxicity by treatment group:
The overall response rate to rituximab monotherapy at interim staging was 100% in the low risk group, 18% in the high risk group and 0% in the very high risk group.
The primary endpoint of this trial, the 2 year EFS KM estimate in the low risk group was 66%. This was 14% higher than in the pre-specified comparator group.
The 2 and 3 year KM estimates of both TTP and PFS were 85%. 2 year PFS in the comparator group was 76%
the 2 and 3 year KM estimated of OS was 100% while in the comparator group it was 88%
In the high risk group, ORR at final staging was 100%.
Median RD was not reached
The 2 and 3 year KM estimate of TTP, PFS and OS were 81%, 54% and 59% respectively.
In the very high risk group, 5/9 could be evaluated for response at final staging. 3/5 patients responded with 2 in CR. Median RD was 1.2 years.
the 2 year KM estimates of TTP, PFS and OS were 33%, 11% and 30% respectively.
Toxicity in the very high risk group was substantial. 63% of the patients suffered grade 3/4 infections.
Discussion:
This prospective, multi center, phase 2 trial tested modified risk stratified sequential treatment of CD 20 positive PTLD in adult SOT recipients. Similar ORR, TTP, OS and PFS were observed compared to the preceding PTLD 1 ST and RSST trials.
36% of pts were treated with rituximab mono therapy consolidation and thus chemotherapy free in the low risk group.
OS and PFS were significantly different in the three groups. However, DR as a measure of the quality of remissions was very similar
2 year EFS in the low risk group was numerically but not statistically superior to the pre-specified comparator group. This the primary endpoint of the trial was not met. The rate of grade 3/4 infections was higher in the low risk group
Limitations of the trial:
Small size
Lack of international recruitment
Level of evidence:
This was a prospective comparative study using results from a previous trial. Level 2
Please summarise this article
Post-transplant lymphoproliferative disorders (PTLD) are complications of immunosuppression after solid organ transplantation (SOT).
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence-based treatment protocol for CD20-positive B-cell PTLD in adults . METHODS
-It is prospective, multicentre, open-label phase II trial enrolled treatment naïve
adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020.
-Diagnostic tissue samples weremcollected and stored centrally, reviewed by two expert haematopathologists and classified according to the WHO classi!cation . Epstein–Barr virus association was confirmed by in-situ hybridization for EBERtranscripts.
– The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients unresponsive to initial immunosuppression reduction.
-This prospective, multicentre, phase II trial tested modified riskstrati
fied sequential treatment of CD20-positive PTLD in adultsafter SOT. They observed similar ORR, TTP, OS and PFS compared to the preceding PTLD-1 ST and RSST trials.
-It concluded that rituximab monotherapy consolidation in an expanded low risk
group including patients with <3 IPI risk factors in PR after rituximab induction is a safe and feasible alternative to CHOP consolidation.
-It used treatment stratification based on response to treatment at interim staging based on CT imaging rather than positron emission tomography (PET) to ensure that the protocol can be implemented worldwide and to maintain
comparability with the earlier PTLD-1 trials.
-patients in partial remission after rituximab induction might hypothetically have been evaluated as complete remission by PET, it is unlikely that interim staging based on PET would have identified additional low-risk patients.
-Patient allocation to the very-high-risk group of the PTLD-2
protocol was based on two previously identified risk factors for
poor outcome: progressive disease under rituximab induction and thoracic organ transplant . The results in this small group remain highly disappointing with six cycles of immunochemotherapy consolidation including oxaliplatin and cytarabine , conclude that intensi!ed immunochemotherapy does not overcome the poor prognosis in this patient subgroup.
-There is no cases of pneumocystis jirovecii pneumonia under stringent antibiotic prophylaxis.
–Limitations
– Its small size and lack of international recruitment due to funding constraints. What is the level of evidence provided by this article?
Level I
Summary:
· According to the principles established in the PTLD-1 trials—sequential treatment and risk-stratification—the prospective multicentre Phase II PTLD-2 study (NCT02042391) examined modified risk-stratification in adult SOT recipients with CD20-positive PTLD.
· Patients in complete remission as well as those in partial remission with IPI <3 at diagnosis (low-risk) continued on rituximab monotherapy after rituximab monotherapy induction and were thus chemotherapy-free.
· The majority of those at high risk received R-CHOP-21. R-CHOP-21 and modified R-DHAOx were given in alternating doses to thoracic SOT patients who advanced (extremely high risk).
· The event-free survival (EFS) rate in the low-risk group was the main endpoint.
· In this study 60 patients were enrolled among them 21 had low risk, 28 had high risk and 9 had very high risk.
· The main hypothesis was that, rituximab monotherapy would be superior to CHOP in comparable patients of the PTLD-1 trial.
· 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% (95% CI 65–90) and 68% (95% CI 55–80) – similar to the PTLD-1 trials.
· Treatment-related mortality was 4/59 (7%, 95% CI 2–17).
· In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP (p = 0.432).
· 2-year OS in the low-risk group was 100%.
· Results with RCHOP-21 in high-risk patients confirmed previous results.
· Immunochemotherapy intensification in very-high-risk patients was disappointing.
· Strengths of this study are prospective and multicenter study.
· Limitations of this study are small size and lack of international recruitment, over-representation of lung transplant as well as high proportion of Burkitt, Burkitt-like lymphoma. Level of evidence : level I
Level of evidence is 1 Introduction
Post-transplant lymphoproliferative diseases (PTLD) are immunosuppression-related problems following solid-organ transplantation (SOT).
The German PTLD study group and European PTLD Network phase II trials produced an evidence-based treatment plan for CD20-positive B-cell PTLD in adults.
They had better median overall survival than smaller rituximab monotherapy trials and lower treatment-related mortality than retrospective case series of first-line chemotherapy.
The PTLD-1 sequential treatment trial showed the safety and efficacy of four cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy and established response to induction as a prognostic factor.
The risk-stratified sequential treatment study (PTLD-1) recommended rituximab monotherapy consolidation for patients in complete remission following induction and R-CHOP-21 for all non-CR patients.
Methodology and study design
From February 3rd, 2015, through July 13th, 2020, treatment-naive adult SOT patients with CD20-positive PTLD were included in this prospective, multicenter, open-label Phase II study at 15 German hospitals.
Discussion
Phase II clinical trials provide evidence for PTLD therapy because of the disease’s rarity and heterogeneity. Patients in the PTLD-1 study who did not react to immunosuppression reduction received four cycles of CHOP-21 followed by four rounds of weekly rituximab. With a median OS of 6.6 years and a plateau in PFS, it performed better than earlier studies with rituximab alone. A response-adapted treatment strategy based on the rituximab monotherapy induction response was investigated using the PTLD-1 RSST. Less chemotherapy was administered, and the long-term effects were kept. Results
The prospective, multicenter Phase II PTLD-2 research investigated the potential for modifying risk stratification in adult SOT patients with CD20-positive PTLD using sequential therapy and risk stratification from the PTLD-1 investigations. After induction, patients receiving rituximab treatment without chemotherapy remained in full and partial remission with IPI 3 at diagnosis (low-risk). Most of the high-risk group received R-CHOP-21. Thoracic SOT progressors were given R-CHOP-21 and modified R-DHAOx. The primary result was low-risk, event-free survival.
60 patients were divided into 21 low-risk, 28 high-risk, and 9 very-high-risk patients. 45 of 48 respondents (94%) Kaplan-Meier anticipated that the illness would advance 78% of the time and that the overall survival rate would be 68%, which is similar to the results of the PTLD-1 trials. 7 percent, or 4 out of 59 patients, passed away following treatment. When compared to the historical comparison that received CHOP, the 2-year EFS in the low-risk group was 66% (95% CI 45-86) as opposed to 52% (p = 0.432).
Introduction
Among the most common complication of solid organ transplantation is the occurrence of post-transplant lymphoproliferative disease as a result of the immunosuppressive state that could enhance dormant EBV infection.
There are treatment protocols that are either in use or those in clinical trials based on the outcome of the previous outcome of initial treatment modalities.
Treatment modalities considered are:
PTLD-1 sequential treatment trial
Phase 11 PTRLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials
The second trial which comprises of German PTLD study group and the European PTLD network demonstrates an improved overall median overall survival compared to the preceding smaller Rituximab monotherapy trials, and lower treatment-related mortality (TRM) compared to prior retrospective case series of first-line chemotherapy
Study design and patient
Prospective, multicentre open-label Phase II trial enrolled treatment involving a total of 60 patients
Inclusion criteria
naïve adult SOT recipients diagnosed with CD20-positive PTLD within the study year
Inadequate response to RI (with or without antiviral therapy)
measurable disease >2cm or bone marrow involvement
Exclusion criteria
CNS involvement
pregnancy or nursing
The concomitant disease that precludes the administration of study therapy
Diagnostic tissues were collected and stored centrally for review by two hematopathologists and classified based on WHO classification
Treatment plan
This is divided into three groups based on the responses (either CR or PR) to the different treatments
low-risk group
high-risk group
very high-risk group
Chemoprophylaxis for PJP was administered to all the groups as was done for the PTLD-1 trial and the final response to treatment was performed one month after the last cycle of therapy
Outcome and toxicity by treatment group
the response rate to rituximab monotherapy at interim staging was 100% in the low-risk group,18% in a high-risk group, and 0% in the very high group
In the low-risk group, ORR at final staging was 95%
The primary endpoint by 2 years in the low-risk group, was 66% (95% CI 45–86)
In the high-risk group, ORR ta final staging was 100%.
The 2- and 3-year KM estimate of OS was 59% (95% CI 39–79, median not reached)
The chemotherapy in the high-risk group was associated with significant toxicity
In the very high-risk group, the 2-year KM estimate of TTP was 33% (95% CI 0–82) with a median OS was 7.4 months
Toxicity in the very high-risk group is very substantial
Prognostic Factor
The three risk groups in this protocol had highly significantly different OS and PFS
only baseline IPI ≥ 3 remained an independent prognostic factor for both TTP and OS.
Thoracic organ SOT was an independent prognostic factor for OS
Strength of the study
is a multicentre study
Limitations of the study
small sample size
lack of international recruitment due to fund constraints
Level of evidence
Level is 1
Brief Summary of PTLD -1 trial
sequential treatment of a sample size of 70 Participants
Composition of the therapy
four cycles of weekly Rituximab
followed by four cycles of CHOP-21
Outcome
established response to Rituximab induction as a prognostic factor
The subsequent trial of risk stratification sequential treatment, PTLD-1, RSST with a sample size of 150. This established Rituximab monotherapy consolidation for those that achieve complete remission after Rituximab and from R-CHOP 21 for those with non-complete remission.
1.Please summarise this article
Using the principles set in the PTLD-1 trials—sequential treatment & risk-stratification—the prospective multicentre (German PTLD study group and European PTLD Network) Phase II PTLD-2 study examined modified risk-stratification in adult SOT patients with B-cell(CD20-positive) PTLD.
Following the start of rituximab monotherapy:
Low risk patients (CR as well as those in PR with IPI < 3 at diagnosis continued with rituximab monotherapy (i.e., chemotherapy free).
High-risk (most others) received R-CHOP-21.
Very-high-risk (thoracic SOT recipients who progressed) received alternating R-CHOP-21 & modified R-DHAOx.
The event-free survival (EFS) rate in the low-risk group was the main endpoint.
Historical controls were offered by the PTLD-1 trials.
Rituximab was given S/C. 60 patients were enrolled:
21 had low risk
28 had high risk
9 had very high risk
The main hypothesis was that rituximab monotherapy consolidation would be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial by demonstrating an EFS at 2 years, based on a lower rate of grade 3/4 infections and similar eff!cacy.
Patients who had experienced a PR following rituximab induction & had <3 IPI risk factors at diagnosis were added to the low-risk group receiving rituximab monotherapy consolidation in comparison to the RSST protocol.
In the PTLD-1 ST trial, a thoracic organ transplant was a predictive factor for a shorter TTP in rituximab non-responders.Therefore, it was postulated that patients who had thoracic SOT as well as disease progression while receiving rituximab induction might benefit from enhanced immunochemotherapy.
For this very-high-risk group, 6 cycles of alternate R-CHOP & modified R-DHAOx every 3 weeks were chosen.
In the low-risk group, 36% of patients got rituximab monotherapy consolidation rather than chemotherapy; 76% of these patients would have received R-CHOP consolidation under the previous PTLD-1 RSST protocol. OS and PFS were related. DR as a gauge of the caliber of remissions, however, was very identical in the three risk categories.
Overall response was 45/48.
2-year Kaplan–Meier estimates of time to progression (TTP) & overall survival (OS) were 78% & 68% – similar to the PTLD-1 trials.
Treatment-related mortality (TRM) was 4/59 (7%) – lower compared to prior retrospective case series of 1st-line chemotherapy.
In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP (p = 0.432).
2-year OS in the low-risk group was 100% – improved compared to preceding smaller rituximab monotherapy trials.
Results with RCHOP-21 in high-risk patients confirmed previous results.
2-year EFS in the low-risk group was numerically, but not
statistically, superior to a pre-speci!ed comparator group from the PTLD-1 ST trial treated with CHOP consolidation.As a result, the trial’s main objective was not achieved, and the original trial hypothesis—that rituximab consolidation causes lower toxicity and comparable efficacy—is disproved.
Intensification of immunochemotherapy in patients at very high risk was unsuccessful.
Limitations of the trial:
Small size
Lack of international recruitment due to funding constraints. This may have resulted in the over-representation of lung transplant recipients (15/60, 25%), who have a poor prognosis.
==================== 2. What is the level of evidence provided by this article?
Introduction:
PTLD are complications of immunosuppression after SOT. PTLD study group established an evidence-based treatment protocol for CD20-positive B-cell PTLD in adults that improve overall survival (OS) and lower treatment-related mortality compared to rituximab monotherapy or first-line chemotherapy. PTLD-1 Study:
The PTLD-1 sequential treatment (ST) trial (n = 70) demonstrated the safety and efficacy of four cycles of weekly rituximab, followed by four cycles of CHOP-21 chemotherapy every 21 days, and established response to rituximab induction as a prognostic factor.
With a median OS of 6.6 years and a clear plateau on the PFS curve it compared favorably to earlier rituximab monotherapy trials
PTLD-1 RSST trial
Risk-stratified sequential treatment, tested response-adapted treatment strategy based on response to rituximab monotherapy induction., n = 152 established rituximab monotherapy consolidation for patients in a CR after rituximab induction and R-CHOP-21 (rituximab and CHOP-21) for all non-CR patients.
Hypothesis:
The PTLD-2 trial tested modified risk-stratification based on these three clinical risk factors.
Rituximab monotherapy consolidation in an expanded low-risk group would be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial
METHODS Study design
– Prospective, multicenter, open-label phase II trial.
– 15 centers in Germany
– February 3rd 2015 until July 13th 2020. Enrollment:
– Treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD
– Insufficient response to upfront immunosuppression reduction (with or without antiviral therapy).
– Measurable disease > 2 cm in diameter (and/or bone marrow involvement)
– Eastern Cooperative Oncology Group (ECOG) performance status < = 2.
Exclusion criteria :
– CNS involvement
– Pregnancy or nursing.
– Concomitant disease that precluded the administration of study therapy; severe uncontrolled heart disease, HIV infection and other
– Severe active infections.
Outcome:
The primary; event-free survival (EFS) in the low-risk group.
Secondary; Overall response rate (ORR), OS, time to progression (TTP), progression-free survival (PFS), response duration (RD) and TRM overall and by risk group.
Treatment plan;
60 patients:
– Consisted of 4 doses of rituximab followed by interim staging and assessment of response to treatment then stratified:
– Low-risk group; CR or PR with <3 IPI à continued with four three-weekly courses of rituximab
– High-risk group à received four cycles of RSC-CHOP-21
– Very-high-risk group; Thoracic SOT recipients who progressed under rituximab à received 6 cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals.
In case of disease progression prior to interim staging, restaging was performed prematurely and treatment in the high-risk or very-high-risk groups started immediately if disease progression was confirmed.
PJP chemoprophylaxis and treatment with G-CSF were obligatory.
Result:
-58 patients could be evaluated for response to rituximab induction,
-48 of which had received all four scheduled applications.
Low risk: 21 patients ( 5 in CR and 16 in PR)
High risk: 28 patients (22 patients completed the protocol ad available for final evaluation)
Very high risk: 9 patients ( 5 patients completed the protocol and available for evaluation)
Outcome and toxicity
Overall response rate at final staging was 94% and CR: 46%
2-year Kaplan–Meier estimates of TTP was 78% and OS was 68% similar to the PTLD-1 trials.
2-year Kaplan–Meier (KM) estimate of RD was 81%.
Median PFS was 3.8 years with a 2-year KM estimate of 56%.
Treatment-related mortality was 7%,
In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP
2-year OS in the low-risk group was 100%.
Toxicity of treatment was significant. Grade ¾ leukopenia was reported in 37% patients at risk while grade 3/4 infections were reported in 42%, 7 patients suffered more than one such infection (up to four).
Response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Immuno-chemotherapy intensification in very-high-risk patients was disappointing
The three risk groups in this protocol had highly significantly different OS and PFS but not TTP or DR
Strength: prospective, multicenter Limitations small size and lack of international recruitment, over-representation of lung transplant as well as high proportion of Burkitt, Burkitt-like lymphoma with 11q aberration and high-grade B-cell lymphoma >> those carries poor prognosis.
Introduction: Post-transplant lymphoproliferative disorders are a common malignancy encountered in solid organ transplant patients the disease epidemiology, pathogenesis, classification, presentation and treatment have reviewed in depth in a previous studies. Immunosuppressive drugs are trigger for disease. This retrospective, multicenter, open label, randomized controlled trail with hypothesis that rituximab monotherapy consolidation in an expanded low-risk group would be superior to CHOP consolidation in comparable patients of PTLD-1ST trial by demonstrating an improved event free survival at 2 years. Inclusion criteria : · Naive adult SOT recipients diagnosed with CD20-positive PTLD. · An insufficient response to upfront immunosuppression reduction (with or without antiviral therapy). · Measurable disease > 2 cm in diameter (and/or bone marrow involvement). · Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Exclusion criteria: · Central nervous system involvement. · Pregnancy and nursing. · Diseases that precluded the administration of study therapy, severe heart disease, HIV infection and other severe, active infections.
Treatment plan: · Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). · Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals. · Response to treatment at interim and final staging was determined according to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging.
Primary outcomes: · The response rate at interim and final staging. · Treatment hematological toxicity and infections.
Secondery end points: · Overall response rate (ORR). · Time to progression (TTP). · Treatment related mortality (TRM)- assed by treating physician.. · Response duration(RD) -from complete or partial response at final staging to disease progression. · Progression free survival (PFS) and Overall survival (OS) -from the start of treatment to progression and death from any cause. Results:
– The overall response rate at final staging was 94%, RD 81% at 2 years.
– The 2-year TTP was 78%, and The OS was 68%.
– Median PFS was 3.8 years with a 2-year estimate of 56%.
– TRM affected 4/59 patients.
– Infections were reported in 25/59 Pts.
– The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
– In the low-risk group, ORR at final staging was 95%, and in the high risk group was 100%.
– The prespecified subgroup analyses (EBV-association and sex) detected no significant differences in ORR, TTP or OS. There were no sex specific differences in the response to rituximab SC compared to rituximab IV in a pre-specified inter-trial comparison with combined data from the PTLD-1 ST and PTLD-1 RSST trials. These were comparable when compared to results from PTLD-1ST with 95% CI. Low-risk (patients in CR after rituximab induction or PR with baseline IPI < 3), very-high risk (thoracic transplant recipients with progressive disease after rituximab induction) and high-risk (all others). Higher risk patients are EBV negative, lung transplant, high LDH, international prognostic index >/= 3. Limitations of the study: · small size and lack of international recruitment due to funding constraints. This may have resulted in the over-representation of lung transplant recipients, who have a poor prognosis. · high proportion of Burkitt, Burkitt-like lymphoma with 11q aberration and high-grade B-cell lymphoma PTLD. Conclusion: Rituximab is safe and good consolidation therapy for low risk EBV related PTLD patients, while in high risk patients may be helpful but still larger studies using other treatment strategies are needed to improve outcome. What is the level of evidence provided by this article? Level of evidence I – multicenter randomized control study.
Summary of the article Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multi-centre phase II PTLD-2 trial
The article is about a prospective, multicentre, open-label phase II trial enrolled treatment- naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020. Inclusion criteria:
· naïve adult SOT recipients diagnosed with CD20-positive PTLD.
· an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy).
· measurable disease > 2 cm in diameter (and/or bone marrow involvement).
· Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Exclusion criteria:
· Central nervous system involvement.
· Pregnancy or nursing.
· Concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections. Treatment plan:
· Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
· Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals.
· Response to treatment at interim and final staging was determined ccording to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging.
Study’s outcome
1. The overall response rate at final staging was 94%.
2. Toxicity of treatment was significant.
· Most common episodes were pneumonia , febrile neutropenia, sepsis and varicella zoster reactivation.
· There were two episodes each of influenza and fungal pneumonia as well as one case each of tuberculosis and CMV encephalitis.
· No cases of pneumocystis jirovecii pneumonia or progressive multifocal leukoencephalopathy.
· Other adverse events include; anaemia, thrombocytopenia, acute renal failure, gastro- intestinal haemorrhage and infusion-related reactions to rituximab IV and local reactions to rituximab SC.
3. The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group. In the low-risk group, ORR at final staging was 95%
4. No significant differences in ORR between rituximab SC and IV, nor a sex-specific difference.
Study’s limitations:
· Small size.
· Lack of international recruitment due to funding constraints. Study’s Conclusion:
· rituximab monotherapy consolidation in an expanded low- risk group including patients with <3 IPI risk factors in PR after rituximab induction is a safe and feasible alternative to CHOP consolidation.
· The intensified immuno- chemotherapy does not overcome the poor prognosis in very-high-risk subgroup. Alternative treatment strategies are needed for this very-high-risk subgroup.
· Those with EBV-associated PTLD, EBV-specific cytotoxic T-cells are a less toxic alternative based on a recent case series.
The level of evidence provided by this article
This is a prospective, multicentre, open-label phase II trial, with level of evidence grade 1.
Introduction: German PTLD study group and European PTLD Network established treatment protocol for CD20-positive B-cell PTLD. There was improvement in survival compared with previous Rituximab trials. The PTLD-1 trial showed safety and efficacy of Rituximab given weekly for four weeks, followed by CHOP chemotherapy every 21 days. It established the response to Rituximab treatment as a prognostic factor. The PTLD-2 trial tested a modifiable risk-stratification, that is, rituximab monotherapy in low risk group to be superior to CHOP in PTLD-1 trial by showing an improved event free survival at 2 years. METHODS Study design
Prospective, multicentre, open-label phase II trial. Treatment plan:
Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). The low risk group patients in CR as well as those in partial remission (PR) continued with four three-weekly courses of rituximab. High-risk group patients received four cycles of RSC-CHOP-21.
Pneumocystis jirovecii chemoprophylaxis and treatment with granulocyte-colony stimulating factor after chemotherapy was mandatory. The final response assessment was performed one month after the last cycle of therapy. Follow up was every three months for two years and then annually. Results:
26/58 patients (45%, 95% CI 33–58) responded to rituximab monotherapy induction and 5/58 (9%, 95% CI 3–19) achieved a CR.
28 atients were allocated to the high-risk group, 26/28 went on to receive treatment with R-CHOP-21. Outcome and toxicity · The overall response rate at final staging was 94% (45/48, 95% CI 83–98). · The 2-year Kaplan–Meier (KM) estimate of RD was 81% (95% CI 68–94). · In the intention-to-treat population (60 patients), TTP was 78% and OS was 68% (5.1 years). · Toxicity of treatment was significant. Grade 3/4 leukopenia was reported in 22/59 (37%, 95% CI 26–50) patients at risk while grade 3/4 infections were reported in 25/59 (42%, 95% CI 31–55). · Most common episodes were pneumonia (9), febrile neutropenia (e8), sepsis (6) and varicella zoster reactivation (3), influenza (2) and fungal pneumonia (2) as well as one case each of tuberculosis and CMV encephalitis. Outcome and toxicity by treatment group: The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group. The primary endpoint of this trial, the 2-year EFS KM estimate in the low-risk group, was 66% (95% CI 45–86). In the high-risk group, ORR at final staging was 100% (22/22; CR 9/22 [41%]). Median RD was not reached; the 2- and 3-year KM estimate was 79% (95% CI 59–98) In the very-high-risk group, 5/9 patients could be evaluated for response at final staging. 3/5 (60%) responded with two patients (40%) in CR. Median RD was 1.2 years. The 2-year KM estimate of TTP was 33% (95% CI 0–82). Prognostic factors
The three risk groups in this protocol had highly significantly different OS and PFS (n = 58, p < 0.001) but not TTP or DR.
In a multivariate analysis, baseline IPI was an independent prognostic factor for both TTP and OS.
DISCUSSION
1. The PTLD-1 trial established sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients not responding to reduction in immunosuppression.
2. The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) successfully tested a response-adapted treatment strategy based on response to rituximab monotherapy induction.
3. This prospective, multicentre, phase II trial tested modified risk stratified sequential treatment of CD20-positive PTLD in adults after SOT. Similar ORR, TTP, OS and PFS were observed compared to the preceding PTLD-1 ST and RSST trials.
4. 2-year EFS in the low-risk group was numerically, but not statistically, superior to a pre-specified comparator group from the PTLD-1 ST trial treated with CHOP consolidation.
5. The primary endpoint of the trial was not met and the original trial hypothesis (rituximab consolidation results in lower toxicity and similar efficacy) is rejected.
6. rituximab monotherapy consolidation in an expanded low risk group is safe alternative to CHOP21.
7. The PTLD-2 study used treatment stratification based on response to treatment based on CT imaging rather than positron emission tomography (PET).
8. In the PTLD-1 ST trial, the hazard ratio (HR) of overall response to rituximab induction for TTP was 0.213 (p = 0.008), increasing to 0.256 (p < 0.001) in the PTLD-1 RSST trial. In an analogous multivariate analysis in the PTLD-2 trial, overall response to rituximab was excluded from the multivariate model at step 1 with a HR of 0.867 (p = 0.811).
9. Patient allocation to the very-high-risk group of the PTLD-2 protocol was based on: progressive disease under rituximab induction and thoracic organ transplant, and intensified immunochemotherapy does not overcome the poor prognosis in this subgroup.
10. The independent prognostic value of ≥3 IPI risk factor for both OS and TTP in CD20-positive PTLD was confirmed in this trial.
11. No significant differences between IV and SC rituximab.
12. Rate of grade ¾ infection was high. Limitations:
1. Small sample size
2. Lack of international recruitment. Level of evidence: 1
Summary of the Article: Introduction: The protocol for CD20-positive B-cell PTLD in adults was established by the German PTLD study group and European PTLD Network. There was an improved overall survival compared to the preceding smaller rituximab monotherapy trials and lower treatment related mortality, compared to previous retrospective case series of first line chemotherapy. The PTLD-1 sequential treatment show safety and efficacy of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 chemotherapy every 21 days and established response to rituximab induction as a prognostic factor. The PTLD-2 trial tested a modifiable risk-stratification, rituximab monotherapy in expanded low risk group, would be superior to CHOP in comparable to PTLD-1 trial by showing an improved event free survival at 2 years, based on a lower rate of grade 3/4 infections and similar efficacy. Rituximab S/C 1400 mg dose was chosen based on its non-inferior pharmacokinetic profile compared to 375 mg/m2 IV in immunocompetent patients with follicular lymphoma, and serum concentration of rituximab.
Ann Arbor stage; (I – 7), (II – 9), (III – 6), (IV – 38).
LDH elevated; 34.
Nodal disease; 46.
Extra nodal disease; (GI-28), (liver-16), (lung-11), (kidney-3), (Bone Marrow-6), (Graft-10).
IPI; (<3-37), (>3-23).
ECOG performance status: (0=22), (1=25), (2=13).
Treatment:
One patient died before start treatment.
One patient died during, but not related to rituximab induction.
48 patients receive all 4 scheduled applications.
26/58 patients responded to rituximab monotherapy induction, and 5/58 achieved a CR.
21 patients allocated in the low-risk group.
28 patients were allocated to the high-risk group.
26/28 receive R-CHOP-21, but 22 patients could be evaluated to final staging.
Outcome and toxicity:
The overall response rate at final stage was 94%.
Toxicity of treatment was significant.
22/59 reported G3/4 leukopenia.
25/59 reported G3/4 infection.
Most infection episode was (pneumonia,9), (febrile neutropenia,8), (sepsis,6), (and Varicella Zoster,3).
Other adverse events include anemia, thrombocytopenia, ARF, GI hemorrhage.
8/59 develop rituximab-infusion reaction.
Discussion:
Treatment protocol still at phase II clinical trial data, because of rarity and heterogenicity of the disease.
The PTLD-1 trial establishing treatment with 4 courses of weekly rituximab followed by 4 cycles of R-CHOP-21for patients those unresponsive to immunosuppressant reduction.
The primary end point of the trial was not met, and the original trial hypothesis is rejected.
Rituximab monotherapy in low-risk group is safe and feasible alternative to CHOP consolidation, this includes the secondary end point OS and PFS in this subgroup, the highly similar response duration in all three risk groups, in all patients in PTLD-1 and PTLD-2 trials, demonstrate PFS irrespective of CR or PR with <3 IPI risk factors after rituximab induction.
The PTLD-2 extend the therapy strategy in PTLD-1, in low-risk group to extended rituximab monotherapy.
In PTLD-2 trial, patient s allocated as very high-risk group based on 2 factors;(progressive disease, and thoracic transplant).
Alternative strategies are needed for very high-risk group in PTLS-2, as the trial are ongoing which show that; Cytotoxic T cell are less toxic, while efficacy is still currently tested.
Limitation of the trial:
Small size.
Lack of international recruitment due to funding constraints.
Level of evidence: the prospective multicenter trial. Level ((II)).
IV. Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial
The study tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the earlier PTLD trials.
Results of the R-CHOP-21 trial in high-risk patients were similar to those of the PTLD-1 trials, which provided historical controls.
Rituximab was applied subcutaneously. Treatment-related mortality was 4/59 (7%, 95% CI 2–17) and 2-year EFS was 66% (95% CI 45–86) in the low-risk group, compared to 52% in the historical comparator.
Post-transplant lymphoproliferative disorders (PTLD) are compli- cations of immunosuppression after solid organ transplantation.
Their epidemiology, pathogenesis, classification, presenta- tion and treatment have been reviewed in depth.
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence-based treatment protocol.
A clinical trial of rituximab followed by cycles of CHOP-21 chemotherapy (cyclophosphamide, ndoxorubicin, vincristine, and prednisone, every 21 days) has been published in the Journal of Clinical Pharmacology and Experimental Therapies.
Rituximab monotherapy con- solidation has been established for patients in a complete remission (CR) after treatment with the drug and R-CHOP-21.
Further analyses of the initial PTLD-1 ST trial identified the prognostic value of international IPI risk factors (≥3 vs <3) and thoracic SOT in addition to response to rituxamab.
Rituximab monotherapy consolidation in an expanded low-risk group was found to be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial.
Patients in this expanded group had a lower rate of grade 3/4 infections and were more likely to have reached a partial remission after treatment.
Patients with thoracic SOT and disease progression under rituximab induction might benefit from intensified immunochemotherapy.
Six cycles of alternating R-CHOP and modified R-DHAOx every three weeks were chosen for this very-high-risk group.
The cytarabine dose was reduced to 50% and the dexamethasone dose instead of four.
Finally, Rituximab at a dose of 1400 mg SC was chosen based on its non-inferior pharmacokinetic profile compared to 375 mg/m 2 intravenously (IV) in immunocompetent patients with follicular lymphoma.
Methods Study design and patients
An open-label phase II trial of treatment-naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 2015 to July 2020.
Main exclusion criteria were central nervous system involvement, pregnancy or pregnancy or concomitant disease that precluded the administration of study therapy.
Treatment plan
Treatment consisted of rituximab (1400 mg SC; first application.375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day.40–50).
Response to treatment at interim and final staging was determined according to PTLD-adapted response criteria for malignant lymphomas.
RESULTS Patients
Median time of follow-up was 2.8 years for 60 patients treated with the drug, and the study was published in Clinical Trials and Reviews.
One patient died before the start of treatment, another during or unrelated to rituximab induction, and one patient died after starting treatment.
26/58 patients responded to rituximab mono- therapy induction and 5/58 (9%, 95% CI 3–19) achieved a CR after starting treatment with the drug.
21 patients were allocated to the low-risk group and 26 went on to receive treatment, with four discontinuation due to infections and deteriorating transplant function.
None of the six patients with BCL with MYC-rearrangement-type PTLD were treated in the low-risk-group or the very-high-risk group.
Outcome and toxicity
The overall response rate at final staging was 94% (45/48, 95% CI 83–98).
The 2-year Kaplan–Meier (KM) estimate of RD was 81% (95% CI 68–94).
In the intention-to-treat population (60 patients), TTP was 78% and OS was 68% (5.1 years).
Toxicity of treatment was significant.
Pneumonia (9).
Febrile neutropenia (8).
Sepsis (6).
And varicella zoster reactivation (3) were the most common episodes of patients treated in the study.
Grade 3/4 infections were reported in 25/59 (42%, 95% CI 31–55) and there were no cases of pneumocystis jirovecii pneumonia or progressive multifocal leukoencephalo-neuropathy.
Infusion-related reactions to rituximab IV occurred in 8/59 patients (14%, 95% CI 7–25; all grade 1 or 2) and local reactions to the drug in 4/59.
Other frequent grade 3/4 adverse events included nanaemia, thrombocytopenia, acute renal failure and gastro- intestinal haemorrhage.
We compared the outcomes of the PTLD-2 trial with those of the ST and RSST cohorts of the previous trials to see if the new drug was superior to that of the older drug, parenteral tetracycline therapy (PTLD-1).
The overall response rate (ORR) to rituximab monotherapy was 100% in the low-risk group.
EFS events included 4 grade 3/4 infections from day 50 to day 143 (19% vs. 32% for the comparator group).
The 2- and 3-year KM estimates of both TTP and PFS were 85%.
In the high-risk group, ORR at final staging was 100% (22/22; CR 9/22 [41%]).
Median RD was not reached; the 2- and 3-year KM estimate was 79% (95% CI 59–98).
Chemotherapy in this group was associated with significant toxicity: 13/26 patients had grade 3/4 infections.
In the very-high-risk group, 5/9 patients could be evaluated for response at final staging. 3/5 (60%) responded with two patients(40%) in CR.
Median RD was 1.2 years. The 2-year KM estimate of TTP was 33%.
Response rates and time-to-event outcomes for rituximab SC were similar to those for the previous treatment regimens, with no significant differences in ORR, TTP or OS.
The pre- specified subgroup analyses (EBV-association and sex) detected no significant differences between the two treatments.
Prognostic factors
The three risk groups in this protocol had highly significantly different OS and PFS (n = 58, p < 0.001) but not TTP or DR.
In a multivariate analysis, baseline IPI was an independent prognostic factor for both TTP and OS.
Patients treated with rituximab monotherapy consolidation in the low-risk groups of PTLD-1 RSST and PTLD-2
Patients treated with rituximab monotherapy consolidation in patients in CR and PR subgroups of trials were compared.
There were no significant differences in the number of patients with ≥3 IPI risk factors or progression-free survival between the two groups.
. Discussion
The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by.establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients.
With a median OS of 6.6 years and a clear plateau on the PFS curve it.compared favourably to earlier rituxemab monotherapy trials.
Patients in the R-CHOP trial were treated with rituximab monotherapy and thus chemotherapy-free in the low-risk group – 76% of them would have received treatment using the preceding PTLD-1st ST and RSST protocol.
OS and PFS were significantly different in the three-risk groups – however, DR as a measure of the quality of the patients’ recovery was very similar.
The 2-year EFS in the low-risk group was numerically, but not.statistically, superior to a pre-specified comparator group from the.
PTLD-1 ST trial treated with CHOP consolidation.
The primary end-point of the trial was not met and the original trial hypothesis is rejected.
The PTLD-2 study used treatment stratification based on response to treatment at interim staging based on CT imaging, rather than positron emission tomography (PET) to ensure the protocol can be implemented worldwide.
We have shown that PET identifies patients at low risk of relapse and offers clinically relevant information in PTLD.
It is unlikely that interim staging based on PET would have identified additional low-risk patients.
Only 5/58 patients were considered high-risk based on a PR at interim staging and an IPI of 3 at diagnosis.
The risk factor has lost its positive prognostic value for TTP in multivariate analysis.
Immuno-chemotherapy does not overcome the poor prognosis in this subgroup of patients with Epstein-Barr virus disease (EBV-associated PTLD).
Alternative treatment strategies are needed for this very-high-risk subgroup.
EBV-specific cytotoxic T-cells are a less toxic alternative that is currently being tested in an ongoing prospective trial (NCT03394365).
The rate of grade 3/4 infections was high (42%) in patients treated with immunochemotherapy for DLBCL, but there were no cases of pneumocystis jirovecii pneumonia under stringent antibiotic prophylaxis.
Outcomes (ORR, TTP and OS) were virtually identical irrespective of EBV-association, in contrast to the differences in genomic profiles between CD20-positive and CD8-positive patients.
We did not find significant differences in ORR between rituximab SC and IV, nor a sex-specific difference.
This is in line with data reported for the same agent in follicular lymphoma and in combination with CHOP in DLBCL [28, 29].
However, CR rates after 4 weekly courses of monotherapy might be slightly lower with ritukumab SC..
This is the first study of its kind to examine the safety and effectiveness of lung transplants on patients with Burkitt-like lymphoma (6/60, 10%) and high-grade B-cell lymphoma.
The latter performed particularly well, with 5/6 patients reaching long-term remission.
The PTLD-2 RSST trial was the first prospective study to evaluate ibrutinib and brentuximab vedotin as first-line treatment for patients with CD20- positive, CD30-positive or EBV-positive lymphomas after solid organ transplantation (SOT).
The OS and PFS were very similar to those reported in the previous RSST trials.
1- Summary: PTLD 2 trial:
This prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive. Inclusion criteria:
– an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy),
– measurable disease > 2 cm in diameter (and/or bone marrow involvement)
– ECOG ≤ 2. Main exclusion criteria:
– central nervous system involvement,
– pregnancy or nursing
– contraindication to treatment ( severe uncontrolled heart disease, HIV infection and other severe, active infections) Treatment plan: Induction with 4 weekly rituximab (first dose IV then SC) Response assessment:by CT scan after 2-4 weeks. Patients were stratified into 3 groups:
1- Low risk: partial or complete response and international prognostic index (IPI)
< 3 : Received four three-weekly rituximab
2- High risk: other patients and received four cycles of RSC-CHOP-21
3- Very high risk group: (thoracic SOT) and received received six cycles of alternating RSC-CHOP and modi!ed RSC-DHAOx in three-week intervals Outcome:
1- The primary endpoint was event free survival ( EFS) in the low-risk group: events (infection, death,progression and death)
2- Secondary endpoints included overall response rate (ORR), OS, time to progression (TTP), progression-free survival (PFS), response duration (RD) and TRM overall and by risk group. Results:
58 patients could be evaluated for response to rituximab induction, 48 of which had received all four scheduled applications.
1- Low risk: 21 patients ( five in CR and sixteen in PR)
2- High risk: 28 patients (22 available for final evaluation)
3- Very high risk: 9 patients ( 5 available for evaluation)
Outcome and toxicity:
The overall response rate at final staging was 94%
The 2-year Kaplan–Meier (KM) estimate of RD was 81%
The 2-year KM estimate of TTP was 78%
The 2-year KM estimate for OS was 68% Median PFS was 3.8 years with a 2-year KM estimate of 56%
Toxicity of treatment was significant. Grade ¾ leukopenia was reported in 22/59 (37%), infections were reported in 25/59 (42%,).
Other frequent adverse events included anaemia, thrombocytopenia, acute renal failure and gastrointestinal haemorrhage.
TRM affected 4/59 patients (7%)
Outcome by treatment groups: (table) Prognostic factors:
1- Risk groups: significantly affect OS and PFS
2- Only baseline IPI > 3remained an independent prognostic factor for both TTP and OS.
3- Thoracic organ SOT was an independent prognostic factor for OS.
Comparison of CR and PR among low risk groups (including PTLD-1 and PTLD-2 patients): – There were no differences in overall survival (p = 0.762, 2-year-KM estimate 100% in the PR group and 92% [95% CI 84-100] in the CR group) Or – Progression-free survival (p = 0.833, 2-year-KM estimate 88% [95% CI 71–100] in the PR group and 90% [95% CI 80–99] in the CR group).
Rituximab monotherapy would be superior to CHOP in low risk individuals.
Patients with thoracic SOT and disease progression after rituximab would benefit from intensive immunochemotherapy.
Methodology Study design: Prospective multicenter open label phase 2 trial Study population: Adult SOT recipients diagnosed with CD20 positive PTLD Study site: 15 German centers Inclusion criteria: Insufficient response to reduced immunosuppression
Measurable disease >2cm in diameter
ECOG perfomance status <2 Exclusion criteria: CNS involvement
Pregnancy or nursing
Concomittant disease that precluded administration of therapy
60 enrolled, 58 analysed.
21 low risk, 28 high risk and 9 very high risk group. Treatment plan
Patients received 4 doses of rituximab followed by interim staging at day 40-50 with CT scan.
Patients who had complete remission or partial remission with IPS <3 received additional 3 weekly doses of rituximab.
Patients with high risk disease at diagnosis received R-CHOP.
Very high risk group received alternating doses of R-CHOP and R-DHAOx.
All received PJP prophylaxis and G-CSF.
Final response assessment was done 1 month after last cycle.
Statistical analysis
Intention to treat analysis. Primary end point: Event free survival in the low risk group. Secondary end points: overall response rate, time to progression, progression-free survival, response duration and treatment related mortality overall and by risk group.
Results Primary endpoint: 2-year EFS estimate in the low-risk group was 66%. Secondary end points: TTP was 78%, Median PFS was 3.8 years, Overall response at final staging was 94%, overall TRM was 7% (0% in low risk group, 8% in high risk group and 25% in very high risk group).
Response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group. Conclusion.
Therapy de-escalation can be used in low risk group.
Intensified immunochemotherapy in very high risk groups doesn’t improve outcomes.
Strengths
They utilised CT staging hence ensuring the protocol can be reproduced worldwide.
It was multicenter
Limitations.
Small sample size
Lack of multinational recruitment due to funding constraints
Introduction:
*PTLD are common complications of immunosuppression in post- SOT
* German PTLD study group and European PTLD Network concluded a two phase study on evidence-based treatment protocol for CD20-positive B-cell PTLD in adults, in which there is improved median overall survival (OS) and lower treatment-related mortality (TRM) compared to prior treatment.
*The PTLD-1 sequential treatment (ST) trial showed the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy.
*The subsequent trial of risk-stratified sequential treatment established rituximab monotherapy consolidation in complete remission (CR) after rituximab
induction and R-CHOP-21 for all non-CR cases.
*The PTLD-1 ST trial identified the prognostic value of international prognostic index (IPI) risk factors (3 vs <3).
*The PTLD-2 trial tested modified risk-stratification based on these three clinical risk factors.
The key hypothesis:
Rituximab monotherapy in low-risk group may be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial by demonstrating an improved event-free survival (EFS) at 2 years.
Patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified immunochemotherapy.
The methods:
*Prospective, multicentre, open-label phase II trial, the recipients native adult SOT diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020.
*The patients with insufficient RI, measurable disease > 2 cm and (ECOG) performance status 2.
*Exclusion criteria were CNS involvement, pregnancy or
nursing, and disease interfere with taking of study therapy,
*Diagnostic tissue samples were collected and classified according to the WHO classification. EBV association was confirmed by in-situ hybridization for EBERtranscripts. (FISH) was performed
*Treatment plan consisted of rituximab followed by interim staging. Patients in CR as well as those in (PR) with <3 (IPI), at diagnosis (low-risk group) continued with four three-weekly courses of rituximab.
*High-risk group received four cycles of RSC-CHOP-21
Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modi!ed RSC-DHAOx in three-week intervals.
*In disease progression restaging and treatment started immediately.
*Pneumocystis jirovecii chemoprophylaxis and treatment
with granulocyte-colony stimulating factor after chemotherapy were obligatory.
*Median follow-up was 2.8 years.
The results:
*In summary, 26/58 patients responded to rituximab monotherapy induction and 5/58 achieved a CR.
21 patients – five in CR and sixteen in PR with baseline
IPI < 3 – were allocated to, received, and were evaluated after rituximab monotherapy consolidation in the low-risk group.
*The primary endpoint was event-free survival (EFS) in the low-risk group.
* The PTLD-1 trials provided historical controls.
*Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48.
*The 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
*Treatment-related mortality was 4/59 . In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP.
* 2-year OS in the low-risk group was 100%. Results with RCHOP- 21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Limitations of the study:
included its small size and lack of international recruitment due to funding constraints.
The aim of the study ; —————————————
The primary endpoint was event-free survival (EFS) in the low-risk group.
The study area ; ——————————————–
15 centres in Germany from February 3rd 2015 until July 13th 2020 .
The ethical approval; ——————————-
The responsible local ethics committees approved the trial and all patients gave written informed consent according to the Declaration of Helsinki. The trial is registered with clinicaltrials.gov (NCT02042391).
The population ; ——————————–
60 patients.
The inclusion criteria; —————————————-
1-an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy),
2- measurable disease > 2 cm in diameter (and/or bone marrow involvement) .
3- an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
The exclusion criteria;
—————————-
1-central nervous system involvement .
2-pregnancy or nursing.
3- concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
The method ; ———————————————————
1-Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
2-Rituximab was applied subcutaneously.
3-Analysis was by intention to treat (ITT) unless otherwise specified.
The result of the trial ; ————————————-
1-Overall response was 94%.
2-2-year Kaplan–Meier estimates of time to progression and overall survival were 78% similar to the PTLD-1 trials.
3-Treatment-related mortality was 7% .
4-In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP . 2-year OS in the low-risk group was 100%.
5-Results with R- CHOP-21 in high-risk patients confirmed previous results.
6-Immunochemotherapy intensification in very-high-risk patients was disappointing.
The strength of this trial ; ————————————————————–
1- Multicentre study .
2- open-label.
The Limitations of this trial ; ———————————————————-
1-Small sample size .
2-lack of international recruitment due to funding constraints
Conclusion;
————————————-
1- Intensified immuno-chemotherapy does not overcome the poor prognosis in this patient subgroup.
2- Alternative treatment strategies are needed for this very-high-risk subgroup.
3- For those with EBV-associated PTLD(6/9 in this trial), EBV-specific cytotoxic T-cells are a less toxic alternative based on a recent case series .
What is the level of evidence provided by this article?
——————————————————————-
Level I
1-SUMMARY OF THE ARTICLE;. Introduction: -Post-transplant lymphoproliferative disorders (PTLD) is a common malignancy following solid organ transplantation(SOT) -PTLD-2 trial hypothesized that; rituximab monotherapy consolidation may be better in low risk group may be better than CHOP consolidation in comparable patients of PTLD1 trial. Patients with severe thoracic SOT might be a candidate for aggressive therapy (6 cycles of R-CHOP and modified R-DHAOx with reduced dose of cytarabine and steroids). Methodology: – A prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany (2015-2020) Inclusion criteria;. 1.An insufficient response to RI (with or without antiviral therapy) 2.Measurable disease > 2cm in diameter (and/or bone marrow involvement) 3.Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Exclusion criteria;. 1.CNS involvement 2.Pregnancy or nursing 3.Concomitant disease that precluded the administration of study therapy (severe uncontrolled heart disease, HIV infection and other severe, active infections) Results: -A total of (60 patients) were enrolled from 2015 to 2020. Median follow up was 2.8 years. -2 patients died. -58 were analysed. -45% responded to rituximab and 9% had CR with rituximab. -21 were in low-risk group, 28 in high risk, and 9 were in very high-risk group. -At final staging 21, 22, and 5 patients were available for evaluation in the low-risk, high-risk, and very high-risk group. -Overall response to rituximab at interim staging was 100% in low risk group, 18% in high risk group, and 0% in very high risk group patients. -Overall response at final staging was 94%. Conclusion: Therapy de-escalation with rituximab consolidation in low-risk group can be used. Intensified immunochemotherapy in very high-risk group does not improve outcomes. Limitations of this trial: 1-Small Sample Size 2-Not a Multinational Trial 3-Over representation of lung transplant recipients (who have poor prognosis), and higher proportion of rarer PTLD forms like Burkitt, Burkitt-like and high grade B cell lymphoma type PTLD. 2-LEVEL OF EVIDENCE: This is RCT ; Multicenter Open label, level of evidence is Ic .
Summary:
· Low risk PTLD was treated with rituximab monotherapy or sequential therapy. While high risk disease was treated with sequential RTX then chemotherapy (CHOP21).
· The response to therapy was assessed by PET-CT scan.
· The overall response rate was 94% with treatment related mortality of 4/59.
· In conclusion
· In low risk patients, use of rituximab was comparable to sequential therapy, without additional benefits or improvement in the outcome (do it can be used here to minimize adverse effects).
· However, high risk patients essentially require sequential therapy. Level of evidence: Prospective RCT (level I).
Immunosuppression in transplant recipients is associated with post-transplant lymphoproliferative disorder (PTLD).
The study (PTLD-2 trial) was a multicentre, prospective, open-label trial which involved patients with CD20 positive PTLD with insufficient response to reduction in immunosuppression (RIS), with measurable disease > 2 cm in diameter, bone marrow involvement, or ECOG (Eastern cooperative oncology group) performance status ≤2. Patients with central nervous system (CNS) involvement, pregnancy or breastfeeding, HIV infection, other active infections, and uncontrolled heart disease were excluded.
Methods:
The patients were initially treated with Injection rituximab (4 weekly doses: first dose 375 mg/m2 intravenous followed by 3 doses of 1400 mg subcutaneous) and then interim staging at day 40-50 was done. The patients were further divided into 3 groups:
a) Low risk: Complete remission, CR or partial remission, PR with <3 international prognostic index, IPI risk factors (age > 60, ECOG status ≥2, Ann Arbor stage ≥3, increased lactate dehydrogenase, and >1 extranodal disease). They were given 4 cycles of 3 weekly rituximab doses. No chemotherapy given to them.
b) Very high risk: Thoracic solid organ transplant patients who progressed despite rituximab treatment. They received 6 cycles of alternating R-CHOP (subcutaneous rituximab, Doxorubicin, cyclophosphamide, vincristine, and prednisolone) and R-DHAOx (subcutaneous rituximab, oxaliplatin, cytarabine, and dexamethasone) every 3 weeks.
c) High risk: remaining patients. They received 4 cycles of subcutaneous rituximab with CHOP every 3 weeks.
The patients were compared with historical controls of the PTLD-1 trial in which patients were given 4 cycles of weekly rituximab followed by 4 cycles of 3 weekly CHOP chemotherapy. PTLD-1 trail had shown the safety and efficacy of this sequential treatment in PTLD.
Primary end point was event free survival (EFS) in low-risk group. Events were infection, disease progression, death, and treatment discontinuation.
Results:
A total of 60 patients were enrolled from 2015 to 2020. Median follow up was 2.8 years. 2 patients died. 58 were analysed. 45% responded to rituximab and 9% had CR with rituximab. 21 were in low-risk group, 28 in high risk, and 9 were in very high-risk group. At final staging 21, 22, and 5 patients were available for evaluation in the low-risk, high-risk, and very high-risk group.
Overall response to rituximab at interim staging was 100% in low risk group, 18% in high risk group, and 0% in very high risk group patients. Overall response at final staging was 94% (CR 46%) – 95% (CR 52%) in low risk group, 100% (CR 41%) in high risk group, and 60% (CR 40%) in very high risk group patients. Leukopenia seen in 37%, 42% had infections like pneumonia, sepsis, febrile neutropenia, varicella zoster virus infections.
The 2 year overall survival was 68%, and 2 year event free survival was 66% in the low-risk group which was similar to the historical controls (52%). The results in the very-high risk group were disappointing with increased incidence of hemato-toxicity, infections, and acute renal failure.
The study concluded that therapy de-escalation with rituximab consolidation in low-risk group can be used. Intensified immunochemotherapy in very high-risk group does not improve outcomes.
Limitations: Small sample size, not a multinational trial, over representation of lung transplant recipients (who have poor prognosis), and higher proportion of rarer PTLD forms like Burkitt, Burkitt-like and high grade B cell lymphoma type PTLD.
2. What is the level of evidence provided by this article?
Multicentre Randomized control trial: Level of evidence Level 1
☆ Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial __________
Summary: ◇ Introduction
▪︎Post-transplant lymphoproliferative disorders (PTLD) are complications of immunosuppression after solid organ transplantation.
▪︎Two phase II trials conducted by the German PTLD study group &European PTLD Network established an evidence-based
treatment protocol for CD20-positive B-cell PTLD in adults.
▪︎The PTLD-1 sequential treatment trial demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days) and established response to rituximab induction as a prognostic factor.
▪︎The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) established rituximab monotherapy consolidation for patients in a complete remission after rituximab induction and R-CHOP-21 (rituximab and CHOP-21) for all non-CR patients. The question raised by this result was whether rituximab monotherapy consolidation might be sufficient treatment for additional PTLD patients.
▪︎Further analyses of the initial
PTLD-1 ST trial identified the prognostic value of international prognostic index risk factors and thoracic SOT in addition to response to rituximab.
▪︎The PTLD-2 trial therefore tested modified risk-stratification based
on these three clinical risk factors. The key hypothesis of this study:
▪︎Patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified immunochemotherapy.
◇ Methodology:
▪︎The prospective multicentre Phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with
CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification.
▪︎ After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free.
▪︎Most others (high-risk) received R-CHOP-21.
▪︎Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx.
◇ Results:
▪︎The primary endpoint was event-free survival (EFS) in the low-risk group.
▪︎The PTLD-1 trials provided historical controls.
▪︎Rituximab was applied subcutaneously.
Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48.
▪︎ 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% – similar to the PTLD-1 trials. ▪︎Treatment-related mortality was 4/59 (7%). In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP. 2-year OS in the low-risk group was 100%.
▪︎ Results with R CHOP-21 in high-risk patients confirmed previous results. ▪︎Immunochemotherapy intensification in very-high-risk patients was disappointing.
Limitations of this trial:
1. Small size
2. Lack of international recruitment due to funding constraints. This may
have resulted in the over-representation of lung transplant recipients, who have a poor prognosis, as well as the comparatively high proportion of Burkitt, Burkitt-like lymphoma with 11q aberration and high-grade B-cell lymphoma PTLD.
Introduction
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence-based treatment protocol for CD20-positive B-cell PTLD in adults. They demonstrated improved overall (OS) survival and lower treatment-related mortality (TRM)
The PTLD-1 sequential treatment (ST) trial (n=70) demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days)
The PTLD-2 trial tested modified risk-stratification based on the clinical risk factors (IPI risk factors of ≥3 vs <3, thoracic SOT, and response to rituximab)
Methods
A prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany (2015-2020)
Additional inclusion criteria were
1. An insufficient response to RI (with or without antiviral therapy)
2. Measurable disease > 2cm in diameter (and/or bone marrow involvement)
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤2
Exclusion criteria
1. CNS involvement
2. Pregnancy or nursing
3. Concomitant disease that precluded the administration of study therapy (severe uncontrolled heart disease, HIV infection and other severe, active infections)
Treatment plan
Rituximab (1400mg SC, first dose 375mg/m2 IV) on days 1, 8, 15 and 22, followed by response assessment by CT imaging (day 40–50)
Patients in CR and in partial remission (PR) with <3 IPI risk factors (age >60 years, Ann Arbor stage ≥ III, performance status ≥2, elevated LDH, and more than one extranodal disease manifestation) at diagnosis (low-risk group) continued with four three-weekly courses of rituximab (day 50, 72, 94 and 116)
High-risk group received four cycles of R-CHOP-21 (PR and IPI 3 or more, stable disease or progressive disease and non-thoracic SOT)
Very-high-risk group (thoracic SOT) received six cycles of alternating RSC-CHOP and modified R-DHAOx in three-week intervals (6 doses)
In case of disease progression prior to interim staging, start treatment immediately as in the high-risk or very-high-risk groups
Pneumocystis jirovecii chemoprophylaxis and treatment GCSF after chemotherapy were obligatory
The final response assessment was one month after the last cycle of therapy
Median follow-up for the whole trial was 2.8 years
Results
Total patients were 60 (only 48 patients completed the four doses of rituximab)
45% responded to induction of rituximab monotherapy and 9% achieved a CR
21 patients were allocated to the low risk group, 28 to the high-risk group, and 9 to the very high-risk group
Overall response was 94%
The 2-year Kaplan–Meier estimates of time to progression (TTP) and overall survival were 78% (similar to the PTLD-1 trials). The 2-year KM estimate for OS was 68% (median 5.1 years)
Treatment-related mortality was 7%
The OR to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group
In the low-risk group, 2-year event-free survival (EFS) was 66%
In the low-risk group, 2-year EFS was 66% versus 52% in the historical that received CHOP
2-year OS in the low-risk group was 100%
Immunochemotherapy intensification in very-high-risk patients was disappointing
Discussion
This prospective, multicentre, phase II trial tested modified riskstratified sequential treatment of CD20-positive PTLD in adults after SOT
Rituximab monotherapy in a low risk group after rituximab induction is a safe and an alternative to CHOP
The PTLD-2 study used treatment stratification based on response to treatment on CT imaging (not PET)
Allocation to the very-high-risk group of the PTLD-2 protocol was based on two previously identified risk factors for poor outcome (progressive disease during rituximab induction and thoracic organ transplant)
The result of very high risk group is highly disappointing
Limitations of the study: small size and lack of international recruitment due to funding constraints
In PTLD-2 trial, two other prospective multicentre phase II trials evaluated ibrutinib and brentuximab vedotin in the treatment of PTLD
What is the level of evidence provided by this article?
Level I (prospective multicenter study)
Introduction
German PTLD study group and European PTLD Network conducted a 2 phase study on evidence-based treatment strategy for CD20-positive B-cell PTLD in adults where better over all survival (OS ) and less treatment-related mortality (TRM) was noted in comparison to previous treatment modalities.
PTLD-1 sequential treatment (ST) trial demonstrated the efficacy of RCHOP therapy
The subsequent risk-stratified sequential treatment trial showed rituximab monotherapy consolidation for those in a complete remission (CR) after rituximab induction and R-CHOP-21 for all non-CR patients.
PTLD-1 ST trial detected the prognostic value of IPI risk factors (≥3 vs <3) .
PTLD-2 trial tested modified risk-stratification depending oh those 3 risk factors.
As it was supposed that Rituximab monotherapy can be more efficient than CHOP therapy in low risk cases .
It was thought that in thoracic SOT , patients who received rituximab induction and suffered worse progression can get profit from intensifing immunochemotherapy. Methodology
This is a prospective, multicentre study conducted on adult SOT recipients with CD20-positive PTLD at 15 centres in Germany within nearly 5 years ,including cases with insufficient response to RI and excluding cases with CNS affection and cases with diseases preventing using the studied therapy.
Treatment plan was Rituximab course followed by interim staging and evaluation of response.
Low-risk group was the cases with CR and those with PR having IPI <3 and they had 4 three-weekly courses of rituximab.
High-risk group took 4 cycles of R-CHOP-21.
Very-high-risk group are those who deteriorated under rituximab and they received 6 cycles of alternating R-CHOP and modified R-DHAOx in 3-week intervals.
Also if deterioration occurred ,restaging and suitable upgraded therapy was introduced without delay.
Pneumocystis jirovecii chemoprophylaxis and GCSF was given.
Median follow up was 2.8 years . Results
26/58 patients responded to rituximab monotherapy induction and 5/58 had a CR and 16 had PR
21 cases were considered low risk and 28 as high risk.
The final overall response rate was 94%.
22/59 cases had grade ¾ leukopenia while grade 3/4 infections were noted in 25/59 mostly pneumonia, febrile neutropenia , sepsis and varicella zoster reactivation , other grade 3/4 adverse events included anaemia, thrombocytopenia, ARF and gastrointestinal haemorrhage and reactions related to Rituximab.
Treatment related mortality occurred in 4/59 cases.
Overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk and 0% in the very-high-risk group.
The 3 risk groups had highly significant difference in Overall Survival (OS) and Progression free survival but not time to progression (TTP) or DR.
IPI ≥ 3 was an independent prognostic factor for TTP and OS ,also independent prognostic factor for OS was Thoracic organ SOT. Discussion
ORR, TTP, OS and PFS was the same as the preceding PTLD-1 ST and RSST trials.
OS and PFS varied significantly in the 3 risk groups, DR was similar.
Rituximab monotherapy consolidation in low risk group including those with <3 IPI risk factors in PR after rituximab induction is an acceptable substitute to CHOP consolidation.
End of treatment PET detected cases with low relapse risk and is informative in PTLD, specially in cases with partial remission by CT imaging.
5/58 patients were high-risk cases according to PR at interim staging and an IPI ≥ 3 at diagnosis.
Applying Rituximab monotherapy consolidation to other groups of patients of higher risk factor other than low risk is not applicable.
Progression of disease under rituximab induction and thoracic organ transplant cases were categorised as very high risk.
Intensifying chemotherapy does not overcome the poor prognosis .
EBV-specific cytotoxic T-cells use are less toxic in EBV-associated PTLD
ORR, TTP and OS were virtually the same apart from EBV status.
TRM was 7% in patients treated with immunochemotherapy with an overall rate of 7%, the same as in old immunocompetent patients treated with R-CHOP immunochemotherapy for DLBCL.
IV or SC Rituximab did not show any significant difference regarding ORR.
The limitations were small sample size thereby overrepresentation of lung transplant cases which had poor outcome.
High-grade B-cell lymphoma PTLD(5/6 patients) had long term remission.
Another prospective trial was assessing brutinib and brentuximab vedotin in the treatment of PTLD.
PTLD is a serious complication of post transplant immunosuppression use.
Rituximab is a well established PTLD treatment in adults with improved survival & lower mortality.
PTLD-1 sequential treatment trial prove the safety & efficacy of weekly rituximab( 4cycles) that followed by 4 cycle of CHOP-21.
PTLD-1 ST trial establish response to rituximab as a prognostic factor.
PTLD-2 trial evaluate the modified risk stratification based on IPI risk factors, thoracic SOT and response to rituximab.
Method:
Prospective, multi-center open labelled study.
Include patients diagnosed with CD4+ve PTLD from 15 centers in Germany.
The study start at Feb. 3rd 2015 to July 13th 2020.
Included patients were naive adult SOT recipients, patients with insufficient response to RIS, measurable disease>2 cm with or without bone marrow involvement & patients with ECOG performance status<2.
Excluded patients include patients with CNS involvement, pregnancy or nursing, patients with contraindication for treatment as heart disease or infections.
Treatment regime was rituximab (1400mg, 1st dose 375m2 IV) on day 0, 8, 15 & 22. Then intro stage (D40-50).
CT image used to assess response to treatment during intermission & final staging.
Treatment of low risk patient at diagnosis, patients with CR or partial remission consist of 4 courses (every 3 weeks) of rituximab.
Treatment of high risk patients was 4 courses of R-CHOP.
Treatment of very high risk patients was 6 cycles of alternating R-CHOP & modified R-DHACX every 3 weeks.
Patients with suspicion of disease progression before intermission staging, need re-staging & treated as high risk or very high risk group if disease progression confirmed.
PJP prophylaxis & G-CSF is mandatory .
Final assessment done 1 month after last cycle of treatment.
The patients followed every 3 months for 2 years.
Result & discussion:
Because PTLD is rare & heterogeneous, its treatment still used on phaseII clinical trials data.
PTLD-2 observe that ORR, TTP, OS & PFS were similar to PTLD-1-ST & RSST trial.
2 year EFS in low risk group was statistically not superior to pre-specified comparator group from PTLD-1.
Rituximab induction followed by consolidation in low risk group found to be safe & feasible alternative to CHOP consolidation.
PTLD-2 use CT image for treatment response evaluation.
End-of- treatment PET can identify patients with low risk of relapse in addition to offering clinical relevant information particularly in patients with part remission by CT image.
Intensify chemotherapy for very high risk group docent overcome poor prognosis & alternative strategies needed.
EBV-specific cytotoxic T cells were less toxic in treatment of PTLD+ve EBV.
Incidence of infection was low.
Limitation of the study:
Small size sample.
Absence of international recruitment .
During PTLD-2 trail, there were 2 multi-center phase II studies to test ibrutimib & brentuximab edition in treatment of PTLD.
Treatment options in patients with CD20+ PTLD not responding to reduction of immunosuppression according to previous trials includes:
Single agent Rituximab in a dose of 375 mg/m2 per week for four weeks,-
Chemotherapy monotherapy (CHOP)
Rituximab consolidation in a dose of 375 mg/m2 per week for four weeks, followed by additional 4 doses of Rituximab given every 21 days for patients who achieved complete remission after initial Rituximab dose.
PTLD-1 Sequential treatment study is a phase II study including 70 PTLD patients who were treated initially by Rituximab given in 4 doses, then rest for 4 weeks followed by 4 cycles of chemotherapy (CHOP) given every 21 days, the result was superior to Rituximab and chemotherapy alone with overall survival of 6.6 years
PTLD-1 risk-stratified sequential treatment (PTLD-1 RSST) is another Phase II trial (including 152 patients) that added Rituximab to chemotherapy (CHOP-R) every 21 days only in patients with good response to the Rituximab induction, that means the response to Rituximab will stratify the risk and help in selecting treatment . the response was assessed using CT scan
The current study (PTLD-2 modified risk stratified sequential treatment) is a phase II multicenter prospective trial, including 60 patients divided as follow
21 were low-risk who responded well (partial or complete remission )to initial Rituximab therapy, this group was treated with Rituximab consolidation without chemotherapy
28 were high-risk patients who did not respond to initial Rituximab therapy, this group was treated with CHOP-R as in PTLD-1 RSST study
9 were very high risk that includes those with thoracic SOT and progressive disease after rituximab induction this group was treated with six cycles of alternating R-CHOP-21 and modified R-DHAOx
The response was assessed using PET scan which provide better assessment for response and remission
Results
The overall response was 45/48 (94%)
The overall survival at 2 years was 68% which is similar to the PTLD-1 trials.
Treatment-related mortality was 4/59
In the low-risk group, 2-year even –free survival ( EFS) was 66% compared to 52% in historical PTLD-1 receiving CHOP
In the low-risk group, the overall survival was 100% at 2 years
In high risk group results are comparable to previous PTLD-1
In very high risk group the results were disappointing even with aggressive chemotherapy
Conclusion
Response to initial Rituximab induction can stratify the patient risk
In low risk group, the use of Rituximab consolidation is comparableto the use if CHOP-21 after initial Rituximab induction, so it can be considered in this type of patients to avoid unwanted chemotherapy side effects.
In high risk group the use of R-CHOP is recommended
In very high risk group carry a very poor prognosis even with the use of very aggressive chemotherapy
Assessment of response by PET scan may be preferred to CT after Rituximab induction
INTRODUCTION:
Immunosuppression following solid organ transplantation causes post-transplant lymphoproliferative diseases (PTLD) (SOT). Epidemiology, etiology, categorization, presentation, and therapy have been extensively explored.
The German PTLD research group and European PTLD Network phase II trials produced an evidence-based treatment plan for CD20-positive B-cell PTLD in adults.
They had better median overall survival (OS) and reduced treatment-related mortality (TRM) than previous, smaller rituximab monotherapy studies.
Methodology:
This prospective, multicenter, open-label phase II study included treatment-naïve adult SOT patients with CD20-positive PTLD at 15 German centers from February 3rd, 2015, through July 13th, 2020.
DISCUSSION:
Because of the rarity and heterogeneity of the disease, evidence for PTLD therapy comes from phase II clinical trials. In the PTLD-1 study, patients who did not respond to immunosuppression reduction were given four rounds of weekly rituximab followed by four cycles of CHOP-21. It did better than previous studies of rituximab alone, with a median OS of 6.6 years and a plateau in PFS. PTLD-1 RSST examined a response-adapted treatment plan based on the rituximab monotherapy induction response. Chemotherapy was kept to a minimum, and long-term results were preserved.
It’s PTLD’s first-line therapy.
Results:
The prospective, multicenter Phase II PTLD-2 study looked at how sequential therapy and risk stratification from the PTLD-1 studies could be used to modify risk stratification in adult SOT patients with CD20-positive PTLD. Patients in full and partial remission with IPI 3 at diagnosis (low-risk) maintained rituximab treatment without chemotherapy after induction. The majority (high-risk) got R-CHOP-21. R-CHOP-21 and modified R-DHAOx were given to thoracic SOT progressors. Low-risk, event-free survival (EFS) was the main outcome.
Of the 60 patients, 21 were low-risk, 28 were high-risk, and 9 were very-high-risk. 45/48 (94%) respondents Similar to the PTLD-1 trials, Kaplan–Meier predicted that the disease would progress 78% of the time and that the overall survival rate would be 68%. 4 of 59 (7%) died after treatment. In the low-risk group, 2-year EFS was 66% (95% CI 45–86) against 52% in the historical comparison that underwent CHOP (p = 0.432). 100% low-risk 2-year OS
Limitation:
Non-randomisation
This experiment was modest and lacked international recruiting owing to financing restrictions. Lung transplant patients (15/60, 25%) and Burkitt-like lymphoma with an 11q abnormality and high-grade B-cell lymphoma PTLD (6/60, 10%) were overrepresented.
the level of evidence: open-label multicenter control trial,Level 1C
Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial
EBV-associated post-transplantation lymphoproliferative disease (PTLD) affects 1–10% of transplant patients. We started a phase 2 experiment to see if adding rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) could help PTLD patients do better than with rituximab alone and stop the bad side effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy.
-Result:
70 of the 74 patients who registered between December 12, 2002, and May 5, 2008, were eligible for therapy. Late-type, monomorphic, and EBV-associated PTLD was found in 53 of 70 individuals. Four patients were denied CHOP. 53 of 59 patients had a full or partial response, with 40 complete responses. At the data cutoff (June 1, 2011), 53 patients had responded to therapy; however, the median response length was not yet attained.
-conclusion:
The results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD.
Post-transplant lymphoproliferative disorders (PTLD) is a common malignancy following solid organ transplantation
PTLD-2 trial hypothesized that; rituximab monotherapy consolidation may be better in low risk group may be better than CHOP consolidation in comparable patients of PTLD1 trial. Patients with severe thoracic SOT might be a candidate for aggressive therapy (6 cycles of R-CHOP and modified R-DHAOx with reduced dose of cytarabine and steroids)
Primary end point was even-free survival (EFS) in the low risk group (PTLD-1= control group)
Methodology:
This was a clinical trial, multi-center,open label for PTLD patients conducted in Germany. They included those with poor response to immune-suppression,disease > 2 cm and ECOP performance status < 2. They excluded any condition that may effect the tested treatment and patients (HIV, severe heart failure) with CNS involvements.
Intention to treat (ITT) analysis
Results:
Total of 60 patients enrlolled: 2 deaths and 58 were assessed for rituximab response
They were divided as follows ; 21 low risk, 28 high risk, and 9 very-high risk
2 years even-free survival (EFS) in low risk group = 66% compared to 52% in the contRol group treated with CHOP
Disappointment with aggressive treatment in very high risk group
Conclusion:
At the moment , the evidence does not challenge the idea of risk-stratified sequential treatment as the first line treatment of CD20 +ve PTLD
This is RCT, multicenter open label, level of evidence is I
The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients unresponsive to initial immunosuppression reduction. With a median overall survival (OS) of 6.6 years and a clear plateau on the patient free survival (PFS) curve it compared favourably to earlier rituximab monotherapy trials.
The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) successfully tested a response-adapted treatment strategy based on response to rituximab monotherapy induction.
Exposure of patients to chemotherapy was limited and long-term outcomes maintained. It is considered a 1st line standard in the treatment of PTLD
Protocol – 4 cycles of weekly Rituximab f/ b 4 cycles of CHOP-21 chemotherapy ( cyclophosphamide , doxorubicin, Vincristine, Prednisone every 21 days ).
Prognostic factor – Response to Rituximab induction.
Subsequent trial – Proved that in patients with CR with Rituximab induction, Rituximab monotherapy is sufficient.
In patients without CR after Rituximab induction – R- CHOP-21 to be used.
PTLD-2 trial – Expanded low risk group – Who achieved CR with Rituximab induction Who acheived PR with Rituximab induction <3 IPI risk factors at diagnosis Rituximab monotherapy Consolidation is sufficient.
Identified prognostic factors – CR with Rituximab induction Thoracic SOT
file:////Users/prakashghogale/Library/Group%20Containers/UBF8T346G9.Office/TemporaryItems/msohtmlclip/clip_image002.jpg International Prognostic index risk factors ( < 3 to > 3 )
Hypothesis of the study – In patients with – Thoracic SOT Disease progression with Rituximab induction
6 cycles of alternating R – CHOP and modified R – DHAOx every 3 weeks may lead to benefit in this very high risk group. In the R-DHAOx regimen due to high risk of infectious complications – cytarabine dose reduced by 50% and dexamethasone was reduced to one dose instead of four. Rituximab was given 1400 mg SC.
Study – prospective,multicentre, open – label phase II trial
Inclusion criteria – All treatment naive adult sot recipients with CD 20 positive P TLD. insufficient response to upfront immunosuppression reduction. measurable disease > 2 cm in diameter and / Or bone marrow involvement ECOG performance status <2
Exclusion criteria –
file:////Users/prakashghogale/Library/Group%20Containers/UBF8T346G9.Office/TemporaryItems/msohtmlclip/clip_image002.jpg CNS involvement Pregnancy Nursing H IV infection Other severe active infection
Treatment plan – Rituximab 1400 mg SC Or 375 mg / m2 iv on days 1,8,15,22
interim Staging day 40-50
Patients in CR Patients in PR with < 3 I P l risk factors
Four 3 weekly doses of Rituximab
High risk group received he cycles of R- CHOP-21.
Those who progressed under Rituximab ( very high riskgroup ) 6 cycles of alternating R- CHOP and modified R – DHAO x in 3weeks interval.
Final response assessment One month after last cycle. Follow up was done every 3months till 2years and annually thereafter.
PCP prophylaxis and G- C SF was given to all.
file:////Users/prakashghogale/Library/Group%20Containers/UBF8T346G9.Office/TemporaryItems/msohtmlclip/clip_image002.jpg Discussion – Modified risk stratified sequential treatment of CD -20 positive PTLD in adults after SOT had similar ORR, TTP ,OS and PFS compared to preceeding PTLD-1 and RSST trials. 36 % patients only needed Rituximab monotherapy Consolidation and thus R- CHOP was avoided in the low risk group. Rituximab Consolidation does not result in lower toxicity and similar efficacy. PTLD – 2 trial used CT imaging, this trial used PET Scan at end of treatment. Intensified chemotherapy does not improve the poor prognosis in very high riskgroup. No significant difference in ORR between Rituximab SC and iv.
Limitations – Small size Lack of international Recruitment.
Small trial of Ibrutinib and Brentuximab did not show any added benefit.
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence based treatment protocol for CD 20 positive B cell PTLD
They demonstrated improved median overall survival and lower treatment related mortality compared to the previous smaller rituximab monotherapy trials.
The PTLD 1 sequential treatment confirmed the safety of rituximab followed by CHOP 21and established response to rituximab induction
The subsequent trial of risk stratified sequential treatment considered rituximab consolidation for patients in complete remission and R and CHOP21 for whom not in complete remission
Patients and methods
Prospective multicenter phase II trial tested modified risk stratification in adult SOT recipients with CD 20 positive PTLD based on the principles established in the PTLD 1 trials : sequential treatment and risk stratification, patients are classified into three groups low risk group, high risk group and very high risk group
After rituximab monotherapy induction, patients of complete remission as well as those in partial remission with IPI less than 3 at diagnosis( low risk ) continued with rituximab monotherapy and thus chemotherapy free.Most others ( high risk ) received R-CHOP21 . Thoracic SOT recipients who progressed( very high risk) received alternating R-CHOP21 and modified R-DHAOx
The primary endpoint was event free survival in the low risk group
The PTLD 1 trials provided historical controls
Rituximab was applied SC
Of 60 patients enrolled, 21 were low risk,28 high risk and 9 very high risk
Results
Overall response was 94%.
2 year Kaplan-Meier estimates of time progression and overall were 78% and 68% similar to the PTLD 1 trials. Treatment related mortality was 7%
In the low risk group, 2 year EFS ( event free survival) was 66% versus 52% the historical comparator that received CHOP. 2 year overall survival in the low risk group was 100%, 18% in high risk group and 0% in very high risk group
Level of evidence 1
Phase 2 in PTLD 2 trial prospective, multicentre, open-label phase II trial enrolled treatment-
nave adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020.
They divided patients to 3 groups:
Low risk :Rituximab mono therapy
High risk :RcHOP-21
Very high risk :RCHOP-21 and modified R-DHAOX
Conclusion:
The overall response rate to rituximab monotherapy 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
This is phase 2 of the PTLD2 trial.It is a prospective, multicentre, open-label study of organ recipients who have CD20-positive PTLD at 15 centers in Germany over 5 years. It had involved 60 patients. It had tested modified risk-stratification.
Patients were divided into :
1- Low risk : 21 patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis. They were provided with rituximab monotherapy alone.
2- high-risk 28 patients who received R-CHOP-21.
3- very-high-risk :9 patients who are thoracic SOT recipients who received alternating R-CHOP-21 and modified R-DHAOx.
the primary endpoint was event-free survival (EFS) in the low-risk group.2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68%. In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP. 2-year OS in the low-risk group was 100%.
The level of evidence is 1 as it is 1
Q1:
Introduction:
PTLD-2 was an open label, multicenter and prospective trial conducted in patients with CD20+ PTLD who had not good response to IS reduction, with more than 2 cm lesion, BM involvement, ECOGroup performance status of ≤2.
Exclusion criteria: CNS involvement, pregnancy or breast feeding, HIV or other active infections and uncontrolled heart disease.
Method:
After initially treatment with rituximab (first dose IV and 3 doses SQ weekly), these patients had interim staging to evaluate their response to treatment on day 40-50 and were divided to the following groups:
Low-risk: patients in CR or in PR but with less than 3 IPI at diagnosis: continued with 4 doses of SQ rituximab every 3 week.
High- risk: patients without CR or PR with≥3 IPI without CHOP every 3 weeks.
Very high- risk: patients with thoracic organ TX who were unresponsive to rituximab. These patients received six alternative courses of R-CHOP or R-DHAO every 3 weeks. These patients were compared with the historical control of PTLD-1 trial. PTLD-1 trial: patients received 4 cycles of CHOP-21 (every 3 weeks).
Primary endpoint was event free survival (EFS) in the low risk patients. Events were infections grade 3-4from day 50 to 143, discontinuation of treatment, disease progression and death.
Results:
During 2.8 years, 60 patients were followed. Two of them died and 58 were analyzed. About 45 percent respond to RTX. They (58 patients) were divided into three groups: low- risk:21, high- risk:28 and very high- risk: 9 patients. At the end only 21, 22 and 5 of them were analyzed.
Low-risk group 100% responded to RXT vs 18% and zero percent in high and very high- risk group, respectively.
At final staging, overall response was 94% with CR of 46%. Two year Kaplan-Meyer estimates of time to progression and overall survival were 78% and 68%, similar to PTLD-1 trials. Treatment related mortality was 7%. In low-risk group, 2 year EFS was 66% vs 52% in the historical control. Two-year overall survival in the low-risk group was 100%. Results with R-CHOP-21 in high-risk group was like the previous study. The treatment of very high-risk patients was disappointing.
Limitations were: high rate of lung TX, small sample size, high rate of Burkitt and Burkitt-like and high grade B cell lymphoma type PTLD.
Q2: The level of evidence provided by this article is level 1 (RCT).
Level 1 evidence
-This prospective phase II trial enrolled treatment of naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020
Treatment
-Rituximab 1400 mg SC then 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
48 patients (21, 22, and 5 in groups A, B, C respectively) were analyzed (48 from 58 patients recruited at the beginning).
100% response to rituximab in low risk group, 18% response to rituximab in high risk group. 0% response to rituximab in very-high risk group.
2-year overall survival was 68%, 2-year event free survival was 66% in low risk group.
Very high-risk group patients had higher risk of infections and AKI.
Conclusion :
The overall response rate to rituximab monotherapy 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Methods
Results
Discussion
Level I (multi-center randomized controlled trial)
This is a prospective, multicentre, open-label phase II trial handling treatment of
SOT adult recipients diagnosed with CD20-positive PTLD at 15
centres in Germany from February 3rd 2015 until July 13th 2020.
Inclusion criteria :
1- Insufficient response to immunosuppression reduction (with or without antiviral therapy)
2- Measurable disease > 2 cm in diameter (and/or bone marrow involvement)
3- Eastern Cooperative Oncology Group (ECOG) performance status “2.
Exclusion criteria :
1- central nervous system involvement
2- pregnancy or nursing
3- concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Treatment plan :
After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free.
Others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx.
The primary endpoint
event-free survival (EFS) in the low-risk group.
Rituximab was applied subcutaneously.
Results
60 patients in this study , 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 .
In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP . 2-year OS in the low-risk group was 100%.
Results with RCHOP- 21 in high-risk patients confirmed previous results.
Immuno-chemotherapy intensification in very-high-risk patients was
disappointing.
level 1
Please summarize this article:
This is a multi-center prospective open label trial (PTLD-2 trial).
Inclusion criteria:
1-CD20 +ve PTLD with weak response to immune-suppression reduction
2-measurable disease 2cm or above in diameter.
3-BM involvement.
4-ECOG performance status below or equals to 2.
Exclusion criteria:
1-CNS involvement.
2-Pregnancy or breast feeding.
3-HIV infection.
4-Other active infections.
5-Uncontrolled heart disease.
Methods:
60 patients were included from 2015 to 2020. 2 patients died. 58 patients were followed up for median 2.8 years.
All patients were treated with 4 doses of Rituximab as per protocol then those patients were divided at day 40-50 into 3 groups according to the risk:
A- 21 low risk patients: complete or partial remission, IPI risk factors include age above 60, ECOG status 2 or above, Ann-Arbor stage 3 or above, high LDH and more than one extra-nodal disease. No chemotherapy was given.
B- 28 high risk patients: treated with CHOP every 3 weeks.
C- 9 very high-risk patients: thoracic SOT recipients with progressive disease despite rituximab treatment. They received 6 cycles of alternating chemotherapy R-CHOP and R-DHAOx.
D- Control group: historical controls of PTLD-1 trial.
Aim:
Primary end-point: event free survival in low risk group including infection, disease progression, death and treatment discontinuation.
Results:
48 patients (21, 22, and 5 in groups A, B, C respectively) were analyzed (48 from 58 patients recruited at the beginning).
100% response to rituximab in low risk group, 18% response to rituximab in high risk group. 0% response to rituximab in very-high risk group.
2-year overall survival was 68%, 2-year event free survival was 66% in low risk group.
Very high-risk group patients had higher risk of hemato-toxicity, infections and AKI.
Leucopenia was found in 37%.
Infections were found in 42%
Limitations of the study:
1- Small number of patients.
2- It is not a multi-national trial.
3- Over representation of lung transplant recipients who carry poor prognosis.
4- Higher percentage of rare PTLD forms
Conclusion:
De-escalation of therapy with rituximab is effective is low risk group patients.
Poor outcomes in very high-risk group even with intensified immune-chemotherapy.
What is the level of evidence provided by this article?
Level I (multi-center randomized controlled trial)
INTRODUCTION
Post-transplant lymphoproliferative disorders (PTLD) are compli- cations of immunosuppression after solid organ transplantation (SOT). Their epidemiology, pathogenesis, classification, presenta- tion and treatment have previously been reviewed in depth
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence-based
treatment protocol for CD20-positive B-cell PTLD in adults [6]. They demonstrated improved median overall survival (OS) compared to preceding smaller rituximab monotherapy trials and lower treatment-related mortality (TRM) compared to prior retrospective case series of first-line chemotherapy
METHODS
Study design and patients
This prospective, multicentre, open-label phase II trial enrolled treatment- naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020. Additional inclusion criteria were an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measur- able disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Main exclusion criteria were central nervous system involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Treatment plan
Treatment consisted of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). Response to treatment at interim and final staging was determined according to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging
Statistical analysis
Analysis was by intention to treat (ITT) unless otherwise specified. The per- protocol (PP) population included all patients treated according to protocol with a minimum number of two treatment cycles and sufficient information to determine remission status. For the calculation of the overall response to full treatment, subjects non-evaluable for response (i.e. subjects suffering TRM before final staging without evidence for PD) were not included in the denominator. The primary endpoint was EFS in the low-risk group. Events were infections grade III/IV from day 50 to day 143, treatment discontinua- tion for any reason, disease progression and death. The pre-specified comparator group included 25 patients in CR or PR with <3 initial IPI risk factors after rituximab IV induction who were treated with CHOP consolidation in the PTLD-1 ST trial
Treatment
One patient died before the start of treatment, another during, but unrelated to rituximab induction .58 patients could be evaluated for response to rituximab induction, 48 of which had received all four scheduled applications. The ten patients that did not receive the four scheduled applications all had disease progression during treatment: three after the first application, two after two doses and four after three doses. In summary, 26/58 patients (45%, 95% CI 33–58) responded to rituximab mono- therapy induction and 5/58 (9%, 95% CI 3–19) achieved a CR.
Outcome and toxicity by treatment group
The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group. Time-to event outcomes RD, TTP, OS and PFS for each risk group are plotted in Supplementary
In the low-risk group, ORR at final staging was 95% (20/21 patients; CR 11/21, 52%). One patient suffered disease progression. Median RD was not reached; the 2-year KM estimate was 89% (95% CI
The primary endpoint of this trial, the 2-year EFS KM estimate in the low-risk group, was 66% .This was 14% higher than in the pre-specified comparator group (52% )
DISCUSSION
Rarity and disease heterogeneity are the reasons evidence for PTLD treatment is still based on phase II clinical trial data. The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients unresponsive to initial immunosuppression reduction. With a median OS of 6.6 years and a clear plateau on the PFS curve it compared favourably to earlier rituximab monotherapy trials. The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) successfully tested a response-adapted treatment strategy based on response to rituximab monotherapy induction. Exposure of patients to chemotherapy was limited and long-term outcomes maintained. It is considered a 1st-line standard in the treatment of PTLD
During the conduct of the PTLD-2 trial, two other prospective multicentre phase II trials evaluated ibrutinib and brentuximab vedotin, respectively, in the treatment of PTLD. Ibrutinib was added to risk-stratified sequential treatment in induction and consolidation (n = 39). It did not result in a sufficiently high CR rate to warrant further investigation, while the OS and PFS outcomes were very similar to those reported in the PTLD-1 RSST trial
A small trial of brentuximab vedotin given concurrently with rituximab for patients with de novo immunosuppression- associated CD30-positive and/or EBV-positive lymphomas included 12 PTLD after solid organ transplantation
Study design and patients -This prospective, multicentre, open-label phase II trial enrolled treatmentnaïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020. Additional inclusion criteria were an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. .. PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification.
Treatment plan -Treatment – consisted of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50)
After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx.
The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Outcome and toxicity by treatment group–
The overall response rate(ORR) to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group. In the low-risk group, ORR at final staging was 95% (20/21 patients; CR 11/21, 52%).In the high-risk group, ORR at final staging was 100% (22/22; CR 9/22 [41%).Toxicity was low; 7/21 (33%) patients suffered a single episode each of grade 3/4 infections (pneumonia in 4/7, none fatal) – three of these were outside the time interval defined for EFS. There was no TRM (0/21, 0%). Only three further adverse events grade 3/4 were reported.
Chemotherapy in the high-risk group was associated with significant toxicity: 13/26 (50%) patients suffered grade 3/4 infections. Most frequent was febrile neutropenia. Haematotoxicity was common (leukopenia grade 3/4 in 16/ 26 [62%]), as was acute renal failure (4/26, 15%), gastrointestinal bleeding (3/26, 12%) and tumour lysis syndrome (2/26, 8%). TRM was 2/26 (8%).
In the very-high-risk group, 5/9 patients could be evaluated for response at final staging. 3/5 (60%) responded with two patients (40%) in CR.Toxicity in the very-high-risk group was substantial: 5/8 (63%) patients suffered grade 3/4 infections (two cases fatal, TRM 2/8 [25%]). Haematotoxicity was very common (leukopenia grade 3/4 in 6/8 [75%]), as was acute renal failure (4/8, 50%). Ten additional single cases of adverse events grade 3/4 were reported among these eight patients and included gastrointestinal bleeding, gastrointestinal perforation, multi-organ failure and cerebral bleeding. The highest rate of haematotoxicity, infections and mortality occurred after the first application of chemotherapy (RSCCHOP) rather than subsequent cycles (either RSC-CHOP or RSCDHAO
population:
Inclusion: Adult SOT recipients diagnosed with CD20-positive PTLD, insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Main exclusion criteria: CNS involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Intervention: After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx
Outcome: event-free survival (EFS) in the low-risk group
Results: Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing
Strength: Good design and follow up, it is good phase II trial with potential options for more stronger evidenceopulation:
Inclusion: Adult SOT recipients diagnosed with CD20-positive PTLD, insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Main exclusion criteria: CNS involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Intervention: After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx
Outcome: event-free survival (EFS) in the low-risk group
Results: Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing
Strength: Good design and follow up, it is good phase II trial with potential options for more stronger evidence
INTRODUCTION:
PTLD is an immunosuppression related malignancy with high morbidity in transplant recipients. The preceding PTLD-I trial showed that stepwise therapy with rituximab followed by CHOPD-21 was effective and had lower adverse effect profile.
This is prospective, multicenter, open-label phase II trial tested modified risk stratified sequential treatment of CD20-positive PTLD in adults after SOT.
METHODS:
Study design and patients, treatment plan and statistical analysis.
Treatment Plan:
Rituximab (1400 mg SC; initial application.375 mg/m2 IV) was administered on days 1, 8, 15, and 22 as part of the treatment. The interim staging was then performed (day.40–50).
PTLD-adapted response criteria for malignant lymphomas were used to assess treatment response at intermediate and final stages.
Results:
45% patients achieved response to Rituximab and 9% achieved complete remission with rituximab after 4 doses as part of induction therapy. 21 low risk cases were assigned to rituximab consolidation therapy (4 additional doses), 28 were allotted to high risk for R-CHOP and 9 were allotted to very high risk for therapy with R-CHOP & R-DHAOx. Overall response was 94% with 46% achieving complete remission. Most severe adverse effects were related to infections (42% overall, 33% in low risk and 46% in high risk category), leukopenia (37%), Anemia (24%), thrombocytopenia (22%), AKI (15%), GI bleed (7%). Overall response rate was 100% in both low risk and high risk arms but treatment related toxicities were higher in the high-risk category. In the very high risk category 3/5 (60%) responded with 2 achieving complete remission.
DISCUSSION:
marked variability in disease subtypes and rarity of disease are factor which have limited deeper insight into this disease. PTLD-I aimed at standardizing chemotherapy protocol for PTLD. PTLD-II aimed at step wise approach based on modified risk stratification with a target to reduce chemotherapy related adverse effects.
Level of evidence is 1
Please summarise this article
INTRODUCTION: The PTLD-2 trial is a multicenter phase II trial with treatment protocols based on modified risk stratification and step up therapy treatment protocol based on risk category. PTLD is an immunosuppression related malignancy with high morbidity in transplant recipients. The preceding PTLD-I trial showed that stepwise therapy with rituximab followed by CHOPD-21 was effective and had lower adverse effect profile.
RESEARCH QUESTION: The question raised was whether Rituximab alone could be sufficient to achieve remission in low risk cases after risk stratification. The hypothesis was that in low risk cases subcutaneous rituximab alone would be as effective as R-CHOP-21 with lower rate of severe infections.
METHODS: Open label multicenter phase II trial, 14 centers in total over 5 years with 60 patients enrolled in total.
TREATMENT PLAN: 4 doses of Rituximab followed by staging of disease. Low risk cases were given further 4 doses of Rituximab, whereas high risk cases were switched to R-CHOP (as per PTLD-I trial). Very high risk cases received 6 cycles of alternating R-CHOP and R-DHAOx. PCPC prophylaxis and G-CSF administration was mandatory. Disease activity was assessed at 1 month after final dose and patients were kept on regular follow up.
RESULTS: 45% patients achieved response to Rituximab and 9% achieved complete remission with rituximab after 4 doses as part of induction therapy. 21 low risk cases were assigned to rituximab consolidation therapy (4 additional doses), 28 were allotted to high risk for R-CHOP and 9 were allotted to very high risk for therapy with R-CHOP & R-DHAOx. Overall response was 94% with 46% achieving complete remission. Most severe adverse effects were related to infections (42% overall, 33% in low risk and 46% in high risk category), leukopenia (37%), Anemia (24%), thrombocytopenia (22%), AKI (15%), GI bleed (7%). Overall response rate was 100% in both low risk and high risk arms but treatment related toxicities were higher in the high risk category. In the very high risk category 3/5 (60%) responded with 2 achieving complete remission.
DISCUSSION: marked variability in disease subtypes and rarity of disease are factor which have limited deeper insight into this disease. PTLD-I aimed at standardizing chemotherapy protocol for PTLD. PTLD-II aimed at step wise approach based on modified risk stratification with a target to reduce chemotherapy related adverse effects.
STRENGTHS OF STUDY: Multicenter, open label trial with predefined risk stratification and treatment protocols. Use of CT rather than PET scan for interval staging.
LIMITATIONS OF STUDY: Lower number of patients and patients in Germany alone.
What is the level of evidence provided by this article?
Level 1 for open label multi-center trial.
INTRODUCTION:
Post renal transplantation,potent immunosuppression may be complicated by post-transplant lymphoproliferative diseases (PTLD) .
This article reviews the epidemiology, aetiology, classification, presentation, and therapy.
Study design and patients:
This is prospective, multicentre, open-label phase II trial tested modified risk strati fied sequential treatment of CD20-positive PTLD in adults after SOT .
Treatment plan:
Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). (Low-risk group) continued with four three-weekly courses of rituximab. Most other patients (high-risk group) received four cycles of RSC-CHOP-21.
Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals.
Outcome and toxicity:
The overall response rate at final staging was 94% .
DISCUSSION:
Rarity and disease heterogeneity are the reasons evidence for PTLD treatment is still based on phase II clinical trial data.
The PTLD-1 trial show a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patient sun responsive to initial immunosuppression reduction. By this regimen Exposure of patients to chemotherapy was limited and long-term outcomes maintained. It is considered a 1st-line standard in the treatment of PTLD.
This study observed similar ORR, TTP, OS and PFS compared to the preceding PTLD-1 ST and RSST trials.
2-year EFS in the low-risk group was numerically, but not statistically, superior to a pre-specified comparator group from the PTLD-1 ST trial treated with CHOP consolidation.
Patient allocation to the very-high-risk group of the PTLD-2 protocol was based on two previously identified risk factors for poor outcome: progressive disease under rituximab induction and thoracic organ transplant.
This trial utilized rituximab in its formulation for subcutaneous injection. In a pre-specified inter-trial comparison, we did not detect significant differences in ORR between rituximab SC and IV, nor a sex-specific difference.
Limitations of this trial included
– small size
– and lack of international recruitment due to funding constraints ( over-representation of lung transplant recipients , high proportion of Burkitt, Burkitt-like lymphoma with 11q aberration and high-grade B-cell lymphoma PTLD .
level of evidence is 1
Summary
Introduction
This article is based on subcutaneous Rituximab treatment in PTLD post solid organ transplantation. Immunochemotherapy intensification was studied in high and low risk groups.
Discussion
PTLD is rare and highly heterogenous. Phase I trial included four courses of weekly Rituximab followed by four cycles of CHOP 21 for patients who were unresponsive to initial immunosuppression induction. This study is based on a phase II trial which tested modified sequential treatment of CD20 positive PTLD in adults after SOT. Rituximab was used in its formulation for subcutaneous treatment. No difference in subcutaneous and IV administration was detected. No sex specific differences were found.
Progressive disease have been found following Rituximab induction. This is a disappointing result. Further studies need to be made in this regard.
Other drugs that were employed in comparison were ibrutinib and brentuximab vedotin in the treatment of PTLD. The former was added to induction therapy and did not result in making a significant impact. Brentuximab vedotin given concurrently with Rituximab for patients with de novo immunosuppression associated EBV lymphomas found a small percentage of development of PTLD in the patients post transplant.
Conclusion
Rituximab given subcutaneously may have reduced rates of CR.
Level of evidence
Level of evidence 1.
Summarise this article:
INTRODUCTION:
After solid organ transplantation, immunosuppression can lead to problems called post-transplant lymphoproliferative diseases (PTLD) (SOT).
In-depth reviews of their epidemiology, aetiology, classification, presentation, and therapy have already been done.
METHODS:
Study design and patients:
· This prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centers in Germany from February 3rd, 2015 until July 13th, 2020.
· Central nervous system involvement, pregnancy, or concurrent diseases that made it impossible to provide study treatment were the main exclusion criteria.
TREATMENT PLAN:
· Rituximab (1400 mg SC; initial application.375 mg/m2 IV) was administered on days 1, 8, 15, and 22 as part of the treatment. The interim staging was then performed (day.40–50).
· PTLD-adapted response criteria for malignant lymphomas were used to assess treatment response at intermediate and final stages.
RESULTS:
Patients
· 60 patients were treated with the medication; the median follow-up period was 2.8 years; 26/58 patients responded to rituximab monotherapy induction; and 5/58 (9%, 95% CI 3-19) patients attained a CR after beginning the medication.
· The six patients who had BCL and PTLD of the MYC-rearrangement type were not treated in the low-risk or very-high-risk groups
· Twenty-six of the 21 patients who were assigned to the low-risk group continued to receive therapy; four patients discontinued due to infections and declining transplant function.
Outcome and toxicity
At the final stage, the response rate was 94% overall (45/48, 95% CI 83-98). The Kaplan-Meier (KM) estimate of RD over a two-year period was 81% (95% CI 68-94). TTP was 78% and OS was 68% in the 60 patients in the population that was intended to be treated (5.1 years).
The toxicity of treatment
· Pneumonia (9).
· Febrile neutropenia (8).
· Sepsis (6).
· reactivation of varicella zoster, (3)
· Infections of grade 3/4 were observed in 25/59 cases (42%, 95% CI 31-55).
· Rituximab IV infusion-related responses occurred in 8/59 patients (14%, 95% CI 7-25; all grade 1 or 2) and local drug reactions in 4/59 individuals.
· Anaemia, thrombocytopenia, acute renal failure and gastrointestinal bleeding were another common grade 3/4 adverse effects.
Outcome and toxicity by treatment group
· In the low-risk group, the overall response rate (ORR) to rituximab monotherapy was 100 percent.
· From day 50 to day 143, there were 4 grade 3/4 infections associated with EFS episodes (19% vs. 32% for the comparison group).
· Both the TTP and PFS projections for the next two and three years were 85%.
· The ORR at the final stage in the high-risk group was 100% (22/22; CR 9/22 [41%]).
· The 2- and 3-year KM estimate was 79% (95% CI 59-98), however, the median RD was not met.
· 13/26 participants in this group of patients experienced grade 3/4 infections after receiving chemotherapy.
· At the final stage, the response in 5/9 patients in the very-high-risk group could be assessed. 2/5 (or 40%) of respondents had two patients in CR.
· 1.2 years was the median RD. The TTP estimate at 2 years was 33%.
· There were no appreciable changes in ORR, TTP, or OS between rituximab SC and the earlier treatment regimens in terms of response rates and time-to-event outcomes.
· EBV-association and sex subgroup analyses that were pre-specified did not find any appreciable differences between the two therapies.
Prognostic factors:
· The three risk groups in this regimen had very varied OS and PFS, but not TTP or DR (n = 58, p 0.001).
· Baseline IPI was a standalone predictive factor for both TTP and OS in a multivariate study.
Discussion:
· The PTLD-1 study established sequential therapy with four rounds of weekly rituximab followed by four cycles of CHOP-21 for patients, creating a new benchmark in CD20-positive B-cell PTLD.
· It contrasted favorably to past rituximab monotherapy studies, with a median OS of 6.6 years and a distinct plateau on the PFS curve.
· Why Patients in the low-risk group of the R-CHOP study received rituximab monotherapy instead of chemotherapy; 76% of these patients would have been treated according to the previous PTLD-1st ST and RSST protocol.
· OS and PFS in the three risk groups were considerably different, although DR, a gauge of how well patients recovered, was relatively comparable.
· The low-risk group’s 2-year EFS was numerically, but not statistically, superior to that of a pre-determined comparison group from the.
· Treatment of the PTLD-1 ST trial with CHOP consolidation.
· Because the experiment’s main objective was not achieved, the initial trial hypothesis was disproved.
· To guarantee that the procedure could be utilized globally, the PTLD-2 trial used therapy stratification based on response to treatment at intermediate staging based on CT imaging rather than positron emission tomography (PET).
· It has been demonstrated that in PTLD, PET identifies individuals at low risk of relapsing and provides clinically useful information.
· It is doubtful that PET-based interim staging would have found more low-risk patients.
· Only 5/58 patients, who had a PR at interim staging and an IPI of 3, were deemed to be high-risk.
· In multivariate analysis, the risk factor no longer has a favorable prognostic value for TTP.
· The poor prognosis in this subset of individuals with Epstein-Barr virus illness is not improved by immuno-chemotherapy (EBV-associated PTLD).
· Other therapy modalities are necessary for this population of patients with an exceedingly high risk.
· Outcomes (ORR, TTP, and OS) were nearly identical irrespective of EBV association, in contrast to the differences in genomic profiles between CD20-positive and CD8-positive patients. The rate of grade 3/4 infections was high (42%) in patients treated with immunochemotherapy for DLBCL, but there were no cases of pneumocystis jirovecii under strict antibiotic prophylaxis.
· This is consistent with findings published for the same drug in follicular lymphoma and in combination with CHOP in DLBCL. We did not discover any variations in ORR between rituximab SC and IV, nor a sex-specific difference.
· However, it’s possible that rituximab SC has somewhat lower CR rates following four weekly cycles of monotherapy.
What is the level of evidence provided by this article:
Level I
Summary
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence-based treatment protocol for CD20-positive B-cell PTLD in adults.The PTLD-1 sequential treatment demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy and established response to rituximab induction as a prognostic factor.
This trial hypothesized that patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified immunochemotherapy.
Six cycles of alternating R-CHOP and modified R-DHAOx every three weeks were chosen for this very-high-risk group, the latter based on efficacy and low renal toxicity. Rituximab at a dose of 1400 mg SC was chosen.
Methods
This is a prospective, multicenter, open-label phase II trial enrolled treatment naive adult SOT recipients diagnosed with CD20-positive PTLD at 15 centers in Germany from February 3rd 2015 until July 13th 2020.
Additional inclusion criteria were an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Main exclusion criteria were central nervous system involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Epstein–Barr virus association was confirmed by in-situ hybridization for EBER transcripts.
Treatment plan:
Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). (Low-risk group) continued with four three-weekly courses of rituximab. Most other patients (high-risk group) received four cycles of RSC-CHOP-21.
Case of clinical signs of disease progression prior to interim staging, restaging was performed prematurely and treatment in the high-risk or very-high-risk groups started immediately if disease progression was confirmed.
Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals.
Pneumocystis jirovecii chemoprophylaxis and treatment with granulocyte-colony stimulating factor after chemotherapy were given.
The final response assessment was performed one month after the last cycle of therapy.
Patients completed follow-up examinations every three months for two years, and annually thereafter.
Result:
60 patients were followed for median time of 2.8 years. One patient died before treatment, other one died during but unrelated to rituximab induction.
26/58 patients (45%) responded to rituximab monotherapy induction and 5/58 (9%) achieved a CR.
21 patients – five in CR and sixteen in PR with baseline IPI < 3 – were allocated to, received, and were evaluated after rituximab monotherapy consolidation in the low-riskgroup.
28 patients were allocated to the high-risk group due to PR with IPI ≥ 3 (five patients), stable disease (10 patients) or progressive disease (13 non-thoracic transplant recipients.
26/28 went on to receive treatment with R-CHOP-21 as two lung transplant recipients did not start treatment due to deteriorating transplant function and tuberculosis, respectively.
Four patients discontinued treatment: One withdrew from trial treatment after one cycle and three patients stopped study treatment due to infections (fatal in two cases: liver abscesses and febrile neutropenia complicated by stroke, respectively).
22/28 patients could be evaluated at final staging.
Outcome and toxicity:
The overall response rate at final stage was 94%.
22/59 reported G3/4 leukopenia.
25/59 reported G3/4 infection.
Most infection episode was (pneumonia,9), (febrile neutropenia,8), (sepsis,6), (and Varicella Zoster,3).
Other adverse events include anemia, thrombocytopenia, ARF, GI hemorrhage.
8/59 develop rituximab-infusion reaction.
Discussion
There was similar ORR, TTP, OS and PFS compared to the preceding PTLD-1 ST and RSST trials.
36% of patients were treated with rituximab monotherapy consolidation and thus chemotherapy-free in the low-risk group – 76% of them would have received R-CHOP consolidation using the preceding PTLD-1 RSST protocol.
OS and PFS were significantly different in the three risk groups – however, DR as a measure of the quality of remissions was very similar. Observed similar ORR, TTP, OS and PFS compared to the preceding PTLD-1 ST and RSST trials.
The 2-year EFS in the low-risk group was numerically, but not statistically, superior to a pre-specified comparator group from the.
The primary end point of the trial was not met, and the original trial hypothesis is rejected.
Alternative treatment strategies are needed for this very-high-risk subgroup.
There was no significant differences in ORR between rituximab SC and IV, nor a sex-specific difference.
Limitations of this trial:
Small size.
Lack of international recruitment due to funding constraints.
Level of evidence : Level 1 prospective open-label phase II trial
PTLD 2 TRIAL
RISK MODIFICATION IN PTLD was achieved in PTLD1 trail
this modification is tested in PTLD 2 TRIAL
PTLD-1 TRIAL FEATURES
RESPONSE TO RITUXIMAB IS PROGNOSTIC FACTOR
RTX monotherapy consolidation for low risk patient
RTX and CHOP for high risk patient
thoracic organ transplant is poor prognostic factor in RTX non responder
so, thoracic SOT and disease progression under rituximab induction may be get benefit from
intensified immunochemotherapy
PTLD 2 TRIAL
open label
phase 2
inclusion – post solid organ transplant with CD 20 positive PTLD in Germany
multicentric
non response to reduction in IS
EXCLUSION – PREGNANCY , HIV ,CNS LESION , inability to atke study drugs
all tissue reviewed by 2 pathologist
WHO classification used
EBV transcript tested
study design
RTX 1400 mg sc on day 1,8,15 and 22
assessment at 40-50 days by ct scan
LOW RISK- patient with CR , patient with PR and less than 3 IPI,>60 yrs , >2 LDH , >stage III __
4 THREE WEEKLY RTX
HIGH RISK – all other
4 CYCLES OF RCHOP
median follow up 2.8 yrs
The primary endpoint was Event Free Survival ( no progression , stoppage of therapy , death or infection III/IV ) in the low-risk group.
these patient were compared with 25 patient from PTDL1 trial wherein CHOP was given to them
58 PATIENTS EVALUATED
48 PATIENT RECIEVED ALL 4 DOSES OF RTX
21 IN LOW RISK GRPOUP,
28 IN HIGH RSK GROUP , 22/28 COULD BE EVALUATED AT FINAAL STAGE
5 HAS CR
21 HAD PR
CONCLUSION
rituximab monotherapy consolidation in an expanded low-rise group including patients with <3 IPI risk factors in PR after
rituximab induction is a safe and feasible alternative to CHOP
consolidation.
Introduction:
Method:
RESULTS:
Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Overall response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 In the low-risk group, 2-year EFS was 66% ( versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with RCHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Discussion:
This prospective, multicenter, phase II trial tested modified risk stratified sequential
treatment of CD20-positive PTLD in adults after SOT. observed similar ORR, TTP, OS
and PFS compared to the preceding PTLD-1 ST and RSST trials
Limitations of this trial :
included its small size .
lack of international recruitment due to funding constraints.
This may have resulted in the over-representation of lung transplant recipients who
have a poor prognosis.
Level I evidence
1. Please summarise this article
INTRODUCTION: (Basis of this trial)
This prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification.
The PTLD-1 sequential treatment (ST) trial demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy.
The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) established rituximab monotherapy consolidation for patients in a complete remission (CR) after rituximab induction and R-CHOP-21 for all non-CR patients.
The question raised by this result was whether rituximab monotherapy consolidation might be sufficient treatment for additional PTLD patients??
Further analyses of the initial PTLD-1 ST trial identified the prognostic value of international prognostic index (IPI) risk factors (≥3 vs <3), Thoracic SOT, response to Retuximab.
PTLD-2 trial tested modified risk-stratification based on these three risk factors
METHODS
Study design
Prospective, multicentre, open-label phase II trial
Period – from February 3rd, 2015 until July 13th, 2020
Patients enrolled from 15 centres in Germany
Patients included –
Treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD
Incomplete response to immunosuppression reduction (RIS)
Measurable disease > 2 cm in diameter (and/or bone marrow involvement) ECOG performance status ≤2.
Exclusion criteria
CNS involvement; pregnancy or nursing
concomitant disease precluding administration of therapy (severe uncontrolled heart disease, HIV, severe active infections).
TREATMENT PLAN
Rituximab 375mg/M2 IV on day-1 followed by Retuximab 1400 mg SC was administered on days 8, 15, and 22
The interim staging with clinical + CT was done on (day 40–50).
PTLD-adapted response criteria for malignant lymphomas were used to assess treatment response.
Patients in CR as well as those in partial remission (low-risk group) continued with four three-weekly courses of rituximab.
Most other patients (high-risk group) received 4 cycles of SC.R-CHOP-21
Thoracic SOT, recipients who progressed under rituximab (very-high-risk group) received six cycles of chemotherapy — RSC-CHOP and RSC-DHAOx alternatively at three-week intervals.
Median follow-up for the whole trial cohort, the low and high-risk group was 2.8 years (4.9 years for the very-high-risk group).
Statistical analysis: Analysis was by intention to treat (ITT) unless otherwise specified.
The primary endpoint was EFS in the low-risk group.
Secondary endpoints – overall response rate (ORR), OS, time to progression (TTP), progression-free survival (PFS), response duration (RD) and Tt Related Mortality (TRM) – overall and by risk group
Pre-specified subgroup analyses were performed according to EBV-association in males and females
RESULTS:
– 60 patients enrolled
– 58 evaluated for response to Retuximab induction – 48 received all 4 doses
– 10 patients had disease progressions, did not receive the four scheduled Retuxi
– 26/58 patients (45%) responded to rituximab monotherapy induction – 5/58 (9%) achieved CR
Low-risk group: 21 patients (5 in CR and 16 in PR with baseline IPI < 3)
· received S/C Rituximab consolidation 4 doses on day 50,72,94, 116.
· ORR to rituximab monotherapy was 100%.
High risk group: 28 patients allocated; 26/28 received treatment with R-CHOP-21
· 22/28 patients could be evaluated at final staging.
Very high-risk group: 9 thoracic SOT recipients, with disease progression at interim staging
· 5/9 patients could be evaluated at final staging.
· 8/15 lung transplant recipients were stratified to the very-high-risk group.
6 patients who had Burkitt’s Lymphoma and high grade BCL type and MYC-rearrangement type PTLD were allocated to high-risk group (not in low-risk nor very-high-risk groups).
Over all Outcome
The overall response rate at final staging was 94% (45/48); CR: 46%;
The 2-year Kaplan–Meier (KM) estimate of RD was 81%
In the ITT population (60 patients) – 2-year KM estimate of TTP was 78%; OS was 68% (5.1 yrs)
Treatment related Toxicity:
Pneumonia (9), Febrile neutropenia (8), Sepsis (6), Varicella zoster (3)
4 patients had grade 3/4 infection – with EFS episodes (19% vs. 32% for the comparison group).
Common grade 3/4 adverse events – anaemia, thrombocytopenia, ARF, GI bleed
IV Rituxi infusion-related reactions seen in 8/59 patients (14%);
Grade 1/ 2 and local drug reactions in 4/59
Outcome and toxicity by treatment group
Low-risk group: ORR to rituximab monotherapy was 100%
4 grade 3/4 infections associated with EFS episodes
Both the TTP and PFS projections for the next two and three years were 85%.
High-risk group: ORR at the final stage was 100% (22/22); CR 9/22 [41%].
The 2- and 3-year KM estimate was 79%, however, the median RD was not met.
13/26 patients experienced grade 3/4 infections after chemotherapy.
Very-High-risk group: at final stage 5/9 patients could be assessed.
2/5 (or 40%) of respondents had CR.
Median RD was 1.2 yrs; TTP estimate at 2 years was 33%.
There were no appreciable changes in ORR, TTP, or OS between rituximab SC and the earlier treatment regimens in terms of response rates and time-to-event outcomes.
EBV-association and sex subgroup analyses that were pre-specified did not find any appreciable differences between the two therapies.
Prognostic factors
3 risk groups in this regimen had very varied OS and PFS, but not TTP or DR
Baseline IPI was a standalone predictive factor for both TTP and OS in a multivariate study.
DISCUSSION :
The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with 4 cycles of weekly IV rituximab, followed by 4 cycles of CHOP-21 for patients unresponsive to initial RIS.
This prospective, multicentre, phase II trial tested modified risk stratified sequential treatment of CD20-positive PTLD in adults after SOT.
PTLD-2 trial used treatment stratification based on response to Retuxi and staging based on CT imaging rather than PET, so that the protocol can be applied worldwide, also to compare with the earlier PTLD-1 trial.
Patient allocation to “very-high-risk group” was based on 2 previously identified poor risk factors – progressive disease under rituximab induction and thoracic SOT.
Intensified immunochemotherapy could not overcome the poor prognosis in the very-high-risk subgroup patients. Although grade 3/4 infections were high (42%), there was no cases of PJP under strict antibiotic prophylaxis.
Complete remission rates after 4 weekly courses of rituximab monotherapy might be slightly lower with rituximab SC
Limitations of this trial
· small size and lack of international enrolment
· Toxicity and efficacy for the PTLD subgroup were not analysed,
The evidence available does not encounter the concept of risk stratified sequential treatment as first-line treatment of CD20- positive PTLD in adults after SOT.
1. What is the level of evidence provided by this article
Prospective, multicentre, open-label phase II trial – level 1
INTRODUCTION
· The PTLD-1 sequential treatment demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy and established response to rituximab induction as a prognostic factor
· The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) established rituximab monotherapy consolidation for patients in a complete remission (CR) after rituximab induction and R-CHOP-21 for all non-CR patients
· Further analyses of the initial PTLD-1 ST trial identified the prognostic value of international prognostic index (IPI) risk factors (≥3 vs<3) and thoracic SOT in addition to response to rituximab
· The PTLD-2 trial tested modified risk-stratification based on these three clinical risk factors
METHODS
Study design and patients
Inclusion Criteria
· treatmentnaïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020
· insufficient response to upfront immunosuppression reduction, measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Exclusion criteria
· central nervous system involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Treatment plan
· rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
· Patients in CR as well as those in partial remission (low-risk group) continued with four three-weekly courses of rituximab
· Most other patients (high-risk group) received four cycles of SC.R-CHOP-21
· Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals
· Median follow-up for the whole trial cohort as well as the low- and high-risk groups was 2.8 years (4.9 years for the very-high-risk group).
DISCUSSION
· The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients unresponsive to initial immunosuppression reduction.
· This prospective, multicentre, phase II trial tested modified risk stratified sequential treatment of CD20-positive PTLD in adults after SOT.
· The PTLD-2 study used treatment stratification based on response to treatment at temporary staging based on CT imaging rather than PET to ensure that the protocol can be applyed worldwide and to maintain comparability with the earlier PTLD-1 trials.
· Patient allocation to the very-high-risk group of the PTLD-2 protocol was based on two previously identified risk factors for poor outcome: progressive disease under rituximab induction and thoracic organ transplant
· intensifying immunochemotherapy does not overcome the poor prognosis in the very-high-risk subgroup patients.
· the rate of grade 3/4 infections was high (42%) but there was no cases of pneumocystis jirovecii pneumonia under strict antibiotic prophylaxis.
· Complete remission rates after 4 weekly courses of rituximab monotherapy might be slightly lower with rituximab SC
Limitations of this trial
· small size and lack of international enrolment due to funding limits.
· Toxicity and efficacy for the PTLD subgroup were not analysed,
· The evidence available does not encounter the concept of risk stratified sequential treatment as first-line treatment of CD20- positive PTLD in adults after SOT.
This is a prospective, multi-centre, with level of evidence grade 1.
Please summarise this article
Epstein-Barr virus (EBV) is a member of the gamma herpes virus family that is associated with a variety of lymphomas and lymphoproliferative disorders (LPD).
It infects more than 90% of the adult population worldwide.
have different clinical presentations include asymptomatic infection to symptomatic disease.
Post-transplant lymphoproliferative disorders (PTLD) are one of the most important malignancies after solid organ transplantation and hematopoietic stem-cell transplant and it develops as a result of uncontrolled B cell proliferation due to blunted immunological surveillance.
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 treatment
What is the level of evidence provided by this article?
level 1
Please summarise this article
INTRODUCTION:
After solid organ transplantation, immunosuppression can lead to problems called post-transplant lymphoproliferative diseases (PTLD) (SOT).
In-depth reviews of their epidemiology, etiology, classification, presentation, and therapy have already been done.
METHODS
Study design and patients
· This prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centers in Germany from February 3rd, 2015 until July 13th, 2020.
· Central nervous system involvement, pregnancy, or concurrent diseases that made it impossible to provide study treatment were the main exclusion criteria.
TREATMENT PLAN
· Rituximab (1400 mg SC; initial application.375 mg/m2 IV) was administered on days 1, 8, 15, and 22 as part of the treatment. The interim staging was then performed (day.40–50).
· PTLD-adapted response criteria for malignant lymphomas were used to assess treatment response at intermediate and final stages.
RESULTS
Patients
· 60 patients were treated with the medication; the median follow-up period was 2.8 years; 26/58 patients responded to rituximab monotherapy induction; and 5/58 (9%, 95% CI 3-19) patients attained a CR after beginning the medication.
· The six patients who had BCL and PTLD of the MYC-rearrangement type were not treated in the low-risk or very-high-risk groups
· Twenty-six of the 21 patients who were assigned to the low-risk group continued to receive therapy; four patients discontinued due to infections and declining transplant function.
Outcome and toxicity
At the final stage, the response rate was 94% overall (45/48, 95% CI 83-98). The Kaplan-Meier (KM) estimate of RD over a two-year period was 81% (95% CI 68-94). TTP was 78% and OS was 68% in the 60 patients in the population that was intended to be treated (5.1 years).
The toxicity of treatment.
· Pneumonia (9).
· Febrile neutropenia (8).
· Sepsis (6).
· reactivation of varicella zoster, (3)
· Infections of grade 3/4 were observed in 25/59 cases (42%, 95% CI 31-55).
· Rituximab IV infusion-related responses occurred in 8/59 patients (14%, 95% CI 7-25; all grade 1 or 2) and local drug reactions in 4/59 individuals.
· Nanaemia, thrombocytopenia, acute renal failure and gastrointestinal bleeding were another common grade 3/4 adverse effects.
Outcome and toxicity by treatment group
· In the low-risk group, the overall response rate (ORR) to rituximab monotherapy was 100 percent.
· From day 50 to day 143, there were 4 grade 3/4 infections associated with EFS episodes (19% vs. 32% for the comparison group).
· Both the TTP and PFS projections for the next two and three years were 85%.
· The ORR at the final stage in the high-risk group was 100% (22/22; CR 9/22 [41%]).
· The 2- and 3-year KM estimate was 79% (95% CI 59-98), however, the median RD was not met.
· 13/26 participants in this group of patients experienced grade 3/4 infections after receiving chemotherapy.
· At the final stage, the response in 5/9 patients in the very-high-risk group could be assessed. 2/5 (or 40%) of respondents had two patients in CR.
· 1.2 years was the median RD. The TTP estimate at 2 years was 33%.
· There were no appreciable changes in ORR, TTP, or OS between rituximab SC and the earlier treatment regimens in terms of response rates and time-to-event outcomes.
· EBV-association and sex subgroup analyses that were pre-specified did not find any appreciable differences between the two therapies.
Prognostic factors
· The three risk groups in this regimen had very varied OS and PFS, but not TTP or DR (n = 58, p 0.001).
· Baseline IPI was a standalone predictive factor for both TTP and OS in a multivariate study.
Discussion
· The PTLD-1 study established sequential therapy with four rounds of weekly rituximab followed by four cycles of CHOP-21 for patients, creating a new benchmark in CD20-positive B-cell PTLD.
· It contrasted favorably to past rituximab monotherapy studies, with a median OS of 6.6 years and a distinct plateau on the PFS curve.
· Why Patients in the low-risk group of the R-CHOP study received rituximab monotherapy instead of chemotherapy; 76% of these patients would have been treated according to the previous PTLD-1st ST and RSST protocol.
· OS and PFS in the three risk groups were considerably different, although DR, a gauge of how well patients recovered, was relatively comparable.
· The low-risk group’s 2-year EFS was numerically, but not statistically, superior to that of a pre-determined comparison group from the.
· Treatment of the PTLD-1 ST trial with CHOP consolidation.
· Because the experiment’s main objective was not achieved, the initial trial hypothesis was disproved.
· To guarantee that the procedure could be utilized globally, the PTLD-2 trial used therapy stratification based on response to treatment at intermediate staging based on CT imaging rather than positron emission tomography (PET).
· It has been demonstrated that in PTLD, PET identifies individuals at low risk of relapsing and provides clinically useful information.
· It is doubtful that PET-based interim staging would have found more low-risk patients.
· Only 5/58 patients, who had a PR at interim staging and an IPI of 3, were deemed to be high-risk.
· In multivariate analysis, the risk factor no longer has a favorable prognostic value for TTP.
· The poor prognosis in this subset of individuals with Epstein-Barr virus illness is not improved by immuno-chemotherapy (EBV-associated PTLD).
· Other therapy modalities are necessary for this population of patients with an exceedingly high risk.
· Outcomes (ORR, TTP, and OS) were nearly identical irrespective of EBV association, in contrast to the differences in genomic profiles between CD20-positive and CD8-positive patients. The rate of grade 3/4 infections was high (42%) in patients treated with immunochemotherapy for DLBCL, but there were no cases of pneumocystis jirovecii under strict antibiotic prophylaxis.
· This is consistent with findings published for the same drug in follicular lymphoma and in combination with CHOP in DLBCL. We did not discover any variations in ORR between rituximab SC and IV, nor a sex-specific difference.
· However, it’s possible that rituximab SC has somewhat lower CR rates following four weekly cycles of monotherapy.
=========================================
What is the level of evidence provided by this article?
Level I
Introduction:
PTLD-1 showed the safety & efficacy of 4 cycles of rituximab (weekly) followed by 4 cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine &prednisolone, every 21 days) with established response to rituximab induction.
It showed the efficacy of rituximab as monotherapy for patients in complete remission after rituximab induction & R-CHOP-21 for all non-complete remission. this result raised the that rituximab monotherapy might be sufficient for additional PTLD patients.
In the PTLD-2 trial, the key hypothesis was to assume that expanding the low-risk group would be superior to CHOP treatment in comparison to the PTLD-1 trial as regard event-free survival at 2 years by lowering rates of infection with the same efficacy.
Study design
This prospective, multicentre, open-label phase II trial enrolled treatment[1]naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15
centres in Germany from February 3rd 2015 until July 13th 202.
Additional inclusion criteria were an insufficient response to upfront
immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an
Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
and an
Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
The main exclusion criteria were central nervous system involvement, pregnancy or
nursing, and concomitant diseases that precluded the administration of
study therapy, in particular severe uncontrolled heart disease, HIV infection
and other severe, active infections.
Treatment plan
– Rituximab 1400 mg SC weekly for four doses & assessment response by CT imaging.
– Low risk group: Patient in complete remission & those in partial remission+IPI <3 risk factors( age>60 , ANN arbor stage III or more , ECOG performance status 2 or mre , elevated LDH & >1 extra nodal disease manifestation) four doses of weekly rituximab
– High-risk group (most other patients) 4 cycles of R-CHOP-21.
– Very high-risk group (thoracic SOT who progressed under rituximab) received 6 cycles of R-CHOP & modified R-DHAOx in a 3-week interval
Conclusion:
– The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group, and 0% in the very-high-risk group.
– the primary endpoint of the trial was not met and the original trial hypothesis(rituximab consolidation results in lower toxicity and similar efficacy) is rejected.
– Level of evidence: level 1
1. Please summarise this article
Introduction;
PTLD is known complication of immunosuppression post-transplantation,
This study was conducted by German PTLD study group with collaboration of European PTLD Network, this was an evidence based study protocol for CD20- positive B-cell PTLD in adults.
They compared the rituximab monotherapy trails with retrospective case series of first line chemotherapy, they denoted improved median overall survival.
PTLD-1 demonstrated the safety and efficacy of four cycles of rituximab followed by CHOP-21(4 cycle), and established rituximab monotherapy response to rituximab induction as a prognostic factor.
The PTLD-1 trial also identified the prognostic value of IPI risk factor >3 -<3. The primary end point was event free survival (EFS) in the low risk group, the PTLD-1 trial rituximab was given subcutaneously, total of 60 patients enrolled
The key hypotheses was that modified in the PTLD-2 trial demonstrated whether rituximab monotherapy consolidation in an expanded low risk group is superior to CHOP consolidation in comparable patient of the PTLD-1 ST trial by denoting a better event free survival at two years, based on lower rate of ¾ infection and similar efficacy. The lower risk group receiving rituximab was expended compared to the RSST protocol.
Thoracic organ transplant was a prognostic factor, those not responding to rituximab in PTLD-1 group ST trial. So this was hypothesized that patients with thoracic SOT and non-responder with rituximab induction might benefit from intensified immunosuppression, these are given alternating six cycles of R-CHOP and modified R-DHAOx every three weeks.
Rituximab dose was modified to 1400mg SC due to non-inferior pharmacological profile to IV.
Methods;
This was multicenter open label phase II trial done at 15 centeres in Germany from February 2015 to July 2020 and they enrolled the recipient diagnosed with CD20 positive PTLD patients.
The inclusion criteria was non-responders with modified immunosuppression,
Disease >2 cm or bone marrow involvement.
ECOG performance status <2.
Exclusion criteria was CNS involvement,
Pregnant, nursing mother, and concomitant disease like heart failure, other infections.
Treatment plan;
The total number of candidates enrolled were catogerized into three groups,
Low risk,
High risk group,
Very high risk group,
Treatment given alternating six cycles of R-CHOP and modified R-DHAOx every three weeks.
Response to monotherapy was 100% in low risk group.
Rituximab dose was modified to 1400mg SC due to non-inferior pharmacological profile to IV followed by interim staging at day 40-50s.
Patient in CR and in partial remission were considered according to IPI score <3 with risk factors of age >60. ECOG score >2, raised LDH continued with four cycle of SC R-CHOP.
Candidate who were given intensified regimen with thoracic SOT recipient were high risk group (response 18%). Response was 0% in very high risk group.
Similarl to PTLD-1 trial PJP chemoprophylaxis were given.
The primary end point by two years low risk 66%.
Prognostic factor;
Thoracic organ SOT was an independent risk factor.
In high risk group had a highly significant different OS and PFS.
The only baseline score IPI >3 remained an independent prognostic factor for both TTP and OS.
Result;
The overall response rate at the end was 94%, RD 81% at two years.
The total number of candidates enrolled were categorized into three groups, treatment related mortality was around 7%.
With monotherapy the response was, Low risk group- 21 patients- 2 year EFS was 66% and OS was 100%.
High risk group, 28-patients, completed the protocol, overall response rate was 18%, while, Very high risk group- 9- patients was zero percent.
The median time of follow-up was 2.8 years.
Level of evidence I
IV. Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicenter phase II PTLD-2 trial
Please summarise this article
Introduction
PTLD is a complication of immunosuppression following SOT. The prospective multicenter Phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20+ PTLD based on two principles established in the PTLD-1 trials i.e., sequential
treatment and risk stratification.
Methods
– prospective, multicenter, open-label phase II trial
– inclusion criteria: –
·treatment naïve adult SOT recipients diagnosed with CD20+ PTLD at 15 centers in Germany between 3rd February 2015 and 13th July 2020
·insufficient response to immunosuppression reduction (± antiviral therapy)
·measurable disease >2cm in diameter (and/ or bone marrow involvement)
·an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
– exclusion criteria: –
·CNS involvement, pregnancy, lactation
·concomitant disease precluding administration of the study drugs e.g., severe uncontrolled heart disease, severe active infections, HIV infection
– the collected tissue samples were reviewed by two expert hematopathologists and classified as per the WHO classification system
– treatment consisted of 4 doses of weekly rituximab followed by interim staging, four 3-weekly courses of rituximab for responders/ low risk group and 4 cycles of R-CHOP-21 for high risk patients
– PCP prophylaxis and G-CSF treatment was offered following chemotherapy
– the PTLD-adapted response criteria was used to assess response to treatment
– follow-up data was evaluated till July 2021
– the primary endpoint was event-free-survival (EFS) in the low-risk group
– PTLD-1 trials provided historical controls
Statistical analysis
– Analysis was by intention to treat (ITT).
– Primary endpoint was EFS in the low-risk group.
– Events included infections, treatment discontinuation, disease progression and death.
– the pre-specified comparator group included 25 patients in either complete (CR) or partial remission (PR).
– Secondary endpoints included overall response rate (ORR), overall survival (OS), time to progression (TTP), progression-free survival (PFS), response duration (RD) and therapy-related mortality (TRM) overall and by risk group.
– Adverse events were documented.
– Pre-specified subgroup analyses were performed according to sex and EBV-association.
– Results from PTLD-1 trials and relevant subgroups based on response to rituximab, IPI and transplanted organ were used for pre-specified historical comparisons of toxicity, survival and efficacy.
Results
Treatment
– 60 patients were enrolled. One patient died before initiation of treatment and another during treatment.
– 58 patients were evaluated for response to rituximab induction, 48 of them received all 4 scheduled doses. The remaining 10 patients had disease progression during treatment.
– 26 patients responded to rituximab monotherapy induction and 5 patients achieved complete remission.
– 21 patients were allocated to the low-risk group, 28 patients were allocated to the high-risk group. 9 were allocated to the very-high risk group.
– 26/28 patients received R-CHOP-21. Two did not receive treatment due to deteriorating transplant function and tuberculosis. Four patients discontinued treatment due to infections hence 22/28 patients were evaluated at final staging.
– 5/9 patients in the very high-risk group were evaluated at the final staging.
– There were differences in the baseline characteristics used for stratification in the different risk groups i.e., transplanted organ, IPI risk factors, rate of early PTLD and rate of EBV association.
Outcome and toxicity
– Overall response rate at final staging was 45/48. Estimates of time to progression and overall survival were 78% and 68% respectively similar to the PTLD-1 trials.
– treatment related mortality (TRM) was 4/59
Outcome and toxicity by treatment group
– Overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
– 2-year event-free survival (EFS) was 66% in the low-risk group vs 52% in the PTLD-1 trial that received CHOP.
– 2-year overall survival was 100% in the low-risk group. The overall response rate at final staging was 100% in the high-risk group.
– There were no significant differences in the overall response rates, time to progression or overall survival.
Prognostic factors
– The overall survival and progression free survival were highly significantly different in the 3 risk groups.
– upon multivariate analysis, only baseline IPI >3 remained an independent prognostic factor for both time to progression and overall survival. Thoracic organ SOT was an independent risk factor for overall survival.
Patients with rituximab monotherapy consolidation in the low-risk groups of PTLD-1 RSST and PTLD-2
– There were no differences in the overall survival or progression free survival.
– The only significant differences were found in the patients who had >3 IPI risk factors and in the presence of individual IPI risk factors i.e., elevated serum LDH activity and extra-nodal disease.
Discussion
This was a prospective, multicenter, phase 2 trial which was testing the modified risk stratified sequential treatment for CD20+ PTLD in adult SOT recipients.
There was no difference in the overall response rate, time to progression and progression free survival compared to the preceding trials i.e., PTLD-1 ST and RSST trials.
Progression free survival and overall survival were significantly different in the three different risk groups i.e., low-risk, high-risk and very-high-risk groups.
The primary end-point of the trial was not met.
Study limitations
– Small size
– Lack of international recruitment
Study strengths
– multicenter
– prospective
Conclusion
In low-risk patients rituximab is a favorable option. It can still be used in high-risk patients but larger studies are needed to look at alternative treatment strategies.
What is the level of evidence provided by this article?
Level I evidence
After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21
The PTLD-1 sequential treatment (ST) trial (n = 70) demonstrated fi the safety and ef cacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days) and established response to rituximab induction as a prognostic factor fi .
The subsequent trial of risk-strati ed sequential treatment (PTLD-1 RSST, n = 152) established rituximab monotherapy consolidation for patients in a complete remission (CR) after rituximab induction and R-CHOP-21 (rituximab and CHOP-21) for all non-CR patients .
Finally, rituximab at a dose of 1400 mg SC was chosen based on fi its non-inferior pharmacokinetic pro le compared to 375 mg/m2 intravenously (IV) in immunocompetent patients with follicular lymphoma and reports of rituximab IV serum concentrations during immunochemotherapy correlating with patient sex and clinical response .
Treatment plan
fi Treatment consisted of rituximab (1400 mg SC; rst application 375 mg/m 2 IV) on days 1, 8, 15 and 22, followed by interim staging (day fi 40–50). Response to treatment at interim and nal staging was determined according to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging .
Patients in CR as well as those in partial remission (PR) with <3 international prognostic index (IPI) ≥ risk factors (age > 60 years, Ann Arbor stage III, ECOG performance status ≥ 2, elevated serum lactate dehydrogenase activity [LDH], and more than one extranodal disease manifestation) at diagnosis (low-risk group) continued with four three-weekly courses of rituximab .
Most other patients (high-risk group) received four cycles of RSC -CHOP-21 (for doses see Supplementary Appendix)
Similar to the PTLD-1 trials, pneumocystis jirovecii chemoprophylaxis and treatment with granulocyte-colony stimulating factor after chemotherapy were fi obligatory. The nal response assessment was performed one month after the last cycle of therapy. Patients completed follow-up examinations every three months for two years, and annually thereafter.
Outcome and toxicity by treatment group The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
The prefi speci ed subgroup analyses (EBV-association and sex) detected fi no signi cant differences in ORR, TTP or OS. There were no sexfi speci c differences in the response to rituximab SC compared to fi rituximab IV in a pre-speci ed inter-trial comparison with combined data from the PTLD-1 ST and PTLD-1 RSST trials
The only signi cant differences were ≥ found in the number of patients with 3 IPI risk factors fi (excluded from the PR group by de nition) and in the presence of individual IPI risk factors (‘elevated serum LDH activity’, ‘extranodal disease’). There were no differences in overall survival
treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients unresponsive to initial immunosuppression reduction.
rituximab monotherapy consolidation in an expanded lowrisk group including patients with <3 IPI risk factors in PR after rituximab induction is a safe and feasible alternative to CHOP consolidation.
As in our preceding trials, the rate of grade 3/4 infections was high (42%). However, we observed no cases of pneumocystis jirovecii pneumonia under stringent antibiotic prophylaxis. TRM occurred exclusively in patients treated with immunochemotherapy with an overall rate of 7%, very similar to immunocompetent patients over 60 years treated with R-CHOP immunochemotherapy for DLBCL .
Limitations of this trial included its small size and lack of international recruitment due to funding constraints.
level of evidence 1
MODIFIED RISK STRATIFIED SEQUENTIAL TX (SC RTX +/- CHEMO) IN B CELL PTLD AFTER SOT;PROSPECTIVE MYLTICENTR PHASE 2 PTLD 2 TRIAL.
INTRODUCTION.
PTLD does occur post transplant from immunity dysfunction from immunosuppressive medications used to aver rejection. European and German PTLD groups had an evidence based TX for CD20+VE pts that showed a fairer median survival compared to smaller RTX monotherapy and less TX related mortality vs retrospective case series of 1st line chemo.
PTLD 1 sequential trial established safety and good outcomes of x4 cycles of RTX followed by x4 cycles of CHOP 21.It recommended RTX monotherapy post induction in pts with CR and R-CHOP 21 for the PR group.
STUDY DESIGN.
-Prospective multicenter open label study.
-Site ; 15 Germany hospitals.
-Study period ; 3/2/2015 -13/7/2020
-Study group-TX naïve adult SOT pts with CD20+VE PTLD.
INCLUSION CRITERIA.
-CD 20+VE PTLD adult SOT.
-Inadequate response to RI +/ ANTIVIRAL THERAPY.
-Quantifiable dx >2 cm diameter + BM involvement.
EXCLUSION CRITERIA.
-CNS involvement.
-Pregnancy /Nursing.
-Concomitant dx that was present before study commenced e.g. RVD +VE status, cardiac dx or any other active infection.
RESULTS.
-Post induction RTX tx pts with no chemo were in CR and PR with IPI3 at diagnosis. The high risk group were given R CHOP 21 with primary result being an event free survival post tx.
-60 pts were involved ;
STUDY STRENGTHS
-Multicenter study.
STUDY LIMITATIONS.
-Small sample size.
-Limited funding.
-Restricted to one part of the continent and as such its findings cannot be extrapolated to other regions and races.
CONCLUSION.
RTX is safe and good option post induction in LR EBV PTLD pts while in HR groups, more studies are needed on other treatment modalities to better our outcomes post transplant.
LEVEL OF EVIDENCE – 1
Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial
Introduction:
Lymphoproliferative Malignancy (PTLD): is the second most common malignancy occurring post solid organ transplant in adults.
It is associated with significant morbidity and mortality with an increased risk of graft loss.
The treatment response has improved after the introduction of rituximab.
The PTLD-1 sequential treatment trial demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 chemotherapy and established response to rituximab induction as a prognostic factor.
The subsequent trial of risk-stratified sequential treatment established rituximab monotherapy consolidation for patients in complete remission after rituximab induction and R-CHOP.
The PTLD-1 trial also identified the prognostic value of IPI risk factors (>3 vs <3)
The PTLD-2 trial therefore tested whether rituximab mono therapy consolidation in an expanded low risk group would be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial by demonstrating an improved event free survival at 2 years, based on a lower rated of grade 3/4 infections and similar efficacy.
Thoracic organ transplant was a prognostic factor for a shorter TTP in rituximab non-responders in the PTLD-1 ST trial.
It was hypothesized that patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified chemotherapy. A dose of 1400 mg of SC rituximab was chosen.
Study design and patient
Prospective, multicentre open-label Phase II trial enrolled treatment involving a total of 60 patients
The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Inclusion criteria
Adult SOT recipients diagnosed with CD20-positive PTLD within the study year
Inadequate response to RI (with or without antiviral therapy)
measurable disease >2cm or bone marrow involvement
Exclusion criteria
CNS involvement
pregnancy or nursing
The concomitant disease that precludes the administration of study therapy
Diagnostic tissues were collected and stored centrally for review by two hematopathologists and classified based on WHO classification
METHODS:
This prospective, multi-centre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020
Phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification.
This is divided into three groups based on the responses (either CR or PR) to the different treatments:
–low-risk group
–high-risk group
–very high-risk group
-Low-risk: patients in complete remission as well as those in partial remission
continued with rituximab monotherapy and thus chemotherapy free
-High-risk: received R-CHOP-21
-Very-high-risk: Thoracic SOT recipients who progressed , received alternating R- CHOP-21 and modified R-DHAO
Chemoprophylaxis for PJP was administered to all the groups as was done for the PTLD-1 trial and the final response to treatment was performed one month after the last cycle of therapy
-Consisted of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
-After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free.
Most others (high-risk) received R-CHOP-21.
Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx
*Outcome: event-free survival (EFS) in the low-risk group
Statistical analysis:
Analysis was by intention to treat (ITT) unless otherwise specified. The per protocol (PP) population included all patients treated according to protocol with a minimum number of two treatment cycles and sufficient information to determine remission status.
Primary outcomes:
-The response rate at interim and final staging.
-Treatment hematological toxicity and infections.
Secondery end points:
-Overall response rate (ORR).
-Time to progression (TTP).
-Treatment related mortality (TRM)- assed by treating physician..
-Response duration(RD) -from complete or partial response at final staging to disease progression.
-Progression free survival (PFS) and Overall survival (OS) -from the start of treatment to progression and death from any cause.
Result:
The response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 . In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP (p = 0.432).
TWO -Year OS in the low-risk group was 100%. Results with RCHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Outcome and toxicity:
The overall response rate at final staging was 94% Toxicity of treatment was significant.
The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Patients treated with rituximab monotherapy consolidation in the low-risk groups of PTLD-1 RSST and PTLD-2:
Phase II PTLD-2 trial :
tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials:
The PTLD-1 sequential treatment (ST) trial (n = 70) demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days) and established response to rituximab induction as a prognostic factor
Strength of the study :
-Multicentric
-Standard Staging protocols
-Better follow ups
Limitations:
–Small sample Size
–Less diversity in sample
-Lack of international recruitment
Conclusion :
The Rituximab monotherapy response at interim staging was 100% in the
low-risk group, 18% in the high-risk group and 0% in the very-high-risk group(may be helpful but still larger studies using other treatment strategies are needed to improve outcome).
Level of Evidence :
A prospective, multi-centre, open-label phase II trial, (level of evidence grade 1).
Please summarise this article
Post transplant lymph proliferative disorders -PTLD are important complication of immune suppression after solid organ transplant. In this prospective , multicentre, open label, phase 2 trial , included treatment naive SOT recipients who had developed CD 20 PTLD. This involved 15 centres in Germany, from February 2015 to July 2020.
Patient in complete or partial remission were labelled as low risk and were continued on Rituximab without chemotherapy
High risk group – Received R- CHOP- 21
Thoracic SOT recipients which progressed received R- CHOP-21 alternating with modified R-DHAO
The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Results
The response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 . In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP (p = 0.432).
2-year OS in the low-risk group was 100%. Results with RCHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Outcomes
Event free survival in low risk group
Strengths
Multicentric
Standard Staging protocols
Better follow ups
Limitations
Small sample
Less diversity in sample
What is the level of evidence provided by this article?
Level of evidence 1
INTRODUCTION
Post-transplant lymphoproliferative disorders (PTLD) are complications of immunosuppression after solid organ transplantation (SOT)
METHODS :
This prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020
Phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification.
low-risk: patients in complete remission as well as those in partial remission
continued with rituximab monotherapy and thus chemotherapy free
high-risk: received R-CHOP-21
very-high-risk: Thoracic SOT recipients who progressed , received alternating R-CHOP-21 and modified R-DHAO
Treatment plan:
consisted of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
Statistical analysis
Analysis was by intention to treat (ITT) unless otherwise specified. The per protocol (PP) population included all patients treated according to protocol with a minimum number of two treatment cycles and sufficient information to determine remission status.
RESULTS:
Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
Overall response was 45/48 . 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
Treatment-related mortality was 4/59 In the low-risk group, 2-year EFS was 66% ( versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with RCHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Outcome and toxicity:
The overall response rate at final staging was 94% Toxicity of treatment was significant.
The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Patients treated with rituximab monotherapy consolidation in the low-risk groups of PTLD-1 RSST and PTLD-2:
Phase II PTLD-2 trial : tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials:
The PTLD-1 sequential treatment (ST) trial (n = 70) demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days) and established response to rituximab induction as a prognostic factor
Limitations of this trial included its small size and lack of international recruitment due to funding constraints.
Conclusion :
The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
This is level 1
Thank you
Population:
Inclusion: Adult SOT recipients diagnosed with CD20-positive PTLD, insufficient response to upfront immunosuppression reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter (and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Main exclusion criteria: CNS involvement, pregnancy or nursing, and concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Intervention: After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx
Outcome: event-free survival (EFS) in the low-risk group
Results: Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing
Strength: Good design and follow up, it is good phase II trial with potential options for more stronger evidence
Thank you
prospective multicenter phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with CD20-positive
*(low-risk) rituximab monotherapy induction, patients in complete remission as well as those in partial remission
**(high-risk) received R-CHOP-21.
***(very-high-risk) Thoracic SOT recipients who progressed received alternating R-CHOP-21 and modified R-DHAOx.. Six cycles of alternating R-CHOP and modified R-DHAOx every three weeks
The R-DHAOx regime was modified due to the high risk of infectious complications in SOT recipients: the cytarabine dose was reduced to 50% and dexamethasone was reduced to
one dose instead of four.
Treatment consisted of rituximab (1400 mg SC; first application375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day40–50). Response to treatment at interim and final staging was determined according to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging Patients in CR
as well as those in partial remission (PR) with <3 international prognostic index (IPI)
risk factors (age > 60 yearselevated serum lactate dehydrogenase activity [LDH], and more than one extranodal disease manifestation) at diagnosis (low-risk group)
pneumocystis jirovecii chemoprophylaxis and treatment with granulocyte-colony stimulating factor after chemotherapy were obligatory.
The final response assessment was performed one month after the last cycle of therapy.
Patients completed follow-up examinations every three months for two years, and annually thereafter
Adverse events
Three patients discontinued treatment after the first cycle of R-CHOP due to infections (two cases of fatal neutropenic sepsis,one case of CMV-encephalitis).
low-risk-group. 8/15 lung transplant recipients were stratified to
Toxicity of treatment was significant. leukopenia was reported in 22/59 patients
infection (up to four). Most common episodes were pneumonia (nine), febrile neutropenia (eight), sepsis (six) and varicellazoster reactivation (three). There were two episodes each of
influenza and fungal pneumonia as well as one case each oftuberculosis and CMV encephalitis,
anaemia, thrombocytopenia, acute renal failure and gastro-intestinal haemorrhage Infusion-related reactionsto rituximab IV occurred in 8/59 patients
The highest rate of haematotoxicity, infections andmortality occurred after the first application of chemotherapy (RSC-CHOP) rather than subsequent cycles (either RSC-CHOP or RSC-DHAOx).
and a pooled analysis of all patients treated with rituximab
monotherapy consolidation in the PTLD-1 RSST and PTLD-2 trials,
The PTLD-2 study used treatment stratification based onresponse to treatment at interim staging based on CT imaging rather than positron emission tomography (PET) to ensure that the protocol can be implemented worldwide and to maintain comparability with the earlier PTLD-1 trials
.
2-What is the level of evidence provided by this article?
well-designed observational studies
Cohort prospective study
A comparison cohort.
Thank you
Introduction:
PTLD is the second most common malignancy occurring post solid organ transplant in adults. It is associated with significant morbidity and mortality with an increased risk of graft loss. The treatment response has improved after the introduction of rituximab. The PTLD-1 sequential treatment trial demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 chemotherapy and established response to rituximab induction as a prognostic factor. The subsequent trial of risk-stratified sequential treatment established rituximab monotherapy consolidation for patients in complete remission after rituximab induction and R-CHOP. The PTLD-1 trial also identified the prognostic value of IPI risk factors (>3 vs <3)
The PTLD-2 trial therefore tested whether rituximab mono therapy consolidation in an expanded low risk group would be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial by demonstrating an improved event free survival at 2 years, based on a lower rated of grade 3/4 infections and similar efficacy. Thoracic organ transplant was a prognostic factor for a shorter TTP in rituximab non-responders in the PTLD-1 ST trial. It was hypothesized that patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified chemotherapy. A dose of 1400 mg of SC rituximab was chosen.
Methodology:
This was a prospective, multi center, open label phase II trial that enrolled treatment naive adult SOT patients diagnosed with CD 20 positive PTLD at 15 centers in Germany. The other additional inclusion criteria were:
The main exclusion criteria were:
Treatment Plan:
Treatment consisted of rituximab 375 mg on days 1, 8, 15, and 22 followed by interim staging between days 40 – 50.
Patients in CR as well as those in partial remission with less than 3 IPI at diagnosis (low risk group) continued with 4 weekly coursed of rituximab
Most others (high risk group) received 4 cycles of SC R-CHOP
Thoracic SOT patients who progressed under rituximab (very high risk group) received intensified chemotherapy
Similar to PTLD 1 trial, PJP chemoprophylaxis and treatment with G-CSF after chemotherapy were obligatory.
Results:
60 patients enrolled in the trial. 2 patients died. 48 out of the 58 patients received all four doses of rituximab induction.
21 patients were classified as low risk and received rituximab monotherapy consolidation.
28 patients were allocated to the high risk group due to partial remission and IPI score of more than 3. 26/28 patients received the R-CHOP 21 therapy while 2 lung transplant recipients did not receive the therapy.
9 thoracic recipients were allocated to the very high risk group \
Outcome and Toxicity:
The overall response rate at final staging was 94%.Median RD was not reached. The 2 year Kapla Meier estimate of RD was 81%. In the ITT analysis, the 2 year KM estimate of TTP was 78%
The 2 year KM estimate for OS was 68%.
Median PFS was 3.8 years with a 2 year KM curve estimate of 56%.
Toxicities of the treatment were significant.
Grade 3/4 leucopenia was reported in 37% of patients while grade 3/4 infections were reported in 42% of patients. 7 patients had more than 1 such infection. Most common episodes were pneumonia, febrile neutropenia, sepsis and VZV reactivation
There were no cases of PJP or PML.
Other frequent grade 3/4 adverse events included anemia, thrombocytopenia, acute renal failure and GI hemorrhage.
Outcome and toxicity by treatment group:
The overall response rate to rituximab monotherapy at interim staging was 100% in the low risk group, 18% in the high risk group and 0% in the very high risk group.
The primary endpoint of this trial, the 2 year EFS KM estimate in the low risk group was 66%. This was 14% higher than in the pre-specified comparator group.
The 2 and 3 year KM estimates of both TTP and PFS were 85%. 2 year PFS in the comparator group was 76%
the 2 and 3 year KM estimated of OS was 100% while in the comparator group it was 88%
In the high risk group, ORR at final staging was 100%.
Median RD was not reached
The 2 and 3 year KM estimate of TTP, PFS and OS were 81%, 54% and 59% respectively.
In the very high risk group, 5/9 could be evaluated for response at final staging. 3/5 patients responded with 2 in CR. Median RD was 1.2 years.
the 2 year KM estimates of TTP, PFS and OS were 33%, 11% and 30% respectively.
Toxicity in the very high risk group was substantial. 63% of the patients suffered grade 3/4 infections.
Discussion:
This prospective, multi center, phase 2 trial tested modified risk stratified sequential treatment of CD 20 positive PTLD in adult SOT recipients. Similar ORR, TTP, OS and PFS were observed compared to the preceding PTLD 1 ST and RSST trials.
36% of pts were treated with rituximab mono therapy consolidation and thus chemotherapy free in the low risk group.
OS and PFS were significantly different in the three groups. However, DR as a measure of the quality of remissions was very similar
2 year EFS in the low risk group was numerically but not statistically superior to the pre-specified comparator group. This the primary endpoint of the trial was not met. The rate of grade 3/4 infections was higher in the low risk group
Limitations of the trial:
Small size
Lack of international recruitment
Level of evidence:
This was a prospective comparative study using results from a previous trial. Level 2
Thank you
Please summarise this article
Post-transplant lymphoproliferative disorders (PTLD) are complications of immunosuppression after solid organ transplantation (SOT).
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence-based treatment protocol for CD20-positive B-cell PTLD in adults .
METHODS
-It is prospective, multicentre, open-label phase II trial enrolled treatment naïve
adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020.
-Diagnostic tissue samples weremcollected and stored centrally, reviewed by two expert haematopathologists and classified according to the WHO classi!cation . Epstein–Barr virus association was confirmed by in-situ hybridization for EBERtranscripts.
– The PTLD-1 trial set a new standard in CD20-positive B-cell PTLD by establishing sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients unresponsive to initial immunosuppression reduction.
-This prospective, multicentre, phase II trial tested modified riskstrati
fied sequential treatment of CD20-positive PTLD in adultsafter SOT. They observed similar ORR, TTP, OS and PFS compared to the preceding PTLD-1 ST and RSST trials.
-It concluded that rituximab monotherapy consolidation in an expanded low risk
group including patients with <3 IPI risk factors in PR after rituximab induction is a safe and feasible alternative to CHOP consolidation.
-It used treatment stratification based on response to treatment at interim staging based on CT imaging rather than positron emission tomography (PET) to ensure that the protocol can be implemented worldwide and to maintain
comparability with the earlier PTLD-1 trials.
-patients in partial remission after rituximab induction might hypothetically have been evaluated as complete remission by PET, it is unlikely that interim staging based on PET would have identified additional low-risk patients.
-Patient allocation to the very-high-risk group of the PTLD-2
protocol was based on two previously identified risk factors for
poor outcome: progressive disease under rituximab induction and thoracic organ transplant . The results in this small group remain highly disappointing with six cycles of immunochemotherapy consolidation including oxaliplatin and cytarabine , conclude that intensi!ed immunochemotherapy does not overcome the poor prognosis in this patient subgroup.
-There is no cases of pneumocystis jirovecii pneumonia under stringent antibiotic prophylaxis.
–Limitations
– Its small size and lack of international recruitment due to funding constraints.
What is the level of evidence provided by this article?
Level I
Thank you
Summary:
· According to the principles established in the PTLD-1 trials—sequential treatment and risk-stratification—the prospective multicentre Phase II PTLD-2 study (NCT02042391) examined modified risk-stratification in adult SOT recipients with CD20-positive PTLD.
· Patients in complete remission as well as those in partial remission with IPI <3 at diagnosis (low-risk) continued on rituximab monotherapy after rituximab monotherapy induction and were thus chemotherapy-free.
· The majority of those at high risk received R-CHOP-21. R-CHOP-21 and modified R-DHAOx were given in alternating doses to thoracic SOT patients who advanced (extremely high risk).
· The event-free survival (EFS) rate in the low-risk group was the main endpoint.
· In this study 60 patients were enrolled among them 21 had low risk, 28 had high risk and 9 had very high risk.
· The main hypothesis was that, rituximab monotherapy would be superior to CHOP in comparable patients of the PTLD-1 trial.
· 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% (95% CI 65–90) and 68% (95% CI 55–80) – similar to the PTLD-1 trials.
· Treatment-related mortality was 4/59 (7%, 95% CI 2–17).
· In the low-risk group, 2-year EFS was 66% (95% CI 45–86) versus 52% in the historical comparator that received CHOP (p = 0.432).
· 2-year OS in the low-risk group was 100%.
· Results with RCHOP-21 in high-risk patients confirmed previous results.
· Immunochemotherapy intensification in very-high-risk patients was disappointing.
· Strengths of this study are prospective and multicenter study.
· Limitations of this study are small size and lack of international recruitment, over-representation of lung transplant as well as high proportion of Burkitt, Burkitt-like lymphoma.
Level of evidence : level I
Thank you
Level of evidence is 1
Introduction
Post-transplant lymphoproliferative diseases (PTLD) are immunosuppression-related problems following solid-organ transplantation (SOT).
The German PTLD study group and European PTLD Network phase II trials produced an evidence-based treatment plan for CD20-positive B-cell PTLD in adults.
They had better median overall survival than smaller rituximab monotherapy trials and lower treatment-related mortality than retrospective case series of first-line chemotherapy.
The PTLD-1 sequential treatment trial showed the safety and efficacy of four cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy and established response to induction as a prognostic factor.
The risk-stratified sequential treatment study (PTLD-1) recommended rituximab monotherapy consolidation for patients in complete remission following induction and R-CHOP-21 for all non-CR patients.
Methodology and study design
From February 3rd, 2015, through July 13th, 2020, treatment-naive adult SOT patients with CD20-positive PTLD were included in this prospective, multicenter, open-label Phase II study at 15 German hospitals.
Discussion
Phase II clinical trials provide evidence for PTLD therapy because of the disease’s rarity and heterogeneity. Patients in the PTLD-1 study who did not react to immunosuppression reduction received four cycles of CHOP-21 followed by four rounds of weekly rituximab. With a median OS of 6.6 years and a plateau in PFS, it performed better than earlier studies with rituximab alone. A response-adapted treatment strategy based on the rituximab monotherapy induction response was investigated using the PTLD-1 RSST. Less chemotherapy was administered, and the long-term effects were kept.
Results
The prospective, multicenter Phase II PTLD-2 research investigated the potential for modifying risk stratification in adult SOT patients with CD20-positive PTLD using sequential therapy and risk stratification from the PTLD-1 investigations. After induction, patients receiving rituximab treatment without chemotherapy remained in full and partial remission with IPI 3 at diagnosis (low-risk). Most of the high-risk group received R-CHOP-21. Thoracic SOT progressors were given R-CHOP-21 and modified R-DHAOx. The primary result was low-risk, event-free survival.
60 patients were divided into 21 low-risk, 28 high-risk, and 9 very-high-risk patients. 45 of 48 respondents (94%) Kaplan-Meier anticipated that the illness would advance 78% of the time and that the overall survival rate would be 68%, which is similar to the results of the PTLD-1 trials. 7 percent, or 4 out of 59 patients, passed away following treatment. When compared to the historical comparison that received CHOP, the 2-year EFS in the low-risk group was 66% (95% CI 45-86) as opposed to 52% (p = 0.432).
Thank you
SUMMARY
Introduction
Among the most common complication of solid organ transplantation is the occurrence of post-transplant lymphoproliferative disease as a result of the immunosuppressive state that could enhance dormant EBV infection.
There are treatment protocols that are either in use or those in clinical trials based on the outcome of the previous outcome of initial treatment modalities.
Treatment modalities considered are:
The second trial which comprises of German PTLD study group and the European PTLD network demonstrates an improved overall median overall survival compared to the preceding smaller Rituximab monotherapy trials, and lower treatment-related mortality (TRM) compared to prior retrospective case series of first-line chemotherapy
Study design and patient
Inclusion criteria
Exclusion criteria
Diagnostic tissues were collected and stored centrally for review by two hematopathologists and classified based on WHO classification
Treatment plan
This is divided into three groups based on the responses (either CR or PR) to the different treatments
Chemoprophylaxis for PJP was administered to all the groups as was done for the PTLD-1 trial and the final response to treatment was performed one month after the last cycle of therapy
Outcome and toxicity by treatment group
Prognostic Factor
Strength of the study
Limitations of the study
Level of evidence
Brief Summary of PTLD -1 trial
Composition of the therapy
Outcome
The subsequent trial of risk stratification sequential treatment, PTLD-1, RSST with a sample size of 150. This established Rituximab monotherapy consolidation for those that achieve complete remission after Rituximab and from R-CHOP 21 for those with non-complete remission.
Excellent
1.Please summarise this article
Using the principles set in the PTLD-1 trials—sequential treatment & risk-stratification—the prospective multicentre (German PTLD study group and European PTLD Network) Phase II PTLD-2 study examined modified risk-stratification in adult SOT patients with B-cell (CD20-positive) PTLD.
Following the start of rituximab monotherapy:
The event-free survival (EFS) rate in the low-risk group was the main endpoint.
Historical controls were offered by the PTLD-1 trials.
Rituximab was given S/C.
60 patients were enrolled:
Limitations of the trial:
====================
2. What is the level of evidence provided by this article?
Thank you.
Introduction:
PTLD are complications of immunosuppression after SOT. PTLD study group established an evidence-based treatment protocol for CD20-positive B-cell PTLD in adults that improve overall survival (OS) and lower treatment-related mortality compared to rituximab monotherapy or first-line chemotherapy.
PTLD-1 Study:
The PTLD-1 sequential treatment (ST) trial (n = 70) demonstrated the safety and efficacy of four cycles of weekly rituximab, followed by four cycles of CHOP-21 chemotherapy every 21 days, and established response to rituximab induction as a prognostic factor.
With a median OS of 6.6 years and a clear plateau on the PFS curve it compared favorably to earlier rituximab monotherapy trials
PTLD-1 RSST trial
Risk-stratified sequential treatment, tested response-adapted treatment strategy based on response to rituximab monotherapy induction., n = 152 established rituximab monotherapy consolidation for patients in a CR after rituximab induction and R-CHOP-21 (rituximab and CHOP-21) for all non-CR patients.
Hypothesis:
The PTLD-2 trial tested modified risk-stratification based on these three clinical risk factors.
Rituximab monotherapy consolidation in an expanded low-risk group would be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial
METHODS
Study design
– Prospective, multicenter, open-label phase II trial.
– 15 centers in Germany
– February 3rd 2015 until July 13th 2020.
Enrollment:
– Treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD
– Insufficient response to upfront immunosuppression reduction (with or without antiviral therapy).
– Measurable disease > 2 cm in diameter (and/or bone marrow involvement)
– Eastern Cooperative Oncology Group (ECOG) performance status < = 2.
Exclusion criteria :
– CNS involvement
– Pregnancy or nursing.
– Concomitant disease that precluded the administration of study therapy; severe uncontrolled heart disease, HIV infection and other
– Severe active infections.
Outcome:
The primary; event-free survival (EFS) in the low-risk group.
Secondary; Overall response rate (ORR), OS, time to progression (TTP), progression-free survival (PFS), response duration (RD) and TRM overall and by risk group.
Treatment plan;
60 patients:
– Consisted of 4 doses of rituximab followed by interim staging and assessment of response to treatment then stratified:
– Low-risk group; CR or PR with <3 IPI à continued with four three-weekly courses of rituximab
– High-risk group à received four cycles of RSC-CHOP-21
– Very-high-risk group; Thoracic SOT recipients who progressed under rituximab à received 6 cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals.
In case of disease progression prior to interim staging, restaging was performed prematurely and treatment in the high-risk or very-high-risk groups started immediately if disease progression was confirmed.
PJP chemoprophylaxis and treatment with G-CSF were obligatory.
Result:
-58 patients could be evaluated for response to rituximab induction,
-48 of which had received all four scheduled applications.
Low risk: 21 patients ( 5 in CR and 16 in PR)
High risk: 28 patients (22 patients completed the protocol ad available for final evaluation)
Very high risk: 9 patients ( 5 patients completed the protocol and available for evaluation)
Outcome and toxicity
Overall response rate at final staging was 94% and CR: 46%
2-year Kaplan–Meier estimates of TTP was 78% and OS was 68% similar to the PTLD-1 trials.
2-year Kaplan–Meier (KM) estimate of RD was 81%.
Median PFS was 3.8 years with a 2-year KM estimate of 56%.
Treatment-related mortality was 7%,
In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP
2-year OS in the low-risk group was 100%.
Toxicity of treatment was significant. Grade ¾ leukopenia was reported in 37% patients at risk while grade 3/4 infections were reported in 42%, 7 patients suffered more than one such infection (up to four).
Response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Immuno-chemotherapy intensification in very-high-risk patients was disappointing
The three risk groups in this protocol had highly significantly different OS and PFS but not TTP or DR
Strength: prospective, multicenter
Limitations small size and lack of international recruitment, over-representation of lung transplant as well as high proportion of Burkitt, Burkitt-like lymphoma with 11q aberration and high-grade B-cell lymphoma >> those carries poor prognosis.
Level of evidence : level 1.
Thank you.
Please summarise this article
Introduction:
Post-transplant lymphoproliferative disorders are a common malignancy encountered in solid organ transplant patients the disease epidemiology, pathogenesis, classification, presentation and treatment have reviewed in depth in a previous studies.
Immunosuppressive drugs are trigger for disease.
This retrospective, multicenter, open label, randomized controlled trail with hypothesis that rituximab monotherapy consolidation in an expanded low-risk group would be superior to CHOP consolidation in comparable patients of PTLD-1ST trial by demonstrating an improved event free survival at 2 years.
Inclusion criteria :
· Naive adult SOT recipients diagnosed with CD20-positive PTLD.
· An insufficient response to upfront immunosuppression reduction (with or without antiviral therapy).
· Measurable disease > 2 cm in diameter (and/or bone marrow involvement).
· Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Exclusion criteria:
· Central nervous system involvement.
· Pregnancy and nursing.
· Diseases that precluded the administration of study therapy, severe heart disease, HIV infection and other severe, active infections.
Treatment plan:
· Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
· Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals.
· Response to treatment at interim and final staging was determined according to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging.
Primary outcomes:
· The response rate at interim and final staging.
· Treatment hematological toxicity and infections.
Secondery end points:
· Overall response rate (ORR).
· Time to progression (TTP).
· Treatment related mortality (TRM)- assed by treating physician..
· Response duration(RD) -from complete or partial response at final staging to disease progression.
· Progression free survival (PFS) and Overall survival (OS) -from the start of treatment to progression and death from any cause.
Results:
– The overall response rate at final staging was 94%, RD 81% at 2 years.
– The 2-year TTP was 78%, and The OS was 68%.
– Median PFS was 3.8 years with a 2-year estimate of 56%.
– TRM affected 4/59 patients.
– Infections were reported in 25/59 Pts.
– The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
– In the low-risk group, ORR at final staging was 95%, and in the high risk group was 100%.
– The prespecified subgroup analyses (EBV-association and sex) detected no significant differences in ORR, TTP or OS. There were no sex specific differences in the response to rituximab SC compared to rituximab IV in a pre-specified inter-trial comparison with combined data from the PTLD-1 ST and PTLD-1 RSST trials.
These were comparable when compared to results from PTLD-1ST with 95% CI.
Low-risk (patients in CR after rituximab induction or PR with baseline IPI < 3), very-high risk (thoracic transplant recipients with progressive disease after rituximab induction) and high-risk (all others).
Higher risk patients are EBV negative, lung transplant, high LDH, international prognostic index >/= 3.
Limitations of the study:
· small size and lack of international recruitment due to funding constraints. This may have resulted in the over-representation of lung transplant recipients, who have a poor prognosis.
· high proportion of Burkitt, Burkitt-like lymphoma with 11q aberration and high-grade B-cell lymphoma PTLD.
Conclusion:
Rituximab is safe and good consolidation therapy for low risk EBV related PTLD patients, while in high risk patients may be helpful but still larger studies using other treatment strategies are needed to improve outcome.
What is the level of evidence provided by this article?
Level of evidence I – multicenter randomized control study.
Thank you.
Summary of the article
Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multi-centre phase II PTLD-2 trial
The article is about a prospective, multicentre, open-label phase II trial enrolled treatment- naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020.
Inclusion criteria:
· naïve adult SOT recipients diagnosed with CD20-positive PTLD.
· an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy).
· measurable disease > 2 cm in diameter (and/or bone marrow involvement).
· Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Exclusion criteria:
· Central nervous system involvement.
· Pregnancy or nursing.
· Concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
Treatment plan:
· Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50).
· Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals.
· Response to treatment at interim and final staging was determined ccording to PTLD-adapted response criteria for malignant lymphomas based on computed tomography imaging.
Study’s outcome
1. The overall response rate at final staging was 94%.
2. Toxicity of treatment was significant.
· Most common episodes were pneumonia , febrile neutropenia, sepsis and varicella zoster reactivation.
· There were two episodes each of influenza and fungal pneumonia as well as one case each of tuberculosis and CMV encephalitis.
· No cases of pneumocystis jirovecii pneumonia or progressive multifocal leukoencephalopathy.
· Other adverse events include; anaemia, thrombocytopenia, acute renal failure, gastro- intestinal haemorrhage and infusion-related reactions to rituximab IV and local reactions to rituximab SC.
3. The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group. In the low-risk group, ORR at final staging was 95%
4. No significant differences in ORR between rituximab SC and IV, nor a sex-specific difference.
Study’s limitations:
· Small size.
· Lack of international recruitment due to funding constraints.
Study’s Conclusion:
· rituximab monotherapy consolidation in an expanded low- risk group including patients with <3 IPI risk factors in PR after rituximab induction is a safe and feasible alternative to CHOP consolidation.
· The intensified immuno- chemotherapy does not overcome the poor prognosis in very-high-risk subgroup. Alternative treatment strategies are needed for this very-high-risk subgroup.
· Those with EBV-associated PTLD, EBV-specific cytotoxic T-cells are a less toxic alternative based on a recent case series.
The level of evidence provided by this article
This is a prospective, multicentre, open-label phase II trial, with level of evidence grade 1.
Thank you.
Introduction:
German PTLD study group and European PTLD Network established treatment protocol for CD20-positive B-cell PTLD. There was improvement in survival compared with previous Rituximab trials. The PTLD-1 trial showed safety and efficacy of Rituximab given weekly for four weeks, followed by CHOP chemotherapy every 21 days. It established the response to Rituximab treatment as a prognostic factor. The PTLD-2 trial tested a modifiable risk-stratification, that is, rituximab monotherapy in low risk group to be superior to CHOP in PTLD-1 trial by showing an improved event free survival at 2 years.
METHODS
Study design
Prospective, multicentre, open-label phase II trial.
Treatment plan:
Rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22, followed by interim staging (day 40–50). The low risk group patients in CR as well as those in partial remission (PR) continued with four three-weekly courses of rituximab. High-risk group patients received four cycles of RSC-CHOP-21.
Pneumocystis jirovecii chemoprophylaxis and treatment with granulocyte-colony stimulating factor after chemotherapy was mandatory. The final response assessment was performed one month after the last cycle of therapy. Follow up was every three months for two years and then annually.
Results:
26/58 patients (45%, 95% CI 33–58) responded to rituximab monotherapy induction and 5/58 (9%, 95% CI 3–19) achieved a CR.
28 atients were allocated to the high-risk group, 26/28 went on to receive treatment with R-CHOP-21.
Outcome and toxicity
·
The overall response rate at final staging was 94% (45/48, 95% CI 83–98).
· The 2-year Kaplan–Meier (KM) estimate of RD was 81% (95% CI 68–94).
· In the intention-to-treat population (60 patients), TTP was 78% and OS was 68% (5.1 years).
· Toxicity of treatment was significant. Grade 3/4 leukopenia was reported in 22/59 (37%, 95% CI 26–50) patients at risk while grade 3/4 infections were reported in 25/59 (42%, 95% CI 31–55).
· Most common episodes were pneumonia (9), febrile neutropenia (e8), sepsis (6) and varicella zoster reactivation (3), influenza (2) and fungal pneumonia (2) as well as one case each of tuberculosis and CMV encephalitis.
Outcome and toxicity by treatment group:
The overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
The primary endpoint of this trial, the 2-year EFS KM estimate in the low-risk group, was 66% (95% CI 45–86).
In the high-risk group, ORR at final staging was 100% (22/22; CR 9/22 [41%]). Median RD was not reached; the 2- and 3-year KM estimate was 79% (95% CI 59–98)
In the very-high-risk group, 5/9 patients could be evaluated for response at final staging. 3/5 (60%) responded with two patients (40%) in CR. Median RD was 1.2 years. The 2-year KM estimate of TTP was 33% (95% CI 0–82).
Prognostic factors
DISCUSSION
1. The PTLD-1 trial established sequential treatment with four courses of weekly rituximab followed by four cycles of CHOP-21 for patients not responding to reduction in immunosuppression.
2. The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) successfully tested a response-adapted treatment strategy based on response to rituximab monotherapy induction.
3. This prospective, multicentre, phase II trial tested modified risk stratified sequential treatment of CD20-positive PTLD in adults after SOT. Similar ORR, TTP, OS and PFS were observed compared to the preceding PTLD-1 ST and RSST trials.
4. 2-year EFS in the low-risk group was numerically, but not statistically, superior to a pre-specified comparator group from the PTLD-1 ST trial treated with CHOP consolidation.
5. The primary endpoint of the trial was not met and the original trial hypothesis (rituximab consolidation results in lower toxicity and similar efficacy) is rejected.
6. rituximab monotherapy consolidation in an expanded low risk group is safe alternative to CHOP21.
7. The PTLD-2 study used treatment stratification based on response to treatment based on CT imaging rather than positron emission tomography (PET).
8. In the PTLD-1 ST trial, the hazard ratio (HR) of overall response to rituximab induction for TTP was 0.213 (p = 0.008), increasing to 0.256 (p < 0.001) in the PTLD-1 RSST trial. In an analogous multivariate analysis in the PTLD-2 trial, overall response to rituximab was excluded from the multivariate model at step 1 with a HR of 0.867 (p = 0.811).
9. Patient allocation to the very-high-risk group of the PTLD-2 protocol was based on: progressive disease under rituximab induction and thoracic organ transplant, and intensified immunochemotherapy does not overcome the poor prognosis in this subgroup.
10. The independent prognostic value of ≥3 IPI risk factor for both OS and TTP in CD20-positive PTLD was confirmed in this trial.
11. No significant differences between IV and SC rituximab.
12. Rate of grade ¾ infection was high.
Limitations:
1. Small sample size
2. Lack of international recruitment.
Level of evidence: 1
Thank you.
Summary of the Article:
Introduction:
The protocol for CD20-positive B-cell PTLD in adults was established by the German PTLD study group and European PTLD Network.
There was an improved overall survival compared to the preceding smaller rituximab monotherapy trials and lower treatment related mortality, compared to previous retrospective case series of first line chemotherapy.
The PTLD-1 sequential treatment show safety and efficacy of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 chemotherapy every 21 days and established response to rituximab induction as a prognostic factor.
The PTLD-2 trial tested a modifiable risk-stratification, rituximab monotherapy in expanded low risk group, would be superior to CHOP in comparable to PTLD-1 trial by showing an improved event free survival at 2 years, based on a lower rate of grade 3/4 infections and similar efficacy.
Rituximab S/C 1400 mg dose was chosen based on its non-inferior pharmacokinetic profile compared to 375 mg/m2 IV in immunocompetent patients with follicular lymphoma, and serum concentration of rituximab.
Results:
Patients:
Treatment:
Outcome and toxicity:
Discussion:
Limitation of the trial:
Level of evidence:
the prospective multicenter trial.
Level ((II)).
Thank you.
Why level II?
Multicenter
Level 1
thank you prof
IV. Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial
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Please summarise this article
NTRODUCTION
Methods
Study design and patients
Treatment plan
RESULTS
Patients
Outcome and toxicity
Toxicity of treatment was significant.
We compared the outcomes of the PTLD-2 trial with those of the ST and RSST cohorts of the previous trials to see if the new drug was superior to that of the older drug, parenteral tetracycline therapy (PTLD-1).
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Outcome and toxicity by treatment group
Prognostic factors
Patients treated with rituximab monotherapy consolidation in the low-risk groups of PTLD-1 RSST and PTLD-2
.
Discussion
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2-What is the level of evidence provided by this article?
The level of evidence is 1
Thank you.
Introduction:
Hypothesized that patients with both thoracic SOT and disease progression under
rituximab induction might benefit from intensified immunochemotherapy.
Six cycles of alternating R-CHOP and modified R-DHAOx every three weeks were
chosen for this very-high-risk group, the latter based on efficacy and low renal toxicity.
The R-DHAOx regime was modified due to the high risk of infectious complications in
SOT recipients.
The cytarabine dose was reduced to 50% and dexamethasone was reduced to one dose
instead of four. Finally, rituximab at a dose of 1400 mg SC was chosen based on its
non-inferior pharmacokinetic profile compared to 375 mg/m2 intravenously (IV) in
immunocompetent patients with follicular lymphoma and reports of rituximab IV serum
concentrations during immunochemotherapy correlating with patient sex and clinical
response.
METHODS Study design and patients:
This prospective, multicenter, open-label phase II trial enrolled treatment naïve adult
SOT recipients diagnosed with CD20-positive PTLD at 15 centers in Germany from
February 3rd 2015 until July 13th 2020.
Additional inclusion criteria were an insufficient response to upfront immunosuppression
reduction (with or without antiviral therapy), measurable disease > 2 cm in diameter
(and/or bone marrow involvement) and an Eastern Cooperative Oncology Group (ECOG
) performance status ≤2.
Epstein–Barr virus association was confirmed.
Treatment plan :
Treatment : consisted of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days
1, 8, 15 and 22, followed by interim staging (day 40–50).
(low-risk group) continued with four three-weekly courses of rituximab . Most other
patients (high-risk group) received four cycles of RSC-CHOP-21 .
case of clinical signs of disease progression prior to interim staging, restaging was
performed prematurely and treatment in the high-risk or very-high-risk groups started
immediately if disease progression was confirmed.
Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received
six cycles of alternating RSC-CHOP and modified RSC-DHAOx in three-week intervals.
pneumocystis jirovecii chemoprophylaxis and treatment with granulocyte-colony
stimulating factor after chemotherapy were obligatory.
The final response assessment was performed one month after the last cycle of therapy.
Patients completed follow-up examinations every three months for two years, and
annually thereafter.
Result:
26/58 patients (45%, 95% CI 33–58) responded to rituximab monotherapy induction and
5/58 (9%, 95% CI 3–19) achieved a CR.
21 patients – five in CR and sixteen in PR with baseline IPI < 3 – were allocated to,
received, and were evaluated after rituximab monotherapy consolidation in the low-risk
group.
28 patients were allocated to the high-risk group due to PR with IPI ≥ 3 (five patients),
stable disease (10 patients) or progressive disease (13 non-thoracic transplant
recipients).
26/28 went on to receive treatment with R-CHOP-21 as two lung transplant recipients
did not start treatment due to deteriorating transplant function and tuberculosis,
respectively.
Four patients discontinued treatment: One withdrew from trial treatment after one cycle
and three patients stopped study treatment due to infections (fatal in two cases: liver
abscesses and febrile neutropenia complicated by stroke, respectively).
22/28 patients could be evaluated at final staging.
Nine thoracic transplant recipients were allocated to the very high-risk group due to
disease progression at interim staging.
Eight started treatment, as one lung transplant recipient declined further treatment in
favor of best supportive care.
Three patients discontinued treatment after the first cycle of R-CHOP due to infections
(two cases of fatal neutropenic sepsis, one case of CMV-encephalitis). 5/9 patients could
be evaluated at final staging.
Discussion:
This prospective, multicenter, phase II trial tested modified risk stratified sequential
treatment of CD20-positive PTLD in adults after SOT. observed similar ORR, TTP, OS
and PFS compared to the preceding PTLD-1 ST and RSST trials
Limitations of this trial :
included its small size .
lack of international recruitment due to funding constraints.
This may have resulted in the over-representation of lung transplant recipients who
have a poor prognosis.
Level of evedence1
Thank you.
1- Summary:
PTLD 2 trial:
This prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive.
Inclusion criteria:
– an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy),
– measurable disease > 2 cm in diameter (and/or bone marrow involvement)
– ECOG ≤ 2.
Main exclusion criteria:
– central nervous system involvement,
– pregnancy or nursing
– contraindication to treatment ( severe uncontrolled heart disease, HIV infection and other severe, active infections)
Treatment plan:
Induction with 4 weekly rituximab (first dose IV then SC)
Response assessment:by CT scan after 2-4 weeks.
Patients were stratified into 3 groups:
1- Low risk: partial or complete response and international prognostic index (IPI)
< 3 : Received four three-weekly rituximab
2- High risk: other patients and received four cycles of RSC-CHOP-21
3- Very high risk group: (thoracic SOT) and received received six cycles of alternating RSC-CHOP and modi!ed RSC-DHAOx in three-week intervals
Outcome:
1- The primary endpoint was event free survival ( EFS) in the low-risk group: events (infection, death,progression and death)
2- Secondary endpoints included overall response rate (ORR), OS, time to progression (TTP), progression-free survival (PFS), response duration (RD) and TRM overall and by risk group.
Results:
58 patients could be evaluated for response to rituximab induction, 48 of which had received all four scheduled applications.
1- Low risk: 21 patients ( five in CR and sixteen in PR)
2- High risk: 28 patients (22 available for final evaluation)
3- Very high risk: 9 patients ( 5 available for evaluation)
Outcome and toxicity:
The overall response rate at final staging was 94%
The 2-year Kaplan–Meier (KM) estimate of RD was 81%
The 2-year KM estimate of TTP was 78%
The 2-year KM estimate for OS was 68%
Median PFS was 3.8 years with a 2-year KM estimate of 56%
Toxicity of treatment was significant. Grade ¾ leukopenia was reported in 22/59 (37%), infections were reported in 25/59 (42%,).
Other frequent adverse events included anaemia, thrombocytopenia, acute renal failure and gastrointestinal haemorrhage.
TRM affected 4/59 patients (7%)
Outcome by treatment groups: (table)
Prognostic factors:
1- Risk groups: significantly affect OS and PFS
2- Only baseline IPI > 3remained an independent prognostic factor for both TTP and OS.
3- Thoracic organ SOT was an independent prognostic factor for OS.
Comparison of CR and PR among low risk groups (including PTLD-1 and PTLD-2 patients):
– There were no differences in overall survival (p = 0.762, 2-year-KM estimate 100% in the PR group and 92% [95% CI 84-100] in the CR group)
Or
– Progression-free survival (p = 0.833, 2-year-KM estimate 88% [95% CI 71–100] in the PR group and 90% [95% CI 80–99] in the CR group).
II- level of evidence: Ib
Thank you.
Hypothesis
Methodology
Study design: Prospective multicenter open label phase 2 trial
Study population: Adult SOT recipients diagnosed with CD20 positive PTLD
Study site: 15 German centers
Inclusion criteria: Insufficient response to reduced immunosuppression
Measurable disease >2cm in diameter
ECOG perfomance status <2
Exclusion criteria: CNS involvement
Pregnancy or nursing
Concomittant disease that precluded administration of therapy
60 enrolled, 58 analysed.
21 low risk, 28 high risk and 9 very high risk group.
Treatment plan
Patients received 4 doses of rituximab followed by interim staging at day 40-50 with CT scan.
Patients who had complete remission or partial remission with IPS <3 received additional 3 weekly doses of rituximab.
Patients with high risk disease at diagnosis received R-CHOP.
Very high risk group received alternating doses of R-CHOP and R-DHAOx.
All received PJP prophylaxis and G-CSF.
Final response assessment was done 1 month after last cycle.
Statistical analysis
Intention to treat analysis.
Primary end point: Event free survival in the low risk group.
Secondary end points: overall response rate, time to progression, progression-free survival, response duration and treatment related mortality overall and by risk group.
Results
Primary endpoint: 2-year EFS estimate in the low-risk group was 66%.
Secondary end points: TTP was 78%, Median PFS was 3.8 years, Overall response at final staging was 94%, overall TRM was 7% (0% in low risk group, 8% in high risk group and 25% in very high risk group).
Response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group.
Conclusion.
Therapy de-escalation can be used in low risk group.
Intensified immunochemotherapy in very high risk groups doesn’t improve outcomes.
Strengths
Limitations.
Level of evidence: 1
Thank you.
Please summarise this article
Introduction:
*PTLD are common complications of immunosuppression in post- SOT
* German PTLD study group and European PTLD Network concluded a two phase study on evidence-based treatment protocol for CD20-positive B-cell PTLD in adults, in which there is improved median overall survival (OS) and lower treatment-related mortality (TRM) compared to prior treatment.
*The PTLD-1 sequential treatment (ST) trial showed the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy.
*The subsequent trial of risk-stratified sequential treatment established rituximab monotherapy consolidation in complete remission (CR) after rituximab
induction and R-CHOP-21 for all non-CR cases.
*The PTLD-1 ST trial identified the prognostic value of international prognostic index (IPI) risk factors (3 vs <3).
*The PTLD-2 trial tested modified risk-stratification based on these three clinical risk factors.
The key hypothesis:
Rituximab monotherapy in low-risk group may be superior to CHOP consolidation in comparable patients of the PTLD-1 ST trial by demonstrating an improved event-free survival (EFS) at 2 years.
Patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified immunochemotherapy.
The methods:
*Prospective, multicentre, open-label phase II trial, the recipients native adult SOT diagnosed with CD20-positive PTLD at 15 centres in Germany from February 3rd 2015 until July 13th 2020.
*The patients with insufficient RI, measurable disease > 2 cm and (ECOG) performance status 2.
*Exclusion criteria were CNS involvement, pregnancy or
nursing, and disease interfere with taking of study therapy,
*Diagnostic tissue samples were collected and classified according to the WHO classification. EBV association was confirmed by in-situ hybridization for EBERtranscripts. (FISH) was performed
*Treatment plan consisted of rituximab followed by interim staging. Patients in CR as well as those in (PR) with <3 (IPI), at diagnosis (low-risk group) continued with four three-weekly courses of rituximab.
*High-risk group received four cycles of RSC-CHOP-21
Thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating RSC-CHOP and modi!ed RSC-DHAOx in three-week intervals.
*In disease progression restaging and treatment started immediately.
*Pneumocystis jirovecii chemoprophylaxis and treatment
with granulocyte-colony stimulating factor after chemotherapy were obligatory.
*Median follow-up was 2.8 years.
The results:
*In summary, 26/58 patients responded to rituximab monotherapy induction and 5/58 achieved a CR.
21 patients – five in CR and sixteen in PR with baseline
IPI < 3 – were allocated to, received, and were evaluated after rituximab monotherapy consolidation in the low-risk group.
*The primary endpoint was event-free survival (EFS) in the low-risk group.
* The PTLD-1 trials provided historical controls.
*Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48.
*The 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% and 68% – similar to the PTLD-1 trials.
*Treatment-related mortality was 4/59 . In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP.
* 2-year OS in the low-risk group was 100%. Results with RCHOP- 21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.
Limitations of the study:
included its small size and lack of international recruitment due to funding constraints.
Level 1
Thank you.
The aim of the study ;
—————————————
The primary endpoint was event-free survival (EFS) in the low-risk group.
The study area ;
——————————————–
15 centres in Germany from February 3rd 2015 until July 13th 2020 .
The ethical approval;
——————————-
The responsible local ethics committees approved the trial and all patients gave written informed consent according to the Declaration of Helsinki. The trial is registered with clinicaltrials.gov (NCT02042391).
The population ;
——————————–
60 patients.
The inclusion criteria;
—————————————-
1-an insufficient response to upfront immunosuppression reduction (with or without antiviral therapy),
2- measurable disease > 2 cm in diameter (and/or bone marrow involvement) .
3- an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
The exclusion criteria;
—————————-
1-central nervous system involvement .
2-pregnancy or nursing.
3- concomitant disease that precluded the administration of study therapy, in particular severe uncontrolled heart disease, HIV infection and other severe, active infections.
The method ;
———————————————————
1-Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk.
2-Rituximab was applied subcutaneously.
3-Analysis was by intention to treat (ITT) unless otherwise specified.
The result of the trial ;
————————————-
1-Overall response was 94%.
2-2-year Kaplan–Meier estimates of time to progression and overall survival were 78% similar to the PTLD-1 trials.
3-Treatment-related mortality was 7% .
4-In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP . 2-year OS in the low-risk group was 100%.
5-Results with R- CHOP-21 in high-risk patients confirmed previous results.
6-Immunochemotherapy intensification in very-high-risk patients was disappointing.
The strength of this trial ;
————————————————————–
1- Multicentre study .
2- open-label.
The Limitations of this trial ;
———————————————————-
1-Small sample size .
2-lack of international recruitment due to funding constraints
Conclusion;
————————————-
1- Intensified immuno-chemotherapy does not overcome the poor prognosis in this patient subgroup.
2- Alternative treatment strategies are needed for this very-high-risk subgroup.
3- For those with EBV-associated PTLD(6/9 in this trial), EBV-specific cytotoxic T-cells are a less toxic alternative based on a recent case series .
What is the level of evidence provided by this article?
——————————————————————-
Level I
Thank you.
1-SUMMARY OF THE ARTICLE;.
Introduction:
-Post-transplant lymphoproliferative disorders (PTLD) is a common malignancy following solid organ transplantation(SOT)
-PTLD-2 trial hypothesized that; rituximab monotherapy consolidation may be better in low risk group may be better than CHOP consolidation in comparable patients of PTLD1 trial. Patients with severe thoracic SOT might be a candidate for aggressive therapy (6 cycles of R-CHOP and modified R-DHAOx with reduced dose of cytarabine and steroids).
Methodology:
– A prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany (2015-2020)
Inclusion criteria;.
1.An insufficient response to RI (with or without antiviral therapy)
2.Measurable disease > 2cm in diameter (and/or bone marrow involvement)
3.Eastern Cooperative Oncology Group (ECOG) performance status ≤2
Exclusion criteria;.
1.CNS involvement
2.Pregnancy or nursing
3.Concomitant disease that precluded the administration of study therapy (severe uncontrolled heart disease, HIV infection and other severe, active infections)
Results:
-A total of (60 patients) were enrolled from 2015 to 2020. Median follow up was 2.8 years.
-2 patients died.
-58 were analysed.
-45% responded to rituximab and 9% had CR with rituximab.
-21 were in low-risk group, 28 in high risk, and 9 were in very high-risk group.
-At final staging 21, 22, and 5 patients were available for evaluation in the low-risk, high-risk, and very high-risk group.
-Overall response to rituximab at interim staging was 100% in low risk group, 18% in high risk group, and 0% in very high risk group patients.
-Overall response at final staging was 94%.
Conclusion:
Therapy de-escalation with rituximab consolidation in low-risk group can be used.
Intensified immunochemotherapy in very high-risk group does not improve outcomes.
Limitations of this trial:
1-Small Sample Size
2-Not a Multinational Trial
3-Over representation of lung transplant recipients (who have poor prognosis), and higher proportion of rarer PTLD forms like Burkitt, Burkitt-like and high grade B cell lymphoma type PTLD.
2-LEVEL OF EVIDENCE:
This is RCT ; Multicenter Open label,
level of evidence is Ic .
Summary:
· Low risk PTLD was treated with rituximab monotherapy or sequential therapy. While high risk disease was treated with sequential RTX then chemotherapy (CHOP21).
· The response to therapy was assessed by PET-CT scan.
· The overall response rate was 94% with treatment related mortality of 4/59.
· In conclusion
· In low risk patients, use of rituximab was comparable to sequential therapy, without additional benefits or improvement in the outcome (do it can be used here to minimize adverse effects).
· However, high risk patients essentially require sequential therapy.
Level of evidence: Prospective RCT (level I).
Thank you.
What are the limitations of this study?
Can you give us brief information about PTLD 1?
Immunosuppression in transplant recipients is associated with post-transplant lymphoproliferative disorder (PTLD).
The study (PTLD-2 trial) was a multicentre, prospective, open-label trial which involved patients with CD20 positive PTLD with insufficient response to reduction in immunosuppression (RIS), with measurable disease > 2 cm in diameter, bone marrow involvement, or ECOG (Eastern cooperative oncology group) performance status ≤2. Patients with central nervous system (CNS) involvement, pregnancy or breastfeeding, HIV infection, other active infections, and uncontrolled heart disease were excluded.
Methods:
The patients were initially treated with Injection rituximab (4 weekly doses: first dose 375 mg/m2 intravenous followed by 3 doses of 1400 mg subcutaneous) and then interim staging at day 40-50 was done. The patients were further divided into 3 groups:
a) Low risk: Complete remission, CR or partial remission, PR with <3 international prognostic index, IPI risk factors (age > 60, ECOG status ≥2, Ann Arbor stage ≥3, increased lactate dehydrogenase, and >1 extranodal disease). They were given 4 cycles of 3 weekly rituximab doses. No chemotherapy given to them.
b) Very high risk: Thoracic solid organ transplant patients who progressed despite rituximab treatment. They received 6 cycles of alternating R-CHOP (subcutaneous rituximab, Doxorubicin, cyclophosphamide, vincristine, and prednisolone) and R-DHAOx (subcutaneous rituximab, oxaliplatin, cytarabine, and dexamethasone) every 3 weeks.
c) High risk: remaining patients. They received 4 cycles of subcutaneous rituximab with CHOP every 3 weeks.
The patients were compared with historical controls of the PTLD-1 trial in which patients were given 4 cycles of weekly rituximab followed by 4 cycles of 3 weekly CHOP chemotherapy. PTLD-1 trail had shown the safety and efficacy of this sequential treatment in PTLD.
Primary end point was event free survival (EFS) in low-risk group. Events were infection, disease progression, death, and treatment discontinuation.
Results:
A total of 60 patients were enrolled from 2015 to 2020. Median follow up was 2.8 years. 2 patients died. 58 were analysed. 45% responded to rituximab and 9% had CR with rituximab. 21 were in low-risk group, 28 in high risk, and 9 were in very high-risk group. At final staging 21, 22, and 5 patients were available for evaluation in the low-risk, high-risk, and very high-risk group.
Overall response to rituximab at interim staging was 100% in low risk group, 18% in high risk group, and 0% in very high risk group patients. Overall response at final staging was 94% (CR 46%) – 95% (CR 52%) in low risk group, 100% (CR 41%) in high risk group, and 60% (CR 40%) in very high risk group patients. Leukopenia seen in 37%, 42% had infections like pneumonia, sepsis, febrile neutropenia, varicella zoster virus infections.
The 2 year overall survival was 68%, and 2 year event free survival was 66% in the low-risk group which was similar to the historical controls (52%). The results in the very-high risk group were disappointing with increased incidence of hemato-toxicity, infections, and acute renal failure.
The study concluded that therapy de-escalation with rituximab consolidation in low-risk group can be used. Intensified immunochemotherapy in very high-risk group does not improve outcomes.
Limitations: Small sample size, not a multinational trial, over representation of lung transplant recipients (who have poor prognosis), and higher proportion of rarer PTLD forms like Burkitt, Burkitt-like and high grade B cell lymphoma type PTLD.
2. What is the level of evidence provided by this article?
Multicentre Randomized control trial: Level of evidence Level 1
Thank you.
☆ Modified risk-stratified sequential treatment (subcutaneous
rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial
__________
Summary:
◇ Introduction
▪︎Post-transplant lymphoproliferative disorders (PTLD) are complications of immunosuppression after solid organ transplantation.
▪︎Two phase II trials conducted by the German PTLD study group &European PTLD Network established an evidence-based
treatment protocol for CD20-positive B-cell PTLD in adults.
▪︎The PTLD-1 sequential treatment trial demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days) and established response to rituximab induction as a prognostic factor.
▪︎The subsequent trial of risk-stratified sequential treatment (PTLD-1 RSST) established rituximab monotherapy consolidation for patients in a complete remission after rituximab induction and R-CHOP-21 (rituximab and CHOP-21) for all non-CR patients. The question raised by this result was whether rituximab monotherapy consolidation might be sufficient treatment for additional PTLD patients.
▪︎Further analyses of the initial
PTLD-1 ST trial identified the prognostic value of international prognostic index risk factors and thoracic SOT in addition to response to rituximab.
▪︎The PTLD-2 trial therefore tested modified risk-stratification based
on these three clinical risk factors.
The key hypothesis of this study:
▪︎Patients with both thoracic SOT and disease progression under rituximab induction might benefit from intensified immunochemotherapy.
◇ Methodology:
▪︎The prospective multicentre Phase II PTLD-2 trial tested modified risk-stratification in adult SOT recipients with
CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification.
▪︎ After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free.
▪︎Most others (high-risk) received R-CHOP-21.
▪︎Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx.
◇ Results:
▪︎The primary endpoint was event-free survival (EFS) in the low-risk group.
▪︎The PTLD-1 trials provided historical controls.
▪︎Rituximab was applied subcutaneously.
Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48.
▪︎ 2-year Kaplan–Meier estimates of time to progression and overall survival were 78% – similar to the PTLD-1 trials. ▪︎Treatment-related mortality was 4/59 (7%). In the low-risk group, 2-year EFS was 66% versus 52% in the historical comparator that received CHOP. 2-year OS in the low-risk group was 100%.
▪︎ Results with R CHOP-21 in high-risk patients confirmed previous results. ▪︎Immunochemotherapy intensification in very-high-risk patients was disappointing.
Limitations of this trial:
1. Small size
2. Lack of international recruitment due to funding constraints. This may
have resulted in the over-representation of lung transplant recipients, who have a poor prognosis, as well as the comparatively high proportion of Burkitt, Burkitt-like lymphoma with 11q aberration and high-grade B-cell lymphoma PTLD.
◇ Level of Evidence: level I
Thank you.
Thank you Prof Ahmed
Please summarise this article
Introduction
Two phase II trials conducted by the German PTLD study group and European PTLD Network established an evidence-based treatment protocol for CD20-positive B-cell PTLD in adults. They demonstrated improved overall (OS) survival and lower treatment-related mortality (TRM)
The PTLD-1 sequential treatment (ST) trial (n=70) demonstrated the safety and efficacy of 4 cycles of weekly rituximab followed by four cycles of CHOP-21 chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days)
The PTLD-2 trial tested modified risk-stratification based on the clinical risk factors (IPI risk factors of ≥3 vs <3, thoracic SOT, and response to rituximab)
Methods
A prospective, multicentre, open-label phase II trial enrolled treatment naïve adult SOT recipients diagnosed with CD20-positive PTLD at 15 centres in Germany (2015-2020)
Additional inclusion criteria were
1. An insufficient response to RI (with or without antiviral therapy)
2. Measurable disease > 2cm in diameter (and/or bone marrow involvement)
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤2
Exclusion criteria
1. CNS involvement
2. Pregnancy or nursing
3. Concomitant disease that precluded the administration of study therapy (severe uncontrolled heart disease, HIV infection and other severe, active infections)
Treatment plan
Rituximab (1400mg SC, first dose 375mg/m2 IV) on days 1, 8, 15 and 22, followed by response assessment by CT imaging (day 40–50)
Patients in CR and in partial remission (PR) with <3 IPI risk factors (age >60 years, Ann Arbor stage ≥ III, performance status ≥2, elevated LDH, and more than one extranodal disease manifestation) at diagnosis (low-risk group) continued with four three-weekly courses of rituximab (day 50, 72, 94 and 116)
High-risk group received four cycles of R-CHOP-21 (PR and IPI 3 or more, stable disease or progressive disease and non-thoracic SOT)
Very-high-risk group (thoracic SOT) received six cycles of alternating RSC-CHOP and modified R-DHAOx in three-week intervals (6 doses)
In case of disease progression prior to interim staging, start treatment immediately as in the high-risk or very-high-risk groups
Pneumocystis jirovecii chemoprophylaxis and treatment GCSF after chemotherapy were obligatory
The final response assessment was one month after the last cycle of therapy
Median follow-up for the whole trial was 2.8 years
Results
Total patients were 60 (only 48 patients completed the four doses of rituximab)
45% responded to induction of rituximab monotherapy and 9% achieved a CR
21 patients were allocated to the low risk group, 28 to the high-risk group, and 9 to the very high-risk group
Overall response was 94%
The 2-year Kaplan–Meier estimates of time to progression (TTP) and overall survival were 78% (similar to the PTLD-1 trials). The 2-year KM estimate for OS was 68% (median 5.1 years)
Treatment-related mortality was 7%
The OR to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk group and 0% in the very-high-risk group
In the low-risk group, 2-year event-free survival (EFS) was 66%
In the low-risk group, 2-year EFS was 66% versus 52% in the historical that received CHOP
2-year OS in the low-risk group was 100%
Immunochemotherapy intensification in very-high-risk patients was disappointing
Discussion
This prospective, multicentre, phase II trial tested modified riskstratified sequential treatment of CD20-positive PTLD in adults after SOT
Rituximab monotherapy in a low risk group after rituximab induction is a safe and an alternative to CHOP
The PTLD-2 study used treatment stratification based on response to treatment on CT imaging (not PET)
Allocation to the very-high-risk group of the PTLD-2 protocol was based on two previously identified risk factors for poor outcome (progressive disease during rituximab induction and thoracic organ transplant)
The result of very high risk group is highly disappointing
Limitations of the study: small size and lack of international recruitment due to funding constraints
In PTLD-2 trial, two other prospective multicentre phase II trials evaluated ibrutinib and brentuximab vedotin in the treatment of PTLD
What is the level of evidence provided by this article?
Level I (prospective multicenter study)
Thank you.
Introduction
German PTLD study group and European PTLD Network conducted a 2 phase study on evidence-based treatment strategy for CD20-positive B-cell PTLD in adults where better over all survival (OS ) and less treatment-related mortality (TRM) was noted in comparison to previous treatment modalities.
PTLD-1 sequential treatment (ST) trial demonstrated the efficacy of RCHOP therapy
The subsequent risk-stratified sequential treatment trial showed rituximab monotherapy consolidation for those in a complete remission (CR) after rituximab induction and R-CHOP-21 for all non-CR patients.
PTLD-1 ST trial detected the prognostic value of IPI risk factors (≥3 vs <3) .
PTLD-2 trial tested modified risk-stratification depending oh those 3 risk factors.
As it was supposed that Rituximab monotherapy can be more efficient than CHOP therapy in low risk cases .
It was thought that in thoracic SOT , patients who received rituximab induction and suffered worse progression can get profit from intensifing immunochemotherapy.
Methodology
This is a prospective, multicentre study conducted on adult SOT recipients with CD20-positive PTLD at 15 centres in Germany within nearly 5 years ,including cases with insufficient response to RI and excluding cases with CNS affection and cases with diseases preventing using the studied therapy.
Treatment plan was Rituximab course followed by interim staging and evaluation of response.
Low-risk group was the cases with CR and those with PR having IPI <3 and they had 4 three-weekly courses of rituximab.
High-risk group took 4 cycles of R-CHOP-21.
Very-high-risk group are those who deteriorated under rituximab and they received 6 cycles of alternating R-CHOP and modified R-DHAOx in 3-week intervals.
Also if deterioration occurred ,restaging and suitable upgraded therapy was introduced without delay.
Pneumocystis jirovecii chemoprophylaxis and GCSF was given.
Median follow up was 2.8 years .
Results
26/58 patients responded to rituximab monotherapy induction and 5/58 had a CR and 16 had PR
21 cases were considered low risk and 28 as high risk.
The final overall response rate was 94%.
22/59 cases had grade ¾ leukopenia while grade 3/4 infections were noted in 25/59 mostly pneumonia, febrile neutropenia , sepsis and varicella zoster reactivation , other grade 3/4 adverse events included anaemia, thrombocytopenia, ARF and gastrointestinal haemorrhage and reactions related to Rituximab.
Treatment related mortality occurred in 4/59 cases.
Overall response rate to rituximab monotherapy at interim staging was 100% in the low-risk group, 18% in the high-risk and 0% in the very-high-risk group.
The 3 risk groups had highly significant difference in Overall Survival (OS) and Progression free survival but not time to progression (TTP) or DR.
IPI ≥ 3 was an independent prognostic factor for TTP and OS ,also independent prognostic factor for OS was Thoracic organ SOT.
Discussion
ORR, TTP, OS and PFS was the same as the preceding PTLD-1 ST and RSST trials.
OS and PFS varied significantly in the 3 risk groups, DR was similar.
Rituximab monotherapy consolidation in low risk group including those with <3 IPI risk factors in PR after rituximab induction is an acceptable substitute to CHOP consolidation.
End of treatment PET detected cases with low relapse risk and is informative in PTLD, specially in cases with partial remission by CT imaging.
5/58 patients were high-risk cases according to PR at interim staging and an IPI ≥ 3 at diagnosis.
Applying Rituximab monotherapy consolidation to other groups of patients of higher risk factor other than low risk is not applicable.
Progression of disease under rituximab induction and thoracic organ transplant cases were categorised as very high risk.
Intensifying chemotherapy does not overcome the poor prognosis .
EBV-specific cytotoxic T-cells use are less toxic in EBV-associated PTLD
ORR, TTP and OS were virtually the same apart from EBV status.
TRM was 7% in patients treated with immunochemotherapy with an overall rate of 7%, the same as in old immunocompetent patients treated with R-CHOP immunochemotherapy for DLBCL.
IV or SC Rituximab did not show any significant difference regarding ORR.
The limitations were small sample size thereby overrepresentation of lung transplant cases which had poor outcome.
High-grade B-cell lymphoma PTLD(5/6 patients) had long term remission.
Another prospective trial was assessing brutinib and brentuximab vedotin in the treatment of PTLD.
-Level of evidence is I
Thank you.
Introduction:
Method:
Result & discussion:
Limitation of the study:
Level of evidence is 1
Thank you.
PTLD is a serious complication of SOT
Treatment options in patients with CD20+ PTLD not responding to reduction of immunosuppression according to previous trials includes:
The current study (PTLD-2 modified risk stratified sequential treatment) is a phase II multicenter prospective trial, including 60 patients divided as follow
The response was assessed using PET scan which provide better assessment for response and remission
Results
Conclusion
The level of evidence provided by this article :
Thank you.
INTRODUCTION:
Immunosuppression following solid organ transplantation causes post-transplant lymphoproliferative diseases (PTLD) (SOT). Epidemiology, etiology, categorization, presentation, and therapy have been extensively explored.
The German PTLD research group and European PTLD Network phase II trials produced an evidence-based treatment plan for CD20-positive B-cell PTLD in adults.
They had better median overall survival (OS) and reduced treatment-related mortality (TRM) than previous, smaller rituximab monotherapy studies.
Methodology:
This prospective, multicenter, open-label phase II study included treatment-naïve adult SOT patients with CD20-positive PTLD at 15 German centers from February 3rd, 2015, through July 13th, 2020.
DISCUSSION:
Because of the rarity and heterogeneity of the disease, evidence for PTLD therapy comes from phase II clinical trials. In the PTLD-1 study, patients who did not respond to immunosuppression reduction were given four rounds of weekly rituximab followed by four cycles of CHOP-21. It did better than previous studies of rituximab alone, with a median OS of 6.6 years and a plateau in PFS. PTLD-1 RSST examined a response-adapted treatment plan based on the rituximab monotherapy induction response. Chemotherapy was kept to a minimum, and long-term results were preserved.
It’s PTLD’s first-line therapy.
Results:
The prospective, multicenter Phase II PTLD-2 study looked at how sequential therapy and risk stratification from the PTLD-1 studies could be used to modify risk stratification in adult SOT patients with CD20-positive PTLD. Patients in full and partial remission with IPI 3 at diagnosis (low-risk) maintained rituximab treatment without chemotherapy after induction. The majority (high-risk) got R-CHOP-21. R-CHOP-21 and modified R-DHAOx were given to thoracic SOT progressors. Low-risk, event-free survival (EFS) was the main outcome.
Of the 60 patients, 21 were low-risk, 28 were high-risk, and 9 were very-high-risk. 45/48 (94%) respondents Similar to the PTLD-1 trials, Kaplan–Meier predicted that the disease would progress 78% of the time and that the overall survival rate would be 68%. 4 of 59 (7%) died after treatment. In the low-risk group, 2-year EFS was 66% (95% CI 45–86) against 52% in the historical comparison that underwent CHOP (p = 0.432). 100% low-risk 2-year OS
Limitation:
Non-randomisation
This experiment was modest and lacked international recruiting owing to financing restrictions. Lung transplant patients (15/60, 25%) and Burkitt-like lymphoma with an 11q abnormality and high-grade B-cell lymphoma PTLD (6/60, 10%) were overrepresented.
the level of evidence:
open-label multicenter control trial,Level 1C
Thank you. Well done. You mentioned PTLD 1 trial, can give us a brief description of this study?
Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial
EBV-associated post-transplantation lymphoproliferative disease (PTLD) affects 1–10% of transplant patients. We started a phase 2 experiment to see if adding rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) could help PTLD patients do better than with rituximab alone and stop the bad side effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy.
-Result:
70 of the 74 patients who registered between December 12, 2002, and May 5, 2008, were eligible for therapy. Late-type, monomorphic, and EBV-associated PTLD was found in 53 of 70 individuals. Four patients were denied CHOP. 53 of 59 patients had a full or partial response, with 40 complete responses. At the data cutoff (June 1, 2011), 53 patients had responded to therapy; however, the median response length was not yet attained.
-conclusion:
The results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD.
Introduction:
Methodology:
Results:
Conclusion:
This is RCT, multicenter open label, level of evidence is I
Thank you. Well done. You mentioned PTLD 1 trial, can give us a brief description of this study?
Welcome prof;
-PTLD-1 trial:
Summary
PTLD -1 sequential treatment trial –
n = 70
Protocol –
4 cycles of weekly Rituximab f/ b 4 cycles of CHOP-21 chemotherapy ( cyclophosphamide , doxorubicin, Vincristine, Prednisone every 21 days ).
Prognostic factor – Response to Rituximab induction.
Subsequent trial –
Proved that in patients with CR with Rituximab induction, Rituximab monotherapy is sufficient.
In patients without CR after Rituximab induction – R- CHOP-21 to be used.
PTLD-2 trial –
Expanded low risk group –
Who achieved CR with Rituximab induction
Who acheived PR with Rituximab induction
<3 IPI risk factors at diagnosis
Rituximab monotherapy Consolidation is sufficient.
Identified prognostic factors –
CR with Rituximab induction
Thoracic SOT
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International Prognostic index risk factors ( < 3 to > 3 )
Hypothesis of the study –
In patients with –
Thoracic SOT
Disease progression with Rituximab induction
6 cycles of alternating R – CHOP and modified R – DHAOx every 3 weeks may lead to benefit in this very high risk group.
In the R-DHAOx regimen due to high risk of infectious complications – cytarabine dose reduced by 50% and dexamethasone was reduced to one dose instead of four.
Rituximab was given 1400 mg SC.
Study –
prospective,multicentre, open – label phase II trial
Inclusion criteria –
All treatment naive adult sot recipients with CD 20 positive P TLD.
insufficient response to upfront immunosuppression reduction.
measurable disease > 2 cm in diameter and / Or bone marrow involvement
ECOG performance status <2
Exclusion criteria –
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CNS involvement
Pregnancy
Nursing
H IV infection
Other severe active infection
Treatment plan –
Rituximab 1400 mg SC Or 375 mg / m2 iv on days 1,8,15,22
interim Staging day 40-50
Patients in CR
Patients in PR with < 3 I P l risk factors
Four 3 weekly doses of Rituximab
High risk group received he cycles of R- CHOP-21.
Those who progressed under Rituximab ( very high riskgroup )
6 cycles of alternating R- CHOP and modified R – DHAO x in 3weeks interval.
Final response assessment One month after last cycle.
Follow up was done every 3months till 2years and annually thereafter.
PCP prophylaxis and G- C SF was given to all.
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Discussion –
Modified risk stratified sequential treatment of CD -20 positive PTLD in adults after SOT had similar ORR, TTP ,OS and PFS compared to preceeding PTLD-1 and RSST trials.
36 % patients only needed Rituximab monotherapy Consolidation and thus R- CHOP was avoided in the low risk group.
Rituximab Consolidation does not result in lower toxicity and similar efficacy.
PTLD – 2 trial used CT imaging, this trial used PET Scan at end of treatment.
Intensified chemotherapy does not improve the poor prognosis in very high riskgroup.
No significant difference in ORR between Rituximab SC and iv.
Limitations –
Small size
Lack of international Recruitment.
Small trial of Ibrutinib and Brentuximab did not show any added benefit.
level of evidence – 1
Thank you.
Thank you.
What is the level of evidence provided by this article Ben?