Results from the phase II PTLD- 1 ( Sequential Treatment of CD20-Positive Post-Transplant Lymphoproliferative Disorder ) trial established sequential treatment with four cycles of weekly rituximab followed by four cycles of chemotherapy with CHOP-21 ( cyclophosphamide , doxorubicin , vincristine , and prednisone every 21 days ) as a standard regimen for patients with post-transplant lymphoproliferative disorders ( PTLDs ). However , in a recent study published in the Journal of Clinical Oncology , researchers questioned whether response to rituximab induction could predict which patients could be successfully treated without additional CHOP therapy .

“ The rarity and the complex medical history of patients with PTLD , in addition to the variety of histologic manifestations of disease , have slowed the development of evidence-based therapies , [ but ] we observed that response to four cycles of rituximab induction was a prognostic

— RALF U . TRAPPE , MD

factor for overall survival ( OS ) after completion of sequential treatment ,” Ralf U . Trappe , MD , from the Department of Internal Medicine II : Hematology and Oncology at DIAKO Hospital Bremen in Germany , and authors explained . “ On this basis , we hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response ( CR ) after rituximab induction .”

The researchers tested the feasibility , safety , and efficacy of this risk-stratified sequential treatment in an international , prospective , multicenter , open-label study performed at 32 centers in Germany , Belgium , France , Australia , Poland , and Italy . Treatment-naïve adult patients who had undergone solid organ transplant and were diagnosed with CD20 + PTLD were enrolled between October 24 , 2006 , and October 3 , 2014 .

Patients were included if they had not responded to upfront immunosuppression ( with or without antiviral therapy ), had measurable disease (> 2 cm in diameter and / or bone marrow involvement ), and had an Eastern Cooperative Oncology Group performance status of ≤2 . Patients were excluded if they had central nervous system involvement , a history of HIV infection , or the presence of severe organ dysfunction not related to PTLD .

A total of 152 patients were enrolled ( median age = 56.4 years ; age range = 18-82 years ). The median time from transplantation to PTLD was nine years ( range = 0.2- 27.9 years ), and patients received the following transplants :

• kidney ( n = 69 ; 45 %)

• liver ( n = 40 ; 26 %)

• lung ( n = 18 ; 12 %)

• heart ( n = 15 ; 10 %)

• heart and kidney ( n = 5 ; 3 %)

• kidney and pancreas ( n = 3 ; 2 %)

• heart and lung ( n = 2 ; 1 %)

All patients received four weekly doses of rituximab induction ( 375 mg / m 2 administered intravenously [ IV ] on days 1 , 8 , 15 , and 22 ), followed by interim staging by computed tomography scan ( days 40-50 ). On day 50 , based on interim staging , patients either :

• continued with 4 courses of rituximab monotherapy every 21 days ( low-risk group – in CR )

• received 4 cycles of rituximab plus CHOP-21 ( R-CHOP-21 ; rituximab 375 mg / m 2 IV on day 1 , cyclophosphamide 750 mg / m 2 IV on day 1 , doxorubicin 50 mg / m 2 IV on day 1 , vincristine 1.4 mg / m 2 IV on day 1 , and prednisone 50 mg / m 2 orally on days 1-5 every 21 days ; high-risk group – not in CR )

At data cutoff ( July 2015 ), after a median follow-up of 4.5 years ( range = 1-120 months ), 148 patients were evaluable for response to rituximab induction . Thirty-seven patients ( 25 %) achieved CR at interim staging , and 34 went on to receive rituximab monotherapy consolidation ( low-risk group ). Of the 111 patients not in CR after rituximab induction , 100 went on to receive R-CHOP-21 ( high-risk group ). Eight patients in that group were lost to follow-up , died , or discontinued treatment , leaving 92 patients were evaluable for response .

The overall response rate ( ORR ) of the risk-stratified sequential treatment protocol was 88 percent ( n = 111 / 126 ; 95 % CI 81-93 ), including a CR rate of 70

percent ( n = 88 / 126 ; 95 % CI 61-77 ). The median response duration and median time to progression for the entire study population were not reached by the data cutoff , but the three-year estimates were 82 percent ( 95 % CI 74-90 ) and 75 percent ( 95 % CI 67-82 ), respectively . Median OS was 6.6 years ( 95 % CI 62-77 ), with a three-year estimate of 70 percent ( 95 % CI 62-77 ).

“ Despite the limiting of chemotherapy to the high-risk group , the ORR and median OS of [ the risk-stratified sequential treatment approach ] closely match the results of sequential treatment [ in the earlier PTLD-1 trial ] where all patients received CHOP chemotherapy ,” Dr . Trappe and authors noted .

The most common treatmentrelated toxicities included grade 3 / 4 leukopenia ( n = 57 / 91 ; 63 %; 95 % CI 52-72 ) and grade 3 / 4 infection ( n = 52 / 151 ; 34 %; 95 % CI 27-42 ) – the most common of which was febrile neutropenia ( n = 24 ). Twelve patients died ( 8 %), and the deaths were deemed treatment-related .

As the investigators hypothesized , response to rituximab induction was a significant predictor of time to progression and OS ( n = 148 ; p < 0.001 ), despite stratification to the low- or high-risk treatment group . Also , baseline International Prognostic Index (< 3 vs . ≥3 ) was a significant prognostic factor of OS ( p = 0.001 ). “ A CR with rituximab induction identifies a group of patients with B-cell PTLD who do not need chemotherapy ,” they wrote .

The authors noted that these findings are limited by the study ’ s non-randomized design , with the lack of a comparator group and a protracted enrollment period of eight years .

REFERENCE

Trappe RU , Dierickx D , Zimmermann H , et al . Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international , prospective , multicenter phase II trial . J Clin Oncol . 2016 December 19 . [ Epub ahead of print ]