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 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-naÃ¯ve 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 â‰¤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/m2 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/m2 IV on day 1, cyclophosphamide 750 mg/m2 IV on day 1, doxorubicin 50 mg/m2 IV on day 1, vincristine 1.4 mg/m2 IV on day 1, and prednisone 50 mg/m2 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 treatment-related 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. â‰¥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.
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]