RITUXIMAB MAINTENANCE VERSUS OBSERVATION AFTER IMMUNOCHEMOTHERAPY (R-CHOP, R-MCP, R-FCM) IN PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA: A RANDOMISED TRIAL OF GLSG AND OSHO

Introduction: Despite frequent long lasting remissions to first-line treatment, follicular lymphoma of advanced stages is characterized by recurrent relapses. In the randomized PRIMA trial of the GELA, rituximab maintenance achieved prolonged progression-free survival (PFS) compared with observation in remission after first-line immunochemotherapy (Salles et al., Lancet 2011). The German study groups GLSG and OSHO initiated in 2007 a double randomized trial to investigate the efficacy and safety of rituximab maintenance versus observation in remission after randomly assigned induction treatment. Methods: Previously untreated patients with Ann Arbor stage II-IV follicular lymphoma in need of therapy and not candidates for autologous stem cell transplantation or curative radiotherapy were randomised to receive 6 cycles of R-CHOP, R-MCP, or R-FCM. Patients responding to induction treatment were subsequently randomised to 2 years rituximab maintenance or observation, stratified by type of induction treatment, quality of remission, and FLIPI. The trial was initially planned to detect with 95% power a 15% difference in complete remission rates between any of the three induction groups and a PFS hazard ratio of 0.60 by postremission strategy. Results: Recruitment was stopped in 2011 after the PRIMA results had been published. Median age of the 206 recruited patients was 66 years (range, 24-86), and FLIPI was low in 13%, intermediate in 28%, and high in 60%. A trend towards higher complete remission rates with R-FCM (43% of 58 patients) compared to R-CHOP (23% of 66) and R-MCP (24% of 66) was observed, but the differences were not statistically significant. High and comparable overall response rates were observed after R-CHOP (88%), R-MCP (89%), and R-FCM (91%). In terms of grade 3-4 leukocytopenia and grade 3-4 thrombocytopenia, R-FCM (92%, 17%) was more toxic than R-MCP (88%, 6%) which was more toxic than R-CHOP (63%, 3%); R-CHOP showed more frequent neurological toxicities (40%) compared with R-MCP (14%) and R-FCM (16%). Rituximab maintenance substantially prolonged progression-free survival in comparison to observation in remission (hazard ratio 0.39, p = 0.0064). In the rituximab maintenance group, 3-years PFS was 89% (8 PFS events among 65 patients) compared with 69% in the observation group (19 events among 63 patients). With 11 events, no differences in overall survival could be observed for maintenance vs. observation (hazard ratio 1.04, 95% CI 0.32-3.43, p = 0.95). Rituximab maintenance was more toxic with regards to leukocytes and the gastro-intestinal tract. Conclusions: In this randomized trial, 2 years rituximab maintenance was associated with substantially prolonged PFS in comparison to observation after response to first-line immunochemotherapy in follicular lymphoma. Our data represent an independent confirmation of the GELA PRIMA trial results. Keywords: follicular lymphoma (FL); immunochemotherapy; rituximab.