A 3-Arm Randomized Phase II Study of Bendamustine/Rituximab with Bortezomib Induction or Lenalidomide Continuation in Untreated Follicular Lymphoma: ECOG-ACRIN E2408

Purpose: We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01332968). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received 6 cycles, respectively. CR rate with BR vs. BVR induction was 62% vs. 75% (P=0.04). One-year DFS rates with BR-R vs. BR-LR were 85% vs. 67%, respectively (P=0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3-4 AEs for BVR vs. BR were neutropenia and sensory neuropathy (12% vs. <1%); 83% of the latter with intravenous bortezomib. The most common grade 3-4 AEs related to LR vs. rituximab maintenance were neutropenia 66% vs. 21% (P<0.0001) and febrile neutropenia 10% vs. 2% (P=0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P=0.36) with OS rates of 87%, 90%, and 84%, respectively (P=0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction are recommended in untreated FL.