Lenalidomide-rituximab or lenalidomide-rituximab-bendamustine for relapsed/refractory follicular lymphoma: primary and final analysis of the randomized phase II HOVON110/ReBeL study

The R2 (lenalidomide-rituximab) and R2 with bendamustine (R2B) regimens are both feasible in relapsed/refractory follicular lymphoma (R/R FL), but prospective phase II data on R2B are lacking. In this multinational, prospective, randomised, non-comparative trial, patients with R/R FL were randomised 1:1 to R2 (arm A) or R2B (arm B). Patients achieving CT-based partial or complete remission (PR/CR) received rituximab maintenance every 3 months for 2 years. Co-primary endpoints were investigator-assessed CR rates at end-of-induction (EOI) and severe toxicity rates. Between December 2014 and July 2019, 92 patients were randomized. The trial was stopped prematurely due to slow accrual. CR rates at EOI were 11.4% (95% CI [3.8, 24.6%]) for R2 and 15.2% (CI [6.3, 28.9%]) for R2B. With a median follow-up of 74 months, predefined severe toxicities occurred in 3 (6.8%; CI [1.4, 18.7%]) and 6 pts (13.0%, CI [4.9, 26.3%]) in Arm A and Arm B respectively, with 2 pneumonia-related deaths in arm A and no treatment-related deaths in arm B; 43% and 66% experienced any grade 3-4 AE (2%/7% grade 4). At 60 months, in arms A and B event free survival (EFS) was 39.5% (CI [25.1, 53.6%]) and 56.4% (CI [40.1, 69.3%]). Overall survival (OS) was excellent at 72.1% and 86.3%, respectively. R2 and R2B are both effective treatment regimens for R/R FL. While CT-based CR rates were low, treatment with R2B resulted in numerically longer median EFS and OS, but this was associated with higher toxicity.