Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R2 regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).
Design. Phase 3, multicenter, international, placebo controlled randomized trial.
Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.
Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.
Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.
Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R2 group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.
Main results. PFS was significantly improved for patients treated with the R2 regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R2 group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R2 group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R2 group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.