Lenalidomide and rituximab for relapsed/refractory follicular lymphoma: a systematic review and meta-analysis

Lenalidomide (len) and rituximab (R 2 ) is standard second-line therapy for follicular lymphoma (FL), and the backbone and comparator for several new therapies. This systematic review and meta-analysis of R 2 or len-anti-CD20 monoclonal antibodies aims to clarify efficacy across trials, and to evaluate the benefit of triplet therapies including R 2 . Across 24 treatment arms involving 2245 patients, 63% received R 2 or len-anti-CD20 and 37% received it with an additional agent. For R 2 /len-anti-CD20, the overall response rate (ORR) was 75.9% (95% CI 72.1–79.3, p = 0.0092; I 2 = 53.5%), and complete response rates (CR), 39.6% (95% CI 32.4–47.3, p < 0.0001, I 2 = 73.2%). ORRs were similar whether studies included or excluded rituximab-refractory, but CR appeared lower (28.6% vs. 42.9%). The number of prior lines of therapy did not affect response. Adding a third agent to R 2 or len-anti-CD20 resulted in similar ORRs but significantly higher CR and 1- and 2-year progression-free survival appeared longer than that seen with R 2 . However, triplet regimens were associated with increased grade ≥3 toxicity. These findings reinforce the role of R 2 in R/R FL in the modern treatment era. R 2 at first relapse is effective across rituximab sensitivity profiles. Triplet combinations built on the R 2 backbone improve efficacy but require careful patient selection and monitoring due to higher toxicity risks.