Efficacy of rituximab plus lenalidomide regimens in follicular lymphoma: a meta-analysis of randomized controlled trials

Follicular lymphoma (FL) is an incurable, indolent non-Hodgkin lymphoma with a high relapse rate despite effective chemoimmunotherapy. Lenalidomide, an immunomodulatory agent, in combination with rituximab (R²), has been evaluated as an alternative to chemoimmunotherapy and to other standard regimens in FL. We conducted a systematic review and meta-analysis to assess the efficacy and safety of R² compared with standard regimens in FL. A PRISMA-guided search of PubMed, Embase, and Cochrane Library through May 2025 identified randomized controlled trials (RCTs) comparing R² to rituximab monotherapy, chemoimmunotherapy, or lenalidomide alone. Four RCTs (n = 1315 patients) were included. Primary endpoints were overall response rate (ORR), complete response (CR) and partial response (PR). Secondary outcomes were 2-year progression-free survival (PFS), 3-year overall survival (OS) and adverse events. R² did not differ significantly from comparators in 2-year PFS in the primary analysis (RR = 1.53, 95% CI: 0.51–4.54; P = 0.236; I² = 85.3%); a PFS benefit emerged only on sensitivity analysis excluding the RELEVANCE trial (RR = 2.05, 95% CI: 1.18–3.55; P = 0.038; I² = 0%), which contributed approximately half of the pooled population and was the only trial comparing R² with chemoimmunotherapy. ORR (RR = 1.09), CR (RR = 1.06) and PR (RR = 1.19) were similar across groups, as was 3-year OS (RR = 1.00). Skin reactions (RR = 2.76, P = 0.043) and diarrhea (RR = 1.98, P = 0.004) were more frequent with R², while severe hematologic toxicities were not significantly different. R² provides efficacy broadly comparable to chemoimmunotherapy and to rituximab or lenalidomide monotherapy in FL, with a manageable, predominantly non-hematologic toxicity profile. A progression-free survival advantage was not evident in the primary analysis and emerged only after exclusion of the largest included trial; R² therefore represents a viable chemotherapy-free option rather than a demonstrably superior one. Longer-term randomized data with standardized comparators are needed.