Rituximab plus lenalidomide (R²) versus standard therapies in follicular lymphoma: A systematic review and meta-analysis of randomized controlled trials

Abstract Introduction: Follicular lymphoma (FL) is a common indolent non-Hodgkin lymphoma characterized by frequent relapses and the need for effective yet tolerable treatment strategies. Combining rituximab with lenalidomide (R²) has emerged as a promising chemo-free regimen aimed at improving patient outcomes while minimizing toxicity. However, the comparative efficacy and safety of R² versus standard therapies, including rituximab/lenalidomide monotherapies and chemoimmunotherapy (BR/RCHOP), remain to be fully clarified. Methods: A PRISMA-compliant systematic review was conducted using PubMed, Embase, and Cochrane Central through May 2025 to identify randomized controlled trials comparing rituximab plus lenalidomide (R²) to standard treatments in follicular lymphoma. Outcomes included complete response (CR), overall response rate (ORR), partial response (PR), 2-year progression-free survival (PFS), 3-year overall survival (OS), and adverse events. Data were extracted and assessed for risk of bias using ROB 2.0. Pooled analyses were conducted using Review Manager version 5.4.1 with random-effects models; heterogeneity was assessed using I², and publication bias was evaluated via Egger's test. Results: Four randomized controlled trials (n = 1,315) evaluating rituximab plus lenalidomide (R²) versus control in follicular lymphoma were included. Baseline characteristics were well-balanced across arms, with a median age range of 55–64 years, 48–52% male patients, and most presenting with advanced-stage disease (Ann Arbor III/IV: 70–90%) and high tumor burden (FLIPI ≥2: 60–75%). Rituximab plus lenalidomide was associated with a non-significant improvement in 2-year progression-free survival (Risk Ratio [RR] = 1.50; 95% CI: 0.50–4.50; P = 0.254), with substantial heterogeneity (I² = 85.3%), which resolved and reached statistical significance upon exclusion of one outlier study (RR = 2.05; 95% CI: 1.18–3.55; P = 0.038; I² = 0%). Overall survival at 3 years was comparable between treatment arms (RR = 1.00; 95% CI: 0.96–1.05; P = 0.593; I² = 0%). Overall response rates (RR = 1.09; 95% CI: 0.81–1.49; P = 0.697; I² = 65.2%) and complete response rates (RR = 0.78; 95% CI: 0.25–2.47; P = 0.549; I² = 82.2%) were similar between groups, with persistently high heterogeneity in the latter. A non-significant trend favoring the R² regimen was observed for partial responses (RR = 1.20; 95% CI: 0.74–1.94; P = 0.325; I² = 24.9%). Hematologic toxicities were more frequent with R², though not statistically significant, including any-grade neutropenia (RR = 1.56; 95% CI: 0.22–11.09; P = 0.434; I² = 75.8%), grade ≥3 neutropenia (RR = 1.39; 95% CI: 0.12–16.03; P = 0.620; I² = 86.9%), any-grade thrombocytopenia (RR = 1.09; 95% CI: 0.19–6.10; P = 0.855; I² = 13.6%), grade ≥3 thrombocytopenia (RR = 1.71; 95% CI: 0.34–8.59; P = 0.289; I² = 0%), any-grade anemia (RR = 1.20; 95% CI: 0.17–8.41; P = 0.727; I² = 60.1%), and grade ≥3 anemia (RR = 2.96; 95% CI: 0.12–71.57; P = 0.504). Non-hematologic toxicities were more prominent with R², particularly skin reactions (RR = 2.79; 95% CI: 1.08–7.17; P = 0.033; I² = 65.2%) and diarrhea (RR = 1.98; 95% CI: 1.65–2.38; P = 0.004; I² = 0%), both of which reached statistical significance. Other adverse events, including fatigue, nausea/vomiting, and elevated aminotransferases, were similar between groups with no statistically significant differences. Publication bias was suggested for progression-free survival (Egger's test p = 0.04), while reporting appeared balanced for other outcomes Conclusion: This meta-analysis of randomized controlled trials suggests that rituximab plus lenalidomide may improve progression-free survival in follicular lymphoma, particularly after accounting for heterogeneity, while demonstrating comparable overall survival and response rates to standard treatments, validating a chemotherapy-free option. These findings support R² as an effective treatment option with a distinct safety profile, warranting further investigation and individualized clinical consideration.