Rituximab versus watchful waiting for asymptomatic advanced stage low tumor burden follicular lymphoma: A systematic review and meta-analysis

Abstract

Abstract Introduction The optimal initial management of asymptomatic patients with advanced-stage, low tumor burden follicular lymphoma (LTB-FL) remains a subject of clinical debate. While a watchful waiting (WW) strategy has traditionally been endorsed due to the indolent nature of the disease, rituximab monotherapy has emerged as a potential alternative, aiming to delay disease progression without compromising long-term outcomes. To compare these two approaches, we performed a systematic review and meta-analysis comparing rituximab monotherapy with WW for patients with advanced-stage LTB-FL as the first line of therapy. Methods This systematic review and meta-analysis adhere to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The authors performed two independent comprehensive literature searches in Embase, PubMed, and the Cochrane Central Register of Controlled Trials databases to identify studies from inception to June 2025. Included studies were randomized controlled trials (RCTs) or observational studies comparing rituximab monotherapy administered as induction or maintenance to WW among adult patients with advanced stage LTB-FL. The primary outcome was overall survival (OS), while histological transformation (HT) and time to new treatment (TTNT) were assessed as secondary outcomes. Statistical analyses were conducted using Review Manager (RevMan) version 5.4.1 (Cochrane Collaboration), and heterogeneity among studies using random-effects models was evaluated with the I² statistic, with values < 25% considered low. Results Three studies comprising 1590 patients were included: two phase III RCTs and one observational retrospective study. Median time of follow up ranged from 4.3 years to 16.2 years. Rituximab regimen ranged from 4 weekly doses to 1 dose every eight weeks for a total of 12 doses. Baseline characteristics were as follows (rituximab and WW, respectively): median age 63.1 (ranged from 60-67) and 63.3 years (ranging from 59-65); male sex 48.6% and 49.9%; Ann Arbor stage III 42.0% and 44.4%; Ann Arbor stage IV, 43.5% and 44.7%; Follicular Lymphoma International Prognostic Index (FLIPI) low-risk, 30.2% and 26.9%; FLIPI intermediate-risk, 42.2% and 36.6%; FLIPI high-risk, 23.7% and 20.7%. For OS, pooled data from the three studies (717 patients in the rituximab group and 873 patients in the WW group) demonstrated no statistically significant difference between groups, although there was a trend toward favouring WW (Hazard Ratio 0.89 [95% CI 0.70-1.12]; p = 0.31; I² = 0%). HT, evaluated in two studies with 930 patients (416 in the rituximab group and 514 in the WW group), revealed a nonsignificant trend toward reduced transformation with rituximab monotherapy (Risk Ratio 0.74 [95% CI 0.54-1.01]; p = 0.06; I² = 0%). TTNT, evaluated in two studies with 747 patients (416 in the rituximab group and 331 in the WW group), was statistically significantly prolonged with rituximab monotherapy (Hazard Ratio 0.50 [95% CI 0.41-0.61]; p < 0.00001; I² = 0%). Conclusion Our findings provide evidence supporting that rituximab monotherapy does not improve OS or reduce the risk of HT in asymptomatic, previously untreated patients with advanced-stage LTB-FL compared to the WW approach. However, rituximab intervention showed a statistically significant prolongation of TTNT. Further prospective studies are needed to explore these outcomes.