Early rituximab monotherapy versus watchful waiting for advanced stage, asymptomatic, low tumour burden follicular lymphoma: long-term results of a randomised, phase 3 trial.

BACKGROUND Initial results of this study, reported after a median follow-up close to 4 years, demonstrated improved time to initiation of new treatment (TTNT) for patients with advanced stage, asymptomatic, low tumour burden follicular lymphoma who received early rituximab monotherapy when compared with watchful waiting. Given the long natural history of follicular lymphoma, the trial was extended to further assess TTNT with longer follow-up. Mature data are presented here. METHODS In this open-label, randomised, phase 3 trial, conducted at 118 centres in five countries, adult patients with asymptomatic, stage II-IV, grade 1-3a low tumour burden follicular lymphoma and Eastern Cooperative Oncology Group performance status 0-1 were randomly assigned (1:1:1) between watchful waiting, rituximab induction (375 mg/m2, intravenous) weekly for four doses (rituximab induction group) and rituximab induction followed by rituximab maintenance at the same dose every 8 weeks for 12 doses (rituximab maintenance group). The rituximab induction group closed early on Sept 30, 2007, and the study was amended to a two-arm trial. The primary endpoint was TTNT, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT00112931, and recruitment and follow-up are complete. FINDINGS Between Oct 15, 2004, and May 1, 2009, 455 patients were randomly assigned, including 183 to watchful waiting, 82 to rituximab induction, and 190 to rituximab maintenance. Median follow-up was 14·7 years (IQR 13·3-15·6). At 15 years, 65% (95% CI 56-72) of patients in the rituximab maintenance group, 48% (36-60) in the rituximab induction group, and 34% (27-42) in the watchful waiting group had not started new treatment. Median TTNT was not yet reached (95% CI 15·6-not estimable) in the rituximab maintenance group, 14·8 years (7·5-not reached) in the rituximab induction group, and 5·6 years (3·8-8·4) in the watchful waiting group. TTNT was longer in both the rituximab induction and rituximab maintenance groups compared with the watchful waiting group (rituximab induction vs watchful waiting: hazard ratio [HR] 0·55 [95% CI 0·38-0·80], p=0·0019; rituximab maintenance vs watchful waiting: HR 0·36 [0·26-0·50], p<0·0001). INTERPRETATION These mature data with 15 years of follow-up confirm that early rituximab monotherapy substantially delays the need for new treatment for patients with advanced stage, asymptomatic low tumour burden follicular lymphoma, providing an evidence base for its use in this setting and confirming its value for patients who seek to defer or avoid treatment with chemotherapy. FUNDING Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.