Mature Data Confirm Benefit of Early Rituximab vs Watchful Waiting in Asymptomatic Follicular Lymphoma

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Long-term follow-up from a phase 3 trial (NCT00112931) has reaffirmed that early rituximab (Rituxan) monotherapy significantly delays the need for new treatment in patients with advanced-stage, asymptomatic, low tumor burden follicular lymphoma. After 15 years, the data reveal stark differences in outcomes between treatment strategies.

In patients treated in the rituximab maintenance group, 65% (95% CI, 56%–72%) had not started new treatment compared with 48% (95% CI, 36%–60%) in the rituximab induction group, and 34% (95% CI, 27%–42%) in the watchful waiting group. Similarly, median time to initiation of new treatment (TTNT) was not yet reached (95% CI,15.6–not estimable) in the rituximab maintenance group, 14.8 years (95% CI, 7·5–not reached) in the rituximab induction group, and 5.6 years (95% CI, 3.8–8.4) in the watchful waiting cohort.

A total of 455 adult patients were randomly assigned 1:1:1 to undergo rituximab induction (375 mg/m², intravenous) weekly for 4 doses (rituximab induction group; n = 82), rituximab induction followed by rituximab maintenance at the same dose every 8 weeks for 12 doses (rituximab maintenance group; n = 190), or watchful waiting (n = 183). The rituximab induction group closed early on September 30, 2007, and the study was amended to a 2-arm trial.

Overall, patients who were treated with rituximab were significantly less likely to start new treatment than those in the watchful waiting group. Specifically, patients in the rituximab induction arm were 45% less likely to start new treatment than those in the watchful waiting group (HR, 0.55; 95% CI, 0.38–0.80; P =.0019) and 64% less likely to start new therapy in the rituximab maintenance group vs watchful waiting (HR, 0.36; 95% CI, 0.26-0.50; P <.0001).

For patients in the watchful waiting group, 48% started a new treatment within 5 years of randomization, while the probability of starting a new treatment during follow-up reduced to 24% and 13% for patients observed for 5 years or longer and 10 years or longer, respectively.

Adult patients with asymptomatic, stage II to IV, grade 1 to 3a low tumor burden follicular lymphoma and an ECOG performance status 0 to 1 were followed between October 15, 2004, and May 1, 2009. The primary end point was TTNT, defined as the time from randomization until the first day systemic chemotherapy or radiotherapy was given. Secondary end points were time to initiation of second new treatment (TT2NT), overall survival, cause-specific mortality, and response and spontaneous remission rate. Additional exploratory end points were incidence of clinical or histological high-grade transformation, and incidence of second primary malignancy.

At baseline, median age for the induction group was 60 years (range, 33-85) and 59 years for both the maintenance group (range, 26-86) and for the watchful waiting group (range, 27-82). Most patients had grade 1 follicular lymphoma (45%, 48%, and 46% across groups), and females constituted 60%, 48%, and 58% of each cohort. 

When looking at subgroup analysis of baseline characteristics, lead author Michael Northend, MBBS, and colleagues wrote that “sex was the only significant predictive factor (P =.006), with female patients having both longer TTNT with rituximab maintenance and shorter TTNT with watchful waiting when compared with males.”

Safety data revealed infrequent grade 3 or higher adverse events: 5 infections and 4 neutropenia episodes in the maintenance group, alongside 3 allergic reactions (1 in induction, 2 in maintenance). 

Although there was a clear benefit among patients treated with rituximab over watchful waiting, there was no significant improvement for patients who received rituximab maintenance over those who had received rituximab induction alone.

“These data confirm early rituximab monotherapy as a valuable, efficacious, non-toxic treatment option for patients who seek to delay chemotherapy due to fitness or personal preference, providing an evidence base for clinical decision making in this setting,” concluded the investigators.

REFERENCE:

Northend M, Wilson W, Ediriwickrema K, et al. Early rituximab monotherapy versus watchful waiting for advanced stage, asymptomatic, low tumour burden follicular lymphoma: long-term results of a randomised, phase 3 trial. Lancet Haematol. 2025;12(5):e335-e345. doi:10.1016/S2352-3026(25)00034-1