Fifteen-Year Follow-Up Data Confirm Rituximab Delays the Need for New Treatment in Advanced Follicular Lymphoma

Rituximab in Advanced Follicular Lymphoma

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Early treatment with rituximab (Rituxan) monotherapy significantly delayed the need for a new treatment compared with watchful waiting in patients with advanced stage, asymptomatic, low tumor burden follicular lymphoma, according to long-term data from a phase 3 study (NCT00112931) published in The Lancet Hematology.

At a median follow-up of 14.7 years (IQR, 13.3-15.6), patients who received rituximab induction and maintenance therapy (n = 190) and those who received induction therapy with rituximab only (n = 82) had not started a new treatment at rates of 65% (95% CI 56%-72%) and 48% (95% CI, 36%-60%). Comparatively, patients who received watchful waiting (n = 183) had not started a new treatment at a rate of 34% (95% CI, 27%-42%). The median times to next treatment (TTNT) in the rituximab induction and maintenance, rituximab induction only, and watchful waiting arms were not reached (NR; 95% CI 15.6-not estimable), 14.8 years (95% CI, 7.5-NR), and 5.6 years (95% CI, 3.8-8.4), respectively.

“These mature data with [approximately] 15 years of follow-up confirm that early rituximab monotherapy substantially delays the need for new treatment for patients with advanced stage, asymptomatic low tumor 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,” the study authors wrote.

Unpacking the Study Design

The open-label study enrolled adult patients with stage II to IV, grade 1 to 3a, low tumor burden follicular lymphoma with no B symptoms or severe pruritus across 118 centers in the United Kingdom, Australia, New Zealand, Turkey, and Poland. Eligible patients were also required to have an ECOG performance status of 0 or 1, measurable disease, normal serum lactate dehydrogenase levels, and no mass larger than 7 cm. Other key inclusion criteria included a maximum of 3 affected sites with lymph nodes larger than 3 cm, no significant serous effusion, no organ compression, as well as adequate bone marrow, kidney, and liver function.

Patients were randomly assigned 1:1:1 to receive rituximab induction therapy, rituximab induction followed by rituximab maintenance, or watchful waiting. In the induction only group, patients received intravenous rituximab at a weekly dose of 375 mg/m2 for 4 doses. In the induction and maintenance group, patients received rituximab induction therapy followed by maintenance therapy with the agent at the same dose every 8 weeks for 12 doses. Enrollment to the induction-only group was closed in September 2007.

The primary end point was TNNT. Secondary end points included time to initiation of second new treatment, overall survival (OS), cause-specific mortality, and response and spontaneous remission rate. Exploratory end points included the incidences of clinical or histological high-grade transformation and of second primary malignancy.

At baseline, the median ages in the watchful waiting, rituximab induction, and rituximab induction and maintenance groups were 59 years (IQR, 49-66), 60 years (IQR, 53-64), and 59 years (IQR, 51-66), respectively. Most patients in each group had an ECOG performance status of 0 (90% vs 93% vs 91%), had normal lactate dehydrogenase concentration (95% vs 96% vs 95%), and β2 microglobulin levels at or below 2.4 mg/L (78% vs 76% vs 74%). Patients had grade 1 (46% vs 45% vs 48%), 2 (44% vs 40% vs 42%), or 3 (10% vs 15% vs 9%) disease.

Further Efficacy Findings and Safety Data

Additional findings revealed that the 15-year OS rates in the rituximab induction and maintenance, rituximab induction only, and watchful waiting arms were 73% (95% CI 65%-79%), 66% (95% CI, 53%-75%), and 68% (95% CI, 59%-75%), respectively. The 15-year cause-specific mortality rates were 12% (95% CI, 8%-18%), 18% (95% CI, 11%-29%), and 14% (95% CI, 9%-20%), respectively. At the data cutoff, patients in the respective arms had not started a second new treatment at rates of 86% (95% CI, 80%-91%), 85% (95% CI, 72%-92%), and 79% (95% CI, 70%-85%).

In terms of safety, grade 3 or worse adverse effects included grade 3 infection in the rituximab induction and maintenance group (n = 5), grade 3 allergies in the induction and maintenance (n = 2) and induction only groups (n = 1), and grade 3 to 4 neutropenia in the induction and maintenance group (n = 4). Second primary malignancies were reported in 16% of patients in the induction and maintenance group, 21% of those in the induction only group, and 23% of those in the watchful waiting group.

“Randomized studies in the pre-rituximab era showed no survival benefit from early cytotoxic treatment in this group, thus establishing initial watchful waiting as a standard of care,” the study authors wrote. “Our study shows that early rituximab monotherapy further delays the need for chemotherapy with little associated toxicity and no detrimental effect on time to second new treatment. These results suggest that some patients will avoid chemotherapy altogether. The optimal approach should be considered on an individual patient basis, taking into account patient preference and fitness for subsequent chemotherapy.”

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