Two recent clinical trials have provided compelling evidence that early rituximab treatment offers significant benefits for patients with advanced-stage, low tumor burden follicular lymphoma, potentially changing treatment paradigms for this patient population.
FLORA Trial Shows Benefits of Early Rituximab Intervention
The phase III JCOG1411/FLORA trial has demonstrated that rituximab induction therapy provides significant benefits for patients with untreated advanced-stage, very low tumor burden follicular lymphoma compared to watchful waiting. The findings, presented at the 2024 American Society of Hematology (ASH) Annual Meeting, suggest a shift in the standard approach to managing these patients.
"We recommend the early administration of rituximab as an initial treatment approach for such patients," said lead investigator Noriko Fukuhara, MD, PhD, of Tohoku University Graduate School of Medicine, Japan.
The multicenter study enrolled 292 patients from 54 centers with low tumor burden follicular lymphoma, as defined by Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Patients were classified into two groups: very low tumor burden (largest mass < 5 cm, two or fewer nodal sites each ≥ 3 cm, and no effusion) and intermediate tumor burden (largest mass ≥ 5 cm but < 7 cm, three nodal sites each ≥ 3 cm, and no serious effusion).
Patients with previously untreated advanced-stage, very low tumor burden disease (grade 1–3A) were randomly assigned to either watchful waiting or immediate rituximab induction (375 mg/m² on days 1, 8, 15, and 22). The primary endpoint was event-free survival, defined as progression to high tumor burden, initiation of cytotoxic chemotherapy and/or radiotherapy, histologic transformation, or death.
With a median follow-up of 2.5 years, the event-free survival was significantly better in the rituximab induction arm than in the watchful waiting arm (hazard ratio [HR] = 0.625; P = .0078). The primary events in both arms were primarily developing high tumor burden and exposure to cytotoxic chemotherapy. Notably, twice as many patients with histologic transformation were found in the control arm.
The 3-year overall survival rates were comparable between the two groups: 97.5% with rituximab and 98.5% with watchful waiting. As expected, adverse events were more common with rituximab, with Grade 3 or 4 lymphocytopenia reported in 11.4% of those given rituximab and 8.9% of those being monitored.
Long-Term Data Confirms Rituximab Benefits
Complementing these findings, mature data from another phase III trial (NCT00112931) with 15 years of follow-up has reaffirmed that early rituximab monotherapy significantly delays the need for new treatment in patients with advanced-stage, asymptomatic, low tumor burden follicular lymphoma.
This study randomized 455 adult patients 1:1:1 to receive rituximab induction (375 mg/m², intravenous) weekly for 4 doses, rituximab induction followed by rituximab maintenance at the same dose every 8 weeks for 12 doses, or watchful waiting. The rituximab induction group closed early, and the study was amended to a 2-arm trial.
After 15 years, 65% of patients in the rituximab maintenance group had not started new treatment, compared with 48% in the rituximab induction group and only 34% in the watchful waiting group. The median time to initiation of new treatment was not yet reached in the rituximab maintenance group, 14.8 years in the rituximab induction group, and 5.6 years in the watchful waiting cohort.
Patients who received 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; P = .0019), and those in the rituximab maintenance group were 64% less likely (HR, 0.36; P < .0001).
Safety data revealed infrequent grade 3 or higher adverse events, including 5 infections and 4 neutropenia episodes in the maintenance group, alongside 3 allergic reactions across both rituximab groups.
Expert Perspectives and Ongoing Debate
Despite these positive findings, some experts express caution about universally adopting early rituximab treatment. Andrew D. Zelenetz, MD, PhD, Medical Director of Quality Informatics at Memorial Sloan Kettering Cancer Center, expressed concerns about the FLORA study's conclusions.
"While the study met its endpoint of event-free survival, there was no statistical difference between the arms for transformation-free, progression-free, or overall survival," Dr. Zelenetz noted. He also questioned the study's definition of failure-free survival, suggesting it may bias toward the initial treatment arm.
Dr. Zelenetz further cautioned about the immunosuppressive effects of rituximab: "We learned from the COVID-19 pandemic that B-cell depletion can be a substantial risk and that avoiding immunosuppressive therapy is still a good idea. Since progression-free and overall survival are not impacted by immediate treatment with rituximab, which is immunosuppressive, I would recommend deferring therapy."
Clinical Implications
These studies provide important evidence for clinical decision-making in the management of advanced-stage, low tumor burden follicular lymphoma. The investigators of the long-term follow-up study concluded: "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."
The findings suggest that while watchful waiting has been the standard approach for these patients, early rituximab intervention may offer significant benefits in delaying disease progression and postponing the need for more aggressive treatments. However, the lack of overall survival benefit and potential immunosuppressive effects must be carefully weighed against these advantages.
As the debate continues, these studies provide clinicians with robust data to inform personalized treatment decisions for patients with advanced-stage, low tumor burden follicular lymphoma, potentially shifting the treatment paradigm toward earlier intervention with rituximab in selected patients.
