Randomized Phase III Study of Watchful Waiting Vs. Rituximab As First-Line Treatment in Patients with Advanced Stage Low Tumor Burden Follicular Lymphoma: JCOG1411/Flora Study

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Background: Watchful waiting (WW) is thought to be a reasonable initial approach for low-tumor-burden follicular lymphoma (LTB-FL), although there is an increased risk of adverse clinical events, including progression to high tumor burden (HTB), resulting in exposure to cytotoxic chemotherapy and histological transformation (HT). Since the previous study (Ardeshna KM et al., Lancet Oncol. 2014), rituximab monotherapy has been as an initial treatment option for LTB-FL. In our clinical practice, rituximab is administered to most patients initially observed and with progression of LTB-FL not meeting HTB. However, the optimal timing for initiating rituximab monotherapy remains unclear. We hypothesized that early rituximab administration, without initial observation, would benefit patients with LTB-FL. Therefore, we conducted a randomized phase III study to confirm the superiority of early rituximab administration over WW in patients with untreated advanced-stage LTB-FL (JCOG1411/FLORA study, UMIN000025187). Patients and Methods: In this study, LTB-FL by Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria were divided into two groups; very low tumor burden (the largest mass <5 cm, two or less nodal sites [each ≥3 cm], no effusion), and intermediate tumor burden (one or more of the followings: the largest mass 5 cm or more but less than 7 cm, three nodal sites [each ≥3 cm], no serious effusion) which is defined as to be compatible with criteria for rituximab administration. Patients aged 20-80 years with previously untreated and advanced-stage, very low tumor burden FL (grade 1-3A) were randomized to the WW arm or rituximab-induction arm (immediately initiating rituximab monotherapy [375 mg/m2, days 1, 8, 15, and 22]). Rituximab monotherapy was administered to both arms when the tumor burden was intermediate repeatedly. The primary endpoint was event-free survival (EFS), defined as follows: HTB based on the GELF criteria, initiation of cytotoxic chemotherapy and/or radiotherapy, HT, or death. Assuming a 3-year EFS of 50% in the WW arm and a 12% increase in the 3-year EFS of the rituximab induction arm, the sample size was set at 145 patients per arm with a one-sided alpha of 5%, power of 80%, an accrual period of 6.5 years, and a follow-up period of 3 years after the completion of accrual. Results: Between December 2016 and March 2023, 292 patients from 54 hospitals in Japan were randomized as follows: 148 and 144 in the WW and rituximab induction arms, respectively. The baseline characteristics were as follows (WW vs. rituximab): median age, 65 vs. 67 years; male, 44.6% vs. 40.3%; Ann Arbor stage III/IV, 55.4/44.6% vs. 52.1/47.9%; and FLIPI low/intermediate/high risk, 13.5/50.7/35.8% vs. 16.0/45.8/38.2%, respectively. In June 2024, the Data and Safety Monitoring Committee of the JCOG recommended the early termination of the study by a pre-planned 2nd interim analysis. With a median follow-up of 2.5 years (range: 0-6.9) among all patients, EFS was significantly better in the rituximab induction arm than in the WW arm (hazard ratio, 0.625; 95% confidence interval, 0.425-0.918; one-sided log-rank P = 0.0078 < 0.0123, alpha adjusted for multiplicity). The detailed EFS events were mainly HTB and exposure to cytotoxic chemotherapy in both arms. An imbalance was observed in the number of HT events (n=18 in the WW arm versus n=9 in the rituximab arm). The 3-year progression-free and overall survival rates were 50.6% and 98.4%, respectively, in the WW arm and 49.6% and 97.3 %, respectively, in the rituximab induction arm. No significant differences were observed in the number of deaths (n=7 in each arm). Conclusion: Rituximab induction has been confirmed to delays disease progression to HTB and the initiation of cytotoxic chemotherapy in patients with untreated advanced-stage very low tumor burden FL. We recommend the early administration of rituximab as an initial treatment approach for such patients.

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