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

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.

Fukuhara:Takeda: Honoraria, Research Funding; Eisai: Honoraria; Gilead: Honoraria; Eli Lilly: Honoraria; Kyowa Kirin: Honoraria, Research Funding; LOXO Oncology: Research Funding; Genmab: Honoraria, Research Funding; Chordia Therapeutics: Research Funding; Chugai Pharma: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; AstraZeneca: Honoraria; Incyte and Takeda: Research Funding; Janssen: Honoraria; Meiji Seika: Honoraria; Nippon kayaku: Honoraria; Novartis: Honoraria; Ono: Honoraria; Soreisia: Honoraria. Maruyama:Zenyaku: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria; Takeda: Honoraria, Research Funding; Taiho: Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Symbio: Honoraria, Research Funding; Otsuka: Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; MSD: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; BMS: Consultancy, Honoraria, Research Funding. Ishizawa:Chugai: Honoraria; Ono: Honoraria; KyowaKirin: Honoraria. Makita:Abbvie: Honoraria; Celgene/BMS: Honoraria; Chugai: Honoraria; Genmab: Honoraria; Gilead: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Munakata:CHUGAI PHARMACEUTICAL, Janssen Pharmaceutical, ONO PHARMACEUTICAL, Kyowa Kirin, Genmab, NIPPON SHINYAKU: Research Funding; Mundipharma, Takeda Pharmaceutical, ONO PHARMACEUTICAL, Eisai, CHUGAI PHARMACEUTICAL, Bristol-Myers Squibb, AstraZeneca, NIPPON SHINYAKU, Gilead Sciences, Nippon Kayaku, MSD, Janssen Pharmaceutical, AbbVie GK, Amgen: Honoraria. Ichikawa:BeiGene: Research Funding. Miyazaki:Sumitomo Pharma: Research Funding; AstraZeneca: Honoraria; Janssen: Honoraria; Ono Pharmaceuticals: Honoraria; SymBio Pharmaceuticals: Honoraria; Zenyaku Kogyo: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Novartis: Honoraria; Asahi Kasei: Honoraria; Chugai: Honoraria, Research Funding; Otsuka: Research Funding; Takeda: Research Funding; Abbvie: Honoraria; Incyte: Honoraria; Meiji Seika: Honoraria; Genmab: Honoraria; Bristol Myers Squibb: Honoraria. Takahashi:Chugai: Honoraria, Research Funding; Astellas Pharma: Research Funding; Dainihon Sumitomo: Research Funding; Eisai: Honoraria, Research Funding; SymBio Pharmaceuticals: Honoraria; Takeda: Honoraria; Mundi Pharma: Honoraria; Meiji Seika Pharma: Honoraria; Bristol Myers: Honoraria. Saito:Meiji Seika Pharma: Research Funding; IQVIA: Research Funding; Abbvie: Research Funding; Astra Zeneca: Research Funding; Nippon-shinyaku: Research Funding; Janssen Pharmaceutical KK: Research Funding. Shimada:Genmab: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; Ono: Honoraria; Meiji Seika Pharma: Honoraria; Nippon Shinyaku: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Eisai: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Ohara: Consultancy; Eli Lilly: Consultancy; Jannsen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Chigai: Consultancy, Honoraria; BeiGene: Consultancy; Mundi Pharma: Honoraria; Sanofi: Honoraria. Kuroda:Bristol Myers Squibb, Pfizer, Janssen Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin, Chugai Pharmaceutical, Japan Blood Product Organization, Sumitomo Pharmaceutical, Otsuka Pharmaceutical, Asahikasei, Taiho Pharmaceutical, Mochida Pharmaceutical: Research Funding; Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, Bristol Myers Squibb, Novartis, AbbVie, Pfizer, Astellas Pharmaceutical, Nippon Shinyaku, Genmab, Pharma Essentia Japan: Honoraria; Janssen Pharmaceutical, AbbVie, Pfizer, BeiGene, Bristol Myers Squibb: Consultancy. Mishima:Bristol Myers Squibb: Research Funding; Eisai: Research Funding. Takayama:Janssen Pharmaceutical K.K.: Honoraria; AvvVie GK: Honoraria; Nippon Shinyaku Co., Ltd: Honoraria; Pfizer: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,Ltd: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding. Suzuki:Nippon Shinyaku: Honoraria; Meiji Seika: Honoraria; Sanofi: Honoraria. Uchida:Takeda: Honoraria; Kyowa Kirin: Honoraria; Nippon Kayaku: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Kissei: Honoraria; Asahi Kasei: Honoraria; Chugai: Honoraria; Eisai: Honoraria; Meiji Seika: Honoraria; Nippon Shinyaku: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Nakamura:Meiji Seika Pharma Co., Ltd.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Nippon Kayaku Co., Ltd.: Honoraria; Sumitomo Pharma Co., Ltd.: Honoraria; MSD: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Abbvie: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; AstraZeneca K.K.: Honoraria. Tabayashi:Janssen Pharmaceutical K.K.: Honoraria; Asahi Kasei Pharma Corporation: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sanofi K.K.: Honoraria. Minami:Takeda: Consultancy; Pfizer: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Speakers Bureau; ONO: Research Funding; CMIC: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau. Dobashi:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc: Research Funding; AbbVie GK.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AstraZeneca K.K.: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; Novartis Pharma K.K.: Speakers Bureau; Amgen K.K.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd: Research Funding. Tsukasaki:Ono Pharma: Consultancy; Daiich-Sankyo: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; HUYABIO: Consultancy, Research Funding; Solasia Pharma: Consultancy; Yakult: Consultancy; Kyowa-hakko/Kirin: Research Funding; Yakult: Consultancy; Bristol Myers Squibb: Research Funding; Byer: Research Funding; Regeneron Pharmaceuticals Inc: Research Funding; Chugai Pharma: Honoraria; Eisai: Honoraria; Takeda: Honoraria; Sekisui Medical: Honoraria. Nagai:Abbvie: Honoraria, Research Funding; Astra Zeneca: Honoraria, Research Funding; Beigene: Research Funding; Genmab: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eli Lilly: Honoraria, Research Funding; Kyowa Kirin: Research Funding; MSD: Honoraria, Research Funding; Eisai: Honoraria; Chugai: Honoraria, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Mitsubishi Tanabe: Research Funding; Mundi pharma: Honoraria; BMS: Honoraria; GSK: Honoraria; Meiji Seika Pharma: Honoraria; Haihe Biopharma: Research Funding; BeiGene: Honoraria; NIPPON SHINYAKU: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Solasia: Research Funding; Sumitomo Pharma: Honoraria; Takeda: Research Funding; Zenyaku Kogyo: Research Funding.