IMPACT OF RITUXIMAB EARLY ADMINISTRATION ON OUTCOMES IN ADVANCED STAGE LOW TUMOR BURDEN FOLLICULAR LYMPHOMA: SUBGROUP ANALYSIS OF PHASE III JCOG1411/FLORA STUDY

Introduction: We conducted a randomized phase III study to confirm the superiority of rituximab early administration over watchful waiting (WW) in untreated advanced stage low tumor burden (LTB) follicular lymphoma (FL) (JCOG1411/FLORA study, UMIN000025187). The primary analysis demonstrated that rituximab early administration significantly improved event-free survival (EFS) as a primary endpoint vs. WW (Fukuhara et al. ASH, 2024). Here, we present subgroup analysis results.

Methods: In this study, LTB-FL by Groupe d’Etude des Lymphomes Folliculaires criteria were divided into two groups; very LTB (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 (pts) aged 20–80 years with previously untreated and advanced stage very LTB-FL (grade 1–3A) were randomized to the WW arm or the rituximab arm (days 1, 8, 15, and 22). Rituximab was administered repeatedly in both arms when the tumor burden reached intermediate.

Results: A total of 292 pts were randomized to the WW arm (148 pts) and the rituximab arm (144 pts). Baseline characteristics were well balanced in terms of age, sex, stage, histologic grade, FLIPI/FLIPI2 risk between the two arms. With a median follow-up of 2.5 years (range: 0-6.9), the EFS was significantly better in the rituximab arm than that in the WW arm (hazard ratio [HR], 0.625; 95% confidence interval [CI], 0.425-0.918; one-sided log-rank p = 0.0078 < 0.0123, alpha adjusted for multiplicity). In the pre-planned subgroup analyses, male (HR, 0.531; 95% CI: 0.302–0.935), histologic grade of 3A (HR, 0.437; 95% CI: 0.224–0.852), intermediate/high risk of FLIPI (HR, 0.665; 95% CI: 0.456–0.970) and FLIPI2 (HR, 0.655; 95% CI: 0.444–0.965) had lower HR of EFS in the rituximab arm (Figure 1), and similar trend was observed in cytotoxic therapy-free survival. In a post-hoc analysis, the subgroup of the interval from diagnosis to enrollment > 91 days favored of EFS in the rituximab arm (HR, 0.490; 95% CI: 0.264–0.909). On the other hand, no subgroups with clear benefit in terms of progression-free and overall survivals were identified. Median rituximab doses were 0 (range, 0–12) in the WW arm and 4 (range, 0–16) in the rituximab arm, respectively. There was a slight imbalance in histologic transformation (HT) events (19 pts in the WW arm vs. 12 pts in the rituximab arm) and lymphoma deaths were occurred only in the WW arm, with 4 out of the 5 deaths having HT.

Conclusions: Rituximab early administration has been confirmed to delay disease progression to high tumor burden and initiation of cytotoxic chemotherapy in patients with untreated advanced stage LTB-FL, including those with specific subgroups, without a significant increase in the number of rituximab administrations.

Research funding declaration: The study was supported in part by National Cancer Center Research and Development Fund (26-A-4, 29-A-3, 2020-J-3, 2023-J-03) and by Japan Agency for Medical Research and Development (AMED) under Grant Number JP17ck0106349, JP18ck0106349, JP19ck0106349, JP21ck0106670, JP22ck0106670, JP23ck0106670, JP24ck0106929.

Keywords: immunotherapy; other therapeutics and clinical trials in lymphoma; indolent non-Hodgkin lymphoma

Potential sources of conflict of interest:

D. Maruyama

Employment or leadership position: None

Consultant or advisory role: Janssen, AstraZeneca, Chugai, Roche, AbbVie, Genmab, Sanofi, BMS, Pfizer

Stock ownership: None

Honoraria: Ono, Nippon Shinyaku, Janssen, Mundipharma, Eisai, Chugai, Kyowa Kirin, MSD, Zenyaku, Sanofi, Symbio, Takeda, AbbVie, AstraZeneca, BMS, Genmab, Novartis, Pfizer, Roche

Educational grants: None

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N. Fukuhara

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Honoraria: Chugai

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K. Ishizawa

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Honoraria: Ono, AbbVie, Micron

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W. Munakata

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Honoraria: Chugai

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S. Ota

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Honoraria: Novartis, Takeda, AstraZeneca, Abbvie, PharmaEssensia, Bristol Myers Squibb, Janssen, Amgen, Sanofi

Educational grants: None

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M. Ichikawa

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Honoraria: Chugai, Ono, Takeda, Kyowa Kirin, Nippon Shinyaku, Bristol Myers Squibb, Sanofi, Abbvie, PharmaEssentia Japan, Genmab, Asahi Kasei Pharma, AstraZeneca

Educational grants: None

Other remuneration: Contracted research/joint research expenses: Janssen, Otsuka, Abbvie, Alexion, Chugai, Bristol Myers Squibb, Regeneron, Ohara, Nippon Shinyaku, Incyte Biosciences Japan

E. Negoro

Employment or leadership position: None

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Honoraria: Janssen, Nippon Kayaku, AbbVie, Nippon Shinyaku, Chugai, Meiji Seika Pharma, Kissei, Novartis, PharmaEssentia Japan, Sanofi, ONO, Amgen

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I. Yoshida

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Honoraria: Chugai, Kyowa Kirin, Astrazeneca, Eisai, Janssen, Daiichi-Sankyo, Abbvie, Nippon Shinyaku

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K. Ohmachi

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Honoraria: Chugai, Kyowa Kirin, Janssen, Novartis, Genmab, AbbVie, Nippon Shinyaku, CSL Behring, Ishiyaku Academy

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H. Takahashi

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Honoraria: AstraZeneca, Bristol Myers Squibb, Chugai, Eisai, Janssen, Kyowa Kirin, Meiji Seika Pharma, Nippon Shinyaku, Mundipharma, Takeda, SymBio, Ono, Sanofi, Fujimoto

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S. Yoshida

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Other remuneration: Grant: Chugai, Kyowa Kirin

K. Nosaka

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Honoraria: Meiji Seika, Janssen, Chugai, Bristol Myers Squibb, Kyowa Kirin, Abbvie, Daiichi Sankyo, Eisai, Gardant, Minophagen, Genmab

Educational grants: None

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Y. Sekiguchi

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Stock ownership: None

Honoraria: Chugai, AbbVie

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J. Makiyama

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Consultant or advisory role: Daiichi Sankyo, Janssen, Takeda

Stock ownership: None

Honoraria: AbbVie, AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Janssen, Meiji Seika Pharma, Nippon Shinyaku, Ono, Sanofi, SymBio, Takeda

Educational grants: Takeda

Other remuneration: None

K. Ishitsuka

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Consultant or advisory role: Kyowa Kirin

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Honoraria: Chugai, Kyowa Kirin

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K. Tsukasaki

Employment or leadership position: None

Consultant or advisory role: Meiji Seika Pharma, Daiich Sankyo

Stock ownership: None

Honoraria: Eizai, Takeda, Meiji Seika Pharma, Sekisui Medical, Daiich Sankyo, Nippon Sinyaku

Educational grants: None

Other remuneration: Research funding: Kyowa Kirin, Meiji Seika Pharma, Bristol Myers Squibb, Byer, Daiich Sankyo

H. Nagai

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Stock ownership: None

Honoraria: Chugai, Kyowa Kirin

Educational grants: None

Other remuneration: None