Background: CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is usually characterized by activated B-cell type, poor prognosis, and frequent central nervous system (CNS) relapse. A sandwich therapy of dose-adjusted (DA)-EPOCH-R combined with high-dose methotrexate (HD-MTX) (DA-EPOCH-R/HD-MTX) showed excellent efficacy in a phase II study for newly diagnosed stage II-IV CD5+ DLBCL, including 2-year (yr) overall survival (OS), progression-free survival (PFS), and CNS relapse rates of 89%, 79%, and 9%, respectively (Miyazaki K, et al. Haematologica, 2020). It has been introduced in practice in Japan; however, the current status of treatment and the prognosis in patients with CD5+ DLBCL are unclear.

Methods: We retrospectively analyzed the prognosis and CNS relapse rate of consecutive patients with untreated CD5+ DLBCL who were diagnosed at 30 hospitals in Japan from January 2016 to December 2021. Patients who were diagnosed with double-/triple-hit lymphoma, those with CNS involvement at diagnosis, and those who had not received any anthracycline-containing chemotherapy with rituximab (R-chemo) were excluded. We identified risk factors for OS using Cox proportional hazards method. The outcomes in the stage II-IV patients who received DA-EPOCH-R/HD-MTX were compared with those of the phase II study. To evaluate the efficacy of CNS prophylaxis, we divided patients into four groups: HD-MTX alone, intrathecal administration of MTX alone (IT MTX), both HD-MTX and IT MTX (HD/IT MTX), and no CNS prophylaxis.

Results: Among the413 enrolled patients, 20 were excluded due to ineligible diagnosis or insufficient clinical information, 18 had CNS involvement at diagnosis, and 27 did not receive R-chemo. As a result, 348 patients were eligible and showed the following features: median age, 71 yrs (range, 23-92); male sex, 54%; stage II-IV, 90%; stage III or IV, 73%; ECOG performance status (PS) > 1, 30%; > 1 extranodal site, 42%; elevated serum lactate dehydrogenase (sLDH) level, 71%; high-intermediate or high International Prognostic Index (IPI), 63%; high CNS-IPI, 41%; and B symptoms, 29%. According to Hans's criteria, the nongerminal center B-cell type accounted for 67% of the 276 cases examined. Among the 348 patients, 62 (18%) received DA-EPOCH-R/HD-MTX, and 286 (82%) were treated with other R-chemo, such as R-CHOP (n = 254). The median age was 63.5 yrs (range, 29-75) in the DA-EPOCH-R/HD-MTX group and 72 yrs (range, 23-92) in the other R-chemo group. The DA-EPOCH-R/HD-MTX group included significantly more patients aged ≤ 60 yrs ( P < 0.001), although it tended to have more patients with ECOG PS > 1 than the other R-chemo group ( P = 0.069). Patients who received IT MTX made up 16% of the DA-EPOCH-R/HD-MTX group and 31% in the other R-chemo group. HD-MTX was used in 100% of patients in the DA-EPOCH-R/HD-MTX group and 17% of patients in the other R-chemo group. Details of CNS prophylaxis were HD-MTX alone in 84 patients (24%), IT MTX alone in 70 (20%), both HD/IT MTX in 28 (8%), and no CNS prophylaxis in 166 (48%).

At a median follow-up of 43 months, the 2-yr OS, PFS, and CNS relapse rates of patients with stage II-IV disease in the DA-EPOCH-R/HD-MTX group were 87% (95% CI, 73-94%), 78% (95% CI, 63-87%), and 7.3% (95% CI, 2.8-18.2%), respectively. There were no significant differences in OS or PFS between stage I and stage II-IV patients in the DA-EPOCH-R/HD-MTX group. In all 348 patients with stage I-IV, both the OS ( P = 0.044) and PFS ( P = 0.043) in the DA-EPOCH-R/HD-MTX group were longer than those in the other R-chemo group. The 2-yr OS in these groups were 89% and 78%, and their 2-yr PFS were 78% and 64%, respectively. Multivariate analysis identified elevated sLDH ( P = 0.005), > 1 extranodal involvement ( P < 0.001), no IT MTX ( P = 0.005), and no DA-EPOCH-R/HD-MTX ( P = 0.005) as independent risk factors for OS. The 2-yr CNS relapse rate was 6.5% in the DA-EPOCH-R/HD-MTX group (n = 4) and 10.0% in the other R-chemo group. There were no significant differences in the CNS relapse rate between the two groups ( P = 0.54). The 2-yr CNS relapse rates of HD-MTX, IT MTX alone, both HD/IT MTX, and no prophylaxis were 9.8%, 9.1%, 3.7% (n = 1), and 10.3%, respectively.

Conclusions: Our results confirmed favorable survival in the phase II study of DA-EPOCH-R/HD-MTX in clinical settings. DA-EPOCH-R/HD-MTX and IT MTX were associated with longer OS of patients with CD5+ DLBCL in our study cohort, warranting further investigation.

Nato:Chugai pharma: Honoraria; Nippon Shinyaku: Honoraria. Miyazaki:Eisai: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding; Takeda: Research Funding; Chugai Pharma: Honoraria, Research Funding; Asahi Kasei: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; AstraZeneca: Honoraria; Abbvie: Honoraria; Meiji Seika: Honoraria; Ono Pharmaceuticals: Honoraria; Otsuka: Research Funding; Zenyaku Kogyo: Research Funding; SymBio Pharmaceuticals: Honoraria; Janssen: Honoraria; Incyte: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria. Maruyama:Novartis: Research Funding; Abbvie: Honoraria, Research Funding; Astellas: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Otsuka: Research Funding; Chugai Pharma: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Eizai: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Taiho: Research Funding; Amgen Astellas Biopharma: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ono Pharmaceuticals: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; AstraZeneca: Honoraria; Mundipharma: Honoraria, Research Funding; SymBio Pharmaceuticals: Honoraria; Zenyaku: Honoraria. Takahashi:Chugai Pharma: Honoraria; Bristol Meyers Squibb: Honoraria; Nippon Shinyaku: Honoraria; AstraZeneca: Honoraria; Eisai: Honoraria; Meiji Seika: Honoraria; Takeda: Honoraria; Mundipharma: Honoraria; Janssen: Honoraria; Kyowa Kirin: Honoraria; Ono pharmaceuticals: Honoraria; SymBio pharmaceuticals: Honoraria; Sanofi: Honoraria. Sunami:Sanofi, BMS and Janssen: Honoraria, Research Funding; Chugai Pharma: Research Funding; Abbvie, Incyte, GlaxoSmithKline, Novartis, Pfizer, BeiGene, Kyowa Kirin, Ono, Otsuka and Chugai: Research Funding. Negoro:Bristol Myers Squibb: Honoraria; Meiji Seika: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; AstraZeneca: Honoraria; Nihon Kayaku: Honoraria; Ono Pharmaceuticals: Honoraria; Takeda: Honoraria; Chugai Pharma: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Kyowa Kirin: Honoraria; Janssen: Honoraria. Okada:Meiji Seika: Research Funding; Chugai Pharma: Research Funding; Eisai: Research Funding; Shionogi: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Takeda: Research Funding; Sysmex: Research Funding; Taiho: Research Funding. Takayama:Janssen Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria; Celgene: Honoraria; SymBio Pharmaceuticals: Honoraria; Eisai: Honoraria; Asahi Kasei: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Momose:Chugai Pharma: Honoraria; SymBio Pharmaceuticals: Honoraria; Takeda: Honoraria. Yoshida:Takeda: Honoraria. Nishikori:Kyowa Kirin: Honoraria; Eisai: Honoraria; Takeda: Honoraria; Nippon Shinyaku: Honoraria; Janssen: Honoraria; Sumitomo Dainippon Pharma: Honoraria; AstraZeneca: Honoraria; Abbvie: Honoraria; Bristol Myers Squibb: Honoraria; Genmab: Honoraria; Ono Pharmaceuticals: Honoraria; Otsuka: Honoraria; Chugai Pharma: Honoraria; SymBio Pharmaceuticals: Honoraria, Research Funding. Takahashi:Chugai Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Astellas: Research Funding; Sumitomo Dainippon Pharma: Research Funding; SymBio Pharmaceuticals: Honoraria; Takeda: Honoraria; Mundipharma: Honoraria; Meiji Seika: Honoraria; Bristol Myers Squibb: Honoraria. Makiyama:Chugai Pharma: Honoraria; Otsuka: Honoraria; Janssen Pharmaceutical: Honoraria; Ono Pharmaceuticals: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika: Honoraria; Takeda: Honoraria; Daiichi Sankyo: Honoraria; SymBio Pharmaceuticals: Honoraria; Bristol Myers Squibb: Honoraria. Suzuki:Astellas: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; BMS: Honoraria; Chugai Pharma: Honoraria; SymBio Pharmaceuticals: Honoraria. Masaki:Chugai Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Asahi Kasei: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Otsuka: Research Funding; Taisyo Toyama: Research Funding; Taiho: Research Funding; Teijin: Research Funding; Astellas: Research Funding; Takeda: Honoraria, Research Funding; Japan Blood Product Organization: Research Funding; Ono Pharmaceuticals: Honoraria; AstraZeneca: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Nihon Kayaku: Honoraria; Nippon Shinyaku: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Meiji Seika: Honoraria. Fukuhara:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; Nihon kayaku: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Incyte: Research Funding; Loxo Oncology: Research Funding; Ono Pharmaceuticals: Honoraria; Janssen: Honoraria; BMS: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Meiji Seika: Honoraria; SymBio Pharmaceuticals: Honoraria; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; HUYA: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Research Funding; Chordia Therapeutics: Research Funding; Chugai Pharma: Honoraria, Research Funding; Bayer: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Okamoto:Chugai Pharma: Research Funding; Ono Pharmaceuticals: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria; Takeda: Honoraria. Tawara:Novartis: Honoraria; Janssen: Honoraria; CSL Behring: Honoraria; Bristol Myers Squibb: Honoraria; AstraZeneca: Honoraria; Astellas: Honoraria; Alexion Pharma: Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Asahi Kasei: Honoraria, Research Funding; Novo Nordisk Pharma: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; SymBio Pharmaceuticals: Honoraria. Asano:Takeda: Honoraria. Izutsu:Nippon Shinyaku: Consultancy; Astellas Amgen: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Incyte: Research Funding; Novartis: Honoraria, Research Funding; Yakult: Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Beigene: Research Funding; Loxo Oncology: Research Funding; Regeneron: Research Funding; Nihon Kayaku: Honoraria; Zenyaku Kogyo: Consultancy; Mitsubishi Tanabe Pharma: Consultancy; Chugai Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Meiji Seika: Honoraria; Eli Lilly: Honoraria; SymBio Pharmaceuticals: Honoraria; Janssen: Honoraria; Genmab: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Ono Pharmaceuticals: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Otsuka: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Kato:Chugai Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Eisai: Consultancy, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono Pharmaceuticals: Honoraria, Research Funding; Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; MSD: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria. Suzuki:AstraZeneca: Honoraria; Novartis: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Sysmex: Research Funding; Taiho: Research Funding; Meiji Seika: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Shionogi: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Nippon Shinyaku: Honoraria. Yamaguchi:Chugai Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; Incyte: Research Funding; Abbvie: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: Honoraria; Meiji Seika: Honoraria; MSD: Honoraria; Nippon Shinyaku: Honoraria; SymBio Pharmaceuticals: Honoraria.

2023
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