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. 2025 Jan 31:80:103078.
doi: 10.1016/j.eclinm.2025.103078. eCollection 2025 Feb.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): long-term results of a multicentre, single-arm, phase 2 trial

Kazuyuki Shimada  1 , Motoko Yamaguchi  2 , Yachiyo Kuwatsuka  3 , Kosei Matsue  4 , Keijiro Sato  5 , Shigeru Kusumoto  6   7 , Hirokazu Nagai  8 , Jun Takizawa  9 , Noriko Fukuhara  10 , Koji Nagafuji  11 , Kana Miyazaki  12 , Eiichi Ohtsuka  13 , Akinao Okamoto  14 , Yasumasa Sugita  15 , Toshiki Uchida  16 , Satoshi Kayukawa  17 , Atsushi Wake  18 , Daisuke Ennishi  19 , Yukio Kondo  20 , Akiko Meguro  21 , Yoshihiro Kin  22 , Yosuke Minami  23 , Daigo Hashimoto  24 , Takahiro Nishiyama  25 , Satoko Shimada  26 , Yasufumi Masaki  27 , Masataka Okamoto  14 , Yoshiko Atsuta  28   29 , Hitoshi Kiyoi  1 , Ritsuro Suzuki  30 , Shigeo Nakamura  26 , Tomohiro Kinoshita  7   31
Affiliations

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): long-term results of a multicentre, single-arm, phase 2 trial

Kazuyuki Shimada et al. EClinicalMedicine. .

Abstract

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma for which prognosis is typically poor without a timely diagnosis. To explore the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy, we conducted a multicentre, single-arm, phase 2 trial in untreated IVLBCL patients without CNS involvement at diagnosis (PRIMEUR-IVL). In the primary analysis, the PRIMEUR-IVL study demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence (3%) of secondary CNS involvement (sCNSi).

Methods: We present a prespecified final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and cumulative incidence of sCNSi. Participants were enrolled between June 2011 and July 2016, and the data cutoff date for the final analysis was 16 November 2021. The trial was registered in the UMIN Clinical Trial Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165).

Findings: With a median follow-up of 7.1 years (interquartile range 5.6-8.7), 5-year PFS in all 37 eligible patients was 68% (95% confidence interval [CI] 50%-80%) and OS was 78% (95% CI 61%-89%). No additional sCNSi was observed after the primary analysis. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). Eight deaths occurred during the observation period after enrolment, due to primary disease (n = 6), sepsis (n = 1) and unknown sudden death (n = 1).

Interpretation: Long-term follow-up data demonstrated durable response for PFS and OS, and low cumulative incidence of sCNSi, indicating the efficacy of standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients.

Funding: This study received financial support from the Japan Agency for Medical Research and Development, Center for Supporting Hematology-Oncology Studies, and National Cancer Center.

Keywords: Central nervous system-directed therapy; Intravascular large B-Cell lymphoma; R-CHOP; Secondary central nervous system involvement.

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Conflict of interest statement

K. Shimada reports grants from the Japan Agency for Medical Research and Development (AMED), during the conduct of the study; grants from Otsuka and Kyowa Kirin, outside of the submitted work; consulting fees from Chugai, Eli Lilly, AbbVie, Kyowa Kirin, BeiGene, and Ohara, outside of the submitted work; payment or honoraria from Takeda, Kyowa Kirin, CSL Behring, Eisai, Chugai, Daiichi Sankyo, AstraZeneca, Janssen, Bristol-Myers Squibb, Nippon Shinyaku, Ono, Gilead, AbbVie, Genmab, Novartis, Incyte, Meiji Seika Pharma, Mundi Pharma, SymBio, Sanofi, and Asahi Kasei, outside of the submitted work. M. Yamaguchi reports grants from AMED during the conduct of the study; grants from AstraZeneca, Chugai, Genmab, Incyte, and AbbVie, outside of the submitted work; consulting fees from Genmab, BeiGene, and Nihon Servier, outside of the submitted work; payment or honoraria from Chugai, Kyowa Kirin, AbbVie, Bristol-Myers Squibb, Janssen, Meiji Seika Pharma, MSD, Nippon Shinyaku, SymBio, Takeda, and Eisai, outside of the submitted work. K. Matsue reports grants from AMED during the conduct of the study and grants from AstraZeneca, outside of the submitted work. S. Kusumoto reports grants from Chugai, Kyowa Kirin, Janssen, and Daiichi Sankyo, outside of the submitted work; and payment or honoraria from Chugai, Kyowa Kirin, Janssen, and Daiichi Sankyo, outside of the submitted work. H. Nagai reports grants from Takeda, Kyowa Kirin, and Chugai, outside of the submitted work; and payment or honoraria from Takeda, Kyowa Kirin, Chugai, and Nippon Kayaku, outside of the submitted work. J. Takizawa reports grants from Janssen, AstraZeneca, AbbVie, Novartis, Kyowa Kirin, Chugai, Nippon Kayaku, Mitsubishi Tanabe, Eli Lilly, and Asahi Kasei, outside of the submitted work and payment or honoraria from Janssen, AstraZeneca, AbbVie, Novartis, Kyowa Kirin, Chugai, and Nippon Kayaku, outside of the submitted work. N. Fukuhara reports grants from AbbVie, Chugai, Chordia therapeutics, Genmab, Incyte, Kyowa Kirin, Loxo Oncology, and Takeda, outside of the submitted work; payment or honoraria from AbbVie, AstraZeneca, Bristol-Myers Squibb, Chugai, CSL Behring, Eisai, Eli Lilly, Genmab, Janssen, Kyowa Kirin, Nippon Shinyaku, Novartis, Ono, Sanofi, SymBio, and Takeda, outside of the submitted work. K. Nagafuji report grants from Kyowa Kirin, Chugai, and Ono, outside of the submitted work. K. Miyazaki reports grants from Eisai, Takeda, Nippon Shinyaku, Otsuka, Chugai, Asahi Kasei, Sumitomo, and Zenyaku Kogyo, outside of the submitted work; payment or honoraria from Chugai, SymBio, Janssen, Eisai, Nippon Shinyaku, AstraZeneca, Bristol-Myers Squibb, Meiji Seika Pharma, AbbVie, Genmab, Novartis, Incyte, Asahi Kasei, and Ono, outside of the submitted work. T. Uchida reports payment or honoraria from Novartis, Janssen, AbbVie, Nippon Shinyaku, Kyowa Kirin, Nippon Kayaku, Takeda, Kissei, Meiji Seika Pharma, Bristol-Myers Squibb, Sanofi, Chugai, Asahi Kasei and Eisai, outside of the submitted work. D. Ennishi reports grants from Nippon Shinyaku, Chugai, and Eisai, outside of the submitted work; payment or honoraria from Eisai, Chugai, SymBio, Bristol-Myers Squibb, Kyowa Kirin, and Nippon Shinyaku, outside of the submitted work. Y. Minami reports consulting fees from Takeda and CMIC, outside of the submitted work and payment or honoraria from Novartis, Astellas, Pfizer, Daiichi Sankyo, and Otsuka, outside of the submitted work. Y. Masaki reports grants from Astellas, Eisai, Pfizer, Taisho, Taiho, Chugai, Nippon Kayaku, MSD, Kyowa Kirin, Ono, Asahi Kasei, Daiichi Sankyo, Takeda, Teijin, and Mochida, outside of the submitted work. M. Okamoto reports grants from Chugai, outside of the submitted work; and payment or honoraria from AbbVie, Janssen, Sanofi, Shinnihonseiyaku, and Kyowa Kirin, outside of the submitted work. Y. Atsuta reports consulting fees from JCR Pharmaceuticals and Kyowa Kirin, outside of the submitted work; and payment or honoraria from Otsuka, Chugai, Novartis, AbbVie, Janssen, and Meiji Seika Pharma, outside of the submitted work. H. Kiyoi reports grants from Chugai, Kyowa Kirin, Zenyaku Kogyo, Sumitomo, Eisai, Daiichi Sankyo, Otsuka, Perseus, CURED, Astellas, Asahi Kasei, AbbVie, Nippon Kayaku, Nippon Shinyaku, JCR Pharmaceuticals, and Takeda, outside of the submitted work; payment of honoraria from Chugai, Eisai, Daiichi Sankyo, Astellas, AbbVie, AstraZeneca, Novartis, SymBio, Bristol-Myers Squibb, Amgen, Meiji Seika Pharma, Pfizer, Nippon Kayaku, Towa, Ono, MSD, Pharma Essentia Japan, Asahi Kasei, and Kissei, outside of the submitted work. R. Suzuki reports grants from Chugai, Kyowa Kirin, Shionogi, Taiho, Eisai, and Otsuka, outside of the submitted work; and payment or honoraria from Chugai, Kyowa Kirin, AbbVie, Bristol-Myers Squibb, Eisai, Otsuka, MSD, Janssen, Takeda, Meiji Seika Pharma, Novartis, and AstraZeneca, outside of the submitted work. T. Kinoshita reports grants from the National Cancer Center during the conduct of the study. Y. Kuwatsuka, K. Sato, E. Ohtsuka, A. Okamoto, Y. Sugita, S. Kayukawa, A. Wake, Y. Kondo, A. Meguro Y. Kin, D. Hashimoto, T. Nishiyama, S. Shimada, and S. Nakamura declares no competing interests.

Figures

Fig. 1
Fig. 1
Trial profile. Trial profile of the study was shown. The profile was previously reported at the primary analysis (Ref13).
Fig. 2
Fig. 2
Progression-free survival and overall survival. Progression-free survival (a) and overall survival (b) in all patients at the final analysis were shown.
Fig. 3
Fig. 3
Cumulative incidence of secondary central nervous system involvement. Cumulative incidence of secondary central nervous system involvement in all patients at the final analysis was shown.
See this image and copyright information in PMC

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