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Phase 1/2 study of venetoclax, a BCL-2 inhibitor, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma

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Abstract

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have limited treatment options. Venetoclax is a potent BCL-2 inhibitor that induces apoptosis in CLL cells. This open-label, phase 1/2 study (NCT02265731) evaluated the safety, pharmacokinetics, and efficacy of venetoclax in Japanese patients with R/R CLL/SLL. Patients enrolled in phase 1 received 400 mg/day venetoclax monotherapy. Patients enrolled in phase 2 received 400 mg/day venetoclax, plus rituximab. Venetoclax was administered with a weekly stepwise ramp-up in doses. In phase 2, efficacy was evaluated by objective response rate (ORR). Twelve patients were enrolled, six in each arm. The most common grade ≥ 3 adverse events were neutropenia (83%), lymphopenia (67%), leukopenia (33%), and thrombocytopenia (17%). Patients receiving venetoclax monotherapy achieved an ORR of 100%, including a complete remission (CR) rate of 17%. Patients receiving combination therapy had an ORR of 67% and a CR rate of 50%. The venetoclax pharmacokinetics profile in Japanese patients was similar to that of Western patients. Venetoclax 400 mg/day monotherapy or in combination with rituximab was well-tolerated and induced promising responses in Japanese patients with R/R CLL/SLL. Although patient numbers were small, the safety profile was largely consistent with other Western studies. Clinical trial registration: clinicaltrials.gov; NCT02265731.

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Acknowledgements

The authors and AbbVie/Genentech would like to thank the patients and their families/caregivers; study investigators and support staff; Norio Komatsu (Juntendo University School of Medicine, Tokyo), Noriko Usui (The Jikei University School of Medicine, Dai-San Hospital, Tokyo), and Sadao Aoki (Niigata University of Pharmacy and Applied Life Sciences), all members of the Data and Safety Monitoring Committee; and Dalia Majumdar, PhD and Mrinal Y. Shah, PhD for medical writing support, both employees of AbbVie, Inc. This study was funded by AbbVie and Genentech.

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Correspondence to Koji Izutsu.

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Koji Izutsu: Honoraria from Eisai, MSD, Kyowa-Kirin, Takeda, Janssen, Dainihon Sumitomo, Mundipharma, Nihon Mediphysics, Chugai, AbbVie, AstraZeneca, Bayer, Ono, Celgene; research funding from Eisai, Janssen, Mundipharma, Chugai, AstraZeneca, AbbVie, Bayer, Ono, Gilead, Zenyaku, Celgene, Solasia, Symbio, Astellas, Astellas Amgen, Bayer, Daiichi Sankyo. Kazuhito Yamamoto: Research funding from AbbVie, ARIAD Pharmaceuticals, AstraZeneca, Bayer, Celgene, Chugai, Eisai, Gilead Sciences, Incyte, MSD, Mundipharma, Nippon Shinyaku, Novartis, Ono, Solasia Pharma, SymBio, Takeda, Zenyaku; honoraria from Chugai, Mundipharma, Takeda. Koji Kato: Honoraria from Chugai, Takeda, MSD, Kyowa-Kirin, Janssen, Celgene, Ono, Mundi, Dainippon-Sumitomo; consulting or advisory role for Novartis, Eisai, Janssen, Celgene; research funding from Chugai, Takeda, Kyowa-Kirin, AbbVie, Novartis, Eisai, Janssen, Celgene, Ono. Takayuki Ishikawa: Investigator in AbbVie-sponsored clinical trials. Noriko Fukuhara: Research funding from AbbVie, Bayer, Eisai, Gilead, Janssen, Ono, Takeda; honoraria from Kyowa Hakko Kirin. Yasuhito Terui: Honoraria from Chugai, Takeda, Janssen, Celgene, Ono, Mundi, Novartis, Eisai, Takeda; research funding from BMS. Ilseung Choi: Investigator in AbbVie-sponsored clinical trials. Kathryn Humphrey: Employee of Roche and may own stock or stock options. Su Young Kim, Sumiko Okubo, Natsumi Ogawa, Yasuko Nishimura, Ahmed Hamed Salem: Employees of AbbVie and may own stock or stock options. Dai Maruyama: Research funding from Chugai Pharma, Ono Pharmaceutical, Celgene, Janssen, GlaxoSmithKline, Eisai, Mundipharma, Takeda, AbbVie, MSD, Astellas Pharma, Amgen, Astellas, BioPharma, Otsuka, Novartis, Nippon Boehringer Ingelheim, Pfizer, Solasia Pharma, Bayer, Zenyaku Kogyo, AstraZeneca; honoraria from Zenyaku Kogyo, Eisai, Takeda, Mundipharma, Janssen, Kyowa Hakko Kirin, Celgene, Fujifilm, Chugai Pharma, MSD, Ono Pharmaceutical. AbbVie/Genentech: AbbVie and Genentech sponsored the study (NCT02265731), contributed to the study design, analysis, interpretation of the data, and participated in the writing, review, and approval of the manuscript. All authors had access to data. Venetoclax (ABT-199/GDC-0199) is being developed in collaboration between AbbVie and Genentech.

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Izutsu, K., Yamamoto, K., Kato, K. et al. Phase 1/2 study of venetoclax, a BCL-2 inhibitor, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Int J Hematol 113, 370–380 (2021). https://doi.org/10.1007/s12185-020-03024-3

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