In this ongoing Phase 1/2 study (NCT01667133), we evaluated ponatinib and assessed its recommended dose in Japanese patients with chronic myeloid leukemia (CML) resistant/intolerant to dasatinib or nilotinib, or with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) resistant/intolerant to ≥1 tyrosine kinase inhibitor (TKI). The primary endpoints were safety of the recommended dose (Phase 1) and major cytogenetic response (MCyR) by 12 months in chronic-phase CML (CP-CML) patients or major hematologic response (MaHR) by 6 months in patients with advanced phase disease (Phase 2). MCyR was achieved/maintained by 12 months in 65% of CP-CML patients; MaHR was achieved by 6 months in 61% of patients with advanced phase disease. The most common nonhematologic grade 3/4 treatment-emergent adverse event (AE) was hypertension (37%); common hematologic grade 3/4 AEs were thrombocytopenia (57%), neutropenia (34%), and leukopenia (26%). Overall, five (14%) patients experienced arterial occlusive events (AOEs); no grade 5 AOEs were reported. The steady-state accumulation ratio of ponatinib (based on area under the curve) ranged from 2.6 (15 mg/day) to 1.3 (45 mg/day). In summary, ponatinib demonstrated efficacy in Japanese patients with CML and Ph+ALL resistant/intolerant to prior TKI treatment; safety data support a recommended starting dose of 45 mg/day in these patients.
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The authors thank Kumiko Yanase, MD, PhD for contributions to this work. Medical writing assistance was provided by Carolyn S. Schober, Ph.D., Evidence Scientific Solutions, Philadelphia, PA, USA, and supported by ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA.
Conflict of interest
Dr. Tojo reports grants from Daiichi Sankyo, Pfizer, BMS, and Chugai Pharma and personal fees from Sysmex, Taiho Pharma, Novartis, Pfizer, BMS, Otsuka, and Takara Bio outside the submitted work; Dr. Yamamoto reports Grants from ARIAD/CMIC, and personal fees from ARIAD/CMIC and Otsuka, during the conduct of the study, and Grants from AbbVie, MSD, Pfizer, Novartis, Celgene, Takeda, Chugai Pharma, and Ono Pharmaceutical and personal fees from Pfizer, Novartis, Celgene, Takeda, Chugai Pharma, Ono Pharmaceutical, Kowa Hakko Kirin, Janssen, BMS, and Sumitomo Dainippon Pharma outside the submitted work; Dr. Nakamae reports Grants from ARIAD, during the conduct of the study, and Grants and other from Otsuka outside the submitted work; Dr. Takahashi reports personal fees and non-financial support from Otsuka, during the conduct of the study, and Grants from Pfizer, Novartis, Chugai Pharma, Kyowa Hakko Kirin, and Fujimoto Pharma and personal fees Pfizer and Novartis outside the submitted work; Dr. Kobayashi reports Grants from ARIAD, Astellas, Pfizer, Otsuka, and Boehringer Ingelheim outside the submitted work; Dr. Okamoto reports Grants from BMS, Novartis, and Otsuka and other from BMS, Novartis, Otsuka, and Pfizer outside the submitted work; Dr. Miyamura reports personal fees from Nippon Shinyaku, Pfizer, Novartis, and Alexion outside the submitted work; Dr. Iwasaki reports personal fees from Novartis, BMS, Kyowa Hakko Kirin, and Otsuka and Grants from BMS, Novartis, Kyowa Hakko Kirin, and Chugai Pharma outside the submitted work; Dr. Matsumura reports personal fees and non-financial support from Otsuka, during the conduct of the study; Dr. Usui reports personal fees and non-financial support from Otsuka during the conduct of the study, and Grants from BMS, Celgene, Fujimoto Pharma, Kyowa Hakko Kirin, Nippon Shinyaku, Novartis, Pfizer and personal fees from Astellas, BMS, Celgene, Chugai Pharma, CIMIC, Eli Lilly Japan, Janssen, Kyowa Hakko Kirin, Otsuka, Pfizer, SymBio, Sysmex, Takada Bio Development Center, and Zenyaku Kogyo outside the submitted work; Dr. Naoe reports Grants from Fuji film outside the submitted work; Dr. Tugnait, Dr. Narasimhan, Dr. Lustgarten, and Dr. Farin report personal fees (employment) from ARIAD and other (stock and other ownership interests) from ARIAD during the conduct of the study; Dr. Haluska reports personal fees (previous employment) from ARIAD and other (stock and other ownership interests) from ARIAD during the conduct of the study; Dr. Kyo, Dr. Tauchi, Dr. Hatake, and Dr. Ohyashiki have nothing to disclose.
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Tojo, A., Kyo, T., Yamamoto, K. et al. Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study. Int J Hematol 106, 385–397 (2017). https://doi.org/10.1007/s12185-017-2238-9
- Japanese population
- Phase 1/2