Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial.

BACKGROUND

BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase.

METHODS

DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0-2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period.

FINDINGS

Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5-83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48-71), with a median follow-up of 366 days (IQR 353-372). Grade 3-4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3-4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed.

INTERPRETATION

Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population.

FUNDING

Bristol-Myers Squibb.

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests KM has received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, Celgene, Eisai, Sanofi, Janssen, and Otsuka Pharmaceuticals. TKu received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Otsuka Pharmaceuticals. HT received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Otsuka Pharmaceuticals. KN received grants from Kyowa-Kirin, and honoraria from Alexion. CY received honoraria from Bristol-Myers Squibb, Novartis KK, Pfizer Japan, Otsuka Pharmaceutical, AbbVie GK, Janssen Pharmaceutical KK, Nippon Shinyaku, and Chugai Pharmaceutical. NU received honoraria from Eisai and Janssen Pharmaceutical. KU received grants from Astellas Pharma, AbbVie, Apellis, SymBio, Daiichi-Sankyo, Novartis, Janssen, Otsuka, Astellas Amgen Biopharma, Takeda, Nippon-Shinyaku, Bristol-Myers Squibb, Amgen, Alexion, Incyte, Ono, Kyowa-Kirin, Celgene, Sumitomo-Dainippon, Chugai, Pfizer, Mundi, Yakult, MSD, Gilead, and Nippon-Boehringer-Ingelheim and honoraria from Novartis, Bristol-Myers-Squibb, Sanofi, Pfizer, Abbvie, Takeda, Ono, Kyowa-Kirin, Astellas, Alexion, Eisai, MSD, Otsuka, Celgene, Daiichi-Sankyo, Nippon-Shinyaku, PharmaEssentia, Yakult, SymBio, Alexion, and Chugai. JK received grants from Bristol-Myers Squibb, Sysmex, Celgene, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Kyowa Kirin, Sanofi, Chugai Pharmaceutical, Eisai, Dainippon Sumitomo Pharma, Nippon Shinyaku, Takeda, Shionogi, Asahi Kasei, Daiichi Sankyo, MSD, Taiho Pharmaceutical, and Abbvie; has received honoraria from Bristol–Myers Squibb, Janssen Pharmaceutical KK, Celgene Corporation, Ono Pharmaceutical, Takeda, Sanofi, Kyowa Kirin, Chugai Pharmaceutical, Eisai, Astellas Pharma, Nippon Shinyaku, Dainippon Sumitomo Pharma, Symbio, Daiichi Sankyo, Fujimoto Pharmaceutical, Abbvie, and Otsuka Pharmaceutical; and consulting fees from Janssen Pharmaceutical KK, Bristol-Myers Squibb, Sanofi, and Abbvie. TO received grants from Celgene, Kyowa Hakko Kirin, Chugai Pharmaceutical, TAIHO Phamaceutical; and honoraria from Celgene, Kyowa Hakko Kirin, Chugai Pharmaceutical, Novartis, Bristol-Myers Squibb, Pfizer, Otsuka Pharmaceutical, ONO Pharmaceutical, Takeda Pharmaceutical, Astellas Pharma, Eisai Pharmaceuticals, Janssen Pharm, Daiichi Sankyo, and Mundipharma. KF received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Otsuka Pharmaceuticals. HS received honoraria from Takeda, Ono, Novartis, Janssen, Chugai, Eizai, Nippon Shinyaku, Sanofi, AstraZeneca, Bristol-Myers Squibb, Otsuka, Mundi Pharma and Kyowa Kirin; and research funding from Janssen, Ono, Celgene, Novartis, Sanofi, AstraZeneca, AbbVie, and Chugai. TKo received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, Otsuka Pharmaceuticals, and Abbvie; and has served in an advisory role for Astellas Pharma and Otsuka Pharmaceutical. YMi received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Astellas; and research funding from Ono and CMIC Holdings. ShK has received honoraria from Bristol-Myers Squibb, Novartis, Pfizer, and Otsuka Pharmaceuticals; and research funding from Bristol-Myers Squibb, Pfizer, Otsuka Pharmaceuticals, and Ohara Pharmaceuticals. All other authors declare no competing interests