Dasatinib Induces a Higher Molecular Response in Japanese Patients with Chronic Myeloid Leukemia After Imatinib Failure Than in Western Populations: Kanto CML Study
Authors: Hatta Yoshihiro , Inokuchi Koiti , Kumagai Takashi , Ohashi Kazuteru , Shinagawa Atsushi , Takeuchi Jin , Okamoto Shinichiro , Wakita Hisashi , Kouzai Yasuji , Shirasugi Yukari , Yoshida Chikashi , Oba Koji , Sakamoto Junichi , Sakamaki Hisashi 
Published: October 2019

Abstract
Abstract 4448

Background
Dasatinib is a potent tyrosine kinase inhibitor and is highly effective against chronic myeloid leukemia (CML). In Japan, dasatinib was approved in 2009 as a second-line therapy for CML after imatinib failure. Therefore, we conducted a phase II study to investigate the efficacy and safety of dasatinib treatment in Japanese CML-chronic phase (CP) patients with intolerance or resistance to imatinib.

Patients and method
CML-CP patients who were unable to continue imatinib therapy (400 mg/day) because of adverse events were registered as being intolerant to imatinib. Resistance to imatinib was defined as failure to achieve a partial cytogenetic response (PCyR) after three months of therapy or a complete cytogenetic response (CCyR) after six months of therapy or the expression of over 100 copies/μg RNA of BCR-ABL after 12 months of therapy. For these patients, dasatinib (100 mg) was administered once daily. Patients with T315I and F317I mutations in BCR-ABL were excluded. Major and complete molecular responses (MMR and CMR) were centrally evaluated using RQ-PCR at the BML laboratory. When the study was designed, a conversion factor (CF) had not been introduced to Japan for the adoption of international scale (IS). Subsequently, 0.1% IS (MMR) was defined as being equivalent to 731 copies/μg RNA based on the BML laboratory specific CF obtained in 2011, and 11 patients were identified as having an MMR at the time of study enrollment.

Results
A total of 61 patients were accrued from 21 centers: 26 with intolerance, and 35 with resistance. The median age was 58 years (range, 16 – 91 years). The median follow-up duration was nine months (range, 0.5 – 18 months). An MMR+CMR was observed in 27 out of 45 patients (60.0%, 13 CMR and 14 MMR) at six months and in 22 out of 31 patients (71.0%, 8 CMR and 14 MMR) at nine months after treatment with dasatinib, respectively. Excluding the patients with an MMR at the time of registration, dasatinib had induced an MMR+CMR in 21 out of 39 patients (53.9%, 11 CMR and 10 MMR) at six months and 19 out of 28 patients (67.9%, 7 CMR and 12 MMR) at nine months, respectively. The response rates in intolerant and resistant patients were comparable. Twelve patients discontinued dasatinib treatment because of drug toxicity (four patients), patient request (one), disease progression or the development of a T315I mutation (three), or unknown causes (four). Although grade 1 – 2 pleural effusion was observed in five patients, no severe cases were observed. Ten mutations in BCR-ABL occurred in eight patients during dasatinib treatment; a low IC50 of dasatinib against tumor cells in five of these mutations (M244V, M351T, F359I, F359V, H396R), an intermediate value against tumor cells in one of these mutations (Q252H), a high value against tumor cells in two of these mutations in three patients (T315I in two patients and E459K), and an unknown sensitivity against tumor cells in one of these mutations (A397P). Patients with M244V+Q252H, H396R, or T315I did not respond to dasatinib treatment.

Conclusion
Dasatinib is a safe and efficacious alternative for the treatment of CML following imatinib failure. Because MMR rate in the global study was 31% at one year and 44% at 5 years, the molecular response rate among Japanese patients was higher than that in western populations. Mutation in BCR-ABL remains a major issue.

Disclosures:
Okamoto: Bristol-Myers Squibb: Research Funding.