Shinya Kimura1, Jun Imagawa2, Kazunori Murai3, Masayuki Hino4, Toshio Kitawaki5, Masaya Okada6, Hideo Tanaka7, Motohiro Shindo8, Takashi Kumagai9, Takayuki Ikezoe10, Nobuhiko Uoshima11, Tsutomu Sato12, Reiko Watanabe13, Shugo Kowata14, Masaya Hayakawa15, Takaaki Hosoki16, Kazuhiko Ikeda17, Tsutomu Kobayashi18, Yasutaka Kakinoki19, Tetsuo Nishimoto20, Naoki Takezako21, Hirohiko Shibayama22, Akifumi Takaori-Kondo5, Hirohisa Nakamae4, Atsushi Kawaguchi23, Hiroshi Ureshino24, Junichi Sakamoto25, Yoji Ishida26. 1. Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: shkimu@cc.saga-u.ac.jp. 2. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. 3. Department of Hematology, Iwate Prefectural Central Hospital, Morioka, Japan. 4. Department of Hematology, Osaka City University Hospital, Osaka, Japan. 5. Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 6. Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan. 7. Department of Hematology, Hiroshima City Asa Hospital, Hiroshima, Japan. 8. Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan. 9. Department of Hematology, Ome Municipal General Hospital, Ome, Japan. 10. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan; Department of Hematology, Fukushima Medical School, Fukushima, Japan. 11. Department of Hematology, Matsushita Memorial Hospital, Osaka, Japan. 12. Department of Medical Oncology and Hematology, Sapporo Medical University Hospital, Sapporo, Japan. 13. Department of Hematology, Saitama Medical Center, Saitama Medical University, Saitama, Japan. 14. Department of Hematology, Iwate Prefecture Ofunato Hospital, Iwate, Japan. 15. Department of Hematology, Ogaki Municipal Hospital, Ogaki, Japan. 16. Department of Hematology and Oncology, Asahikawa Kosei Hospital, Asahikawa, Japan. 17. Department of Hematology, Fukushima Medical School, Fukushima, Japan. 18. Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. 19. Department of Hematology, Asahikawa City Hospital, Asahikawa, Japan. 20. Department of Hematology, Ashiya Municipal Hospital, Ashiya, Japan. 21. Division of Hematology, National Hospital Organization Disaster Medical Center, Tachikawa, Japan. 22. Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan. 23. Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan. 24. Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. 25. Epidemiological and Clinical Research Information Network, Okazaki, Japan. 26. Department of Hematology and Oncology, Iwate Medical University, Morioka, Japan.
Abstract
BACKGROUND: A previous dasatinib discontinuation (DADI) trial showed that 31 (49%) of 63 patients with chronic-phase chronic myeloid leukaemia who were treated with second-line or subsequent dasatinib could discontinue the drug safely. However, the safety and efficacy of discontinuing first-line dasatinib remains unclear. In this trial (the first-line DADI trial) we aimed to assess molecular relapse-free survival at 6 months after discontinuation of dasatinib in patients with chronic myeloid leukaemia who had been treated with first-line dasatinib and had maintained deep molecular response for at least 1 year. METHODS: The first-line DADI trial was a single-arm, multicentre, phase 2 trial done at 23 hospitals in Japan. Patients with newly diagnosed chronic-phase chronic myeloid leukaemia without hepatosplenomegaly and extramedullary mass, who received at least 24-month dasatinib treatment and had a sustained deep molecular response (defined as BCR-ABL1/ABL1 international scale ≤0·0069% in at least four successive samples spanning a 12 month period) were enrolled. Other eligibility criteria were an age of 15 years or older, an Eastern Cooperative Oncology Group performance status score of 0-2, and no primary organ dysfunction. The primary outcome was molecular relapse-free survival (also known as treatment-free remission) after discontinuation of dasatinib at 6 months and was analysed in all patients who completed the 12-month consolidation phase. Safety was assessed in all patients who received treatment. This study closed early due to accrual and is registered with the UMIN Clinical Trials Registry (UMIN000011099). FINDINGS: Between Sept 20, 2013 and July 12, 2016, 68 patients who had a deep molecular response after receiving first-line dasatinib for at least 24 months were enrolled and assigned to the consolidation phase. Nine patients were excluded during the consolidation phase and one patient was excluded after study completion because of meeting exclusion criteria. 58 patients discontinued dasatinib and were assessed. 32 (55%) of 58 patients had treatment-free remission at 6 months after dasatinib discontinuation, and median follow-up was 23·3 months (IQR 11·7-31·0). Treatment-free remission at 6 months was 55·2% (95% CI 43·7-69·6). No non-haematological adverse events worse than grade 2 occurred before dasatinib discontinuation. The most common haematological adverse event was anaemia (14 [21%] of 68 treated patients); three (4%) of 68 treated patients had grade 3 neutropenia and one (1%) had grade 4 lymphopenia. INTERPRETATION: Our findings suggest that dasatinib could be safely discontinued after first-line treatment in patients with chronic myeloid leukaemia who had received at least 36 months of therapy and sustained deep molecular response; however, further confirmation in larger trials is needed. FUNDING: Epidemiological and Clinical Research Information Network.
BACKGROUND: A previous dasatinib discontinuation (DADI) trial showed that 31 (49%) of 63 patients with chronic-phase chronic myeloid leukaemia who were treated with second-line or subsequent dasatinib could discontinue the drug safely. However, the safety and efficacy of discontinuing first-line dasatinib remains unclear. In this trial (the first-line DADI trial) we aimed to assess molecular relapse-free survival at 6 months after discontinuation of dasatinib in patients with chronic myeloid leukaemia who had been treated with first-line dasatinib and had maintained deep molecular response for at least 1 year. METHODS: The first-line DADI trial was a single-arm, multicentre, phase 2 trial done at 23 hospitals in Japan. Patients with newly diagnosed chronic-phase chronic myeloid leukaemia without hepatosplenomegaly and extramedullary mass, who received at least 24-month dasatinib treatment and had a sustained deep molecular response (defined as BCR-ABL1/ABL1 international scale ≤0·0069% in at least four successive samples spanning a 12 month period) were enrolled. Other eligibility criteria were an age of 15 years or older, an Eastern Cooperative Oncology Group performance status score of 0-2, and no primary organ dysfunction. The primary outcome was molecular relapse-free survival (also known as treatment-free remission) after discontinuation of dasatinib at 6 months and was analysed in all patients who completed the 12-month consolidation phase. Safety was assessed in all patients who received treatment. This study closed early due to accrual and is registered with the UMIN Clinical Trials Registry (UMIN000011099). FINDINGS: Between Sept 20, 2013 and July 12, 2016, 68 patients who had a deep molecular response after receiving first-line dasatinib for at least 24 months were enrolled and assigned to the consolidation phase. Nine patients were excluded during the consolidation phase and one patient was excluded after study completion because of meeting exclusion criteria. 58 patients discontinued dasatinib and were assessed. 32 (55%) of 58 patients had treatment-free remission at 6 months after dasatinib discontinuation, and median follow-up was 23·3 months (IQR 11·7-31·0). Treatment-free remission at 6 months was 55·2% (95% CI 43·7-69·6). No non-haematological adverse events worse than grade 2 occurred before dasatinib discontinuation. The most common haematological adverse event was anaemia (14 [21%] of 68 treated patients); three (4%) of 68 treated patients had grade 3 neutropenia and one (1%) had grade 4 lymphopenia. INTERPRETATION: Our findings suggest that dasatinib could be safely discontinued after first-line treatment in patients with chronic myeloid leukaemia who had received at least 36 months of therapy and sustained deep molecular response; however, further confirmation in larger trials is needed. FUNDING: Epidemiological and Clinical Research Information Network.