title: Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial.
abstract: BACKGROUND
  First-line imatinib treatment can be successfully discontinued in patients with chronic myeloid leukaemia after deep molecular response has been sustained for at least 2 years. We investigated the safety and efficacy of discontinuing second-line or subsequent dasatinib after at least 1 year of deep molecular response.
  
  
  METHODS
  The Dasatinib Discontinuation trial was a prospective multicentre trial done in Japan. Eligible patients taking dasatinib and with confirmed stable deep molecular response were enrolled between April 1, 2011, and March 31, 2012. All patients received dasatinib consolidation therapy for at least 1 year. In those with sustained deep molecular response, dasatinib was discontinued. Patients were followed up every month in year 1 (clinical cutoff), every 3 months in year 2, and every 6 months in year 3 for deep molecular response and immunological profiles. The primary endpoint was the proportion of patients with treatment-free remission at 6 months after discontinuation. Molecular relapse was defined as loss of deep molecular response at any assessment. This study is registered, number UMIN000005130.
  
  
  RESULTS
  88 patients were enrolled in the consolidation phase, 24 were excluded from the discontinuation phase due to fluctuations in BCR-ABL1 transcript levels. One patient was excluded because of positive expression of major and minor BCR-ABL1 transcripts in chronic myeloid leukaemia cells and the detection of minor BCR-ABL1 transcripts during consolidation. Thus, 63 patients discontinued dasatinib treatment. The 25 patients who were excluded from discontinuation continued to receive dasatinib and none showed disease progression. Median follow-up was 20.0 months (IQR 16.5-24.0). Of the 63 patients who discontinued and were not excluded, 30 patients maintained deep molecular response while 33 patients had molecular relapses, all within the first 7 months after discontinuation. The estimated overall treatment-free remission was 49% (95% CI 36-61) at 6 months. No severe treatment-related toxic effects were seen. Treatment was restarted in the 33 patients with relapse; rapid molecular responses were seen in all 33 patients, of whom 29 (88%) regained deep molecular response within 3 months, as did the remaining four by 6 months.
  
  
  CONCLUSIONS
  Dasatinib discontinuation after sustained deep molecular response for more than 1 year is feasible.
  
  
  BACKGROUND
  Epidemiological and Clinical Research Information Network (ECRIN).
authors.affiliation: Department of Haematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Imagawa
authors.affiliation: Department of Haematology, Hiroshima City Asa Hospital, Hiroshima, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Division of Haematology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Haematology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Nakamae
authors.affiliation: Department of Haematology and Oncology, Iwate Medical University, Morioka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hino
authors.affiliation: Department of Haematology and Oncology, Iwate Medical University, Morioka, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Murai
authors.affiliation: Department of Haematology and Oncology, Iwate Medical University, Morioka, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Department of Haematology, Ohme Municipal General Hospital, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumagai
authors.affiliation: Department of Internal Medicine, Fujimoto Sogo Hospital, Miyakonojo, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Sato
authors.affiliation: Haematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Centre Komagome Hospital, Tokyo, Japan.
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Haematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Centre Komagome Hospital, Tokyo, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sakamaki
authors.affiliation: Division of Haematology and Oncology, Japanese Red Cross Narita Hospital, Narita, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Wakita
authors.affiliation: Department of Haematology, Matsushita Memorial Hospital, Moriguchi, Osaka, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Uoshima
authors.affiliation: Department of Haematology, Japanese Red Cross Medical Centre, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Division of Blood Transfusion and Division of Medical Oncology and Haematology, Kobe University Hospital, Kobe, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Minami
authors.affiliation: Department of Haematology, Sapporo Hokuyu Hospital, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ogasawara
authors.affiliation: Division of Haematology and Immunology, Otsu Red Cross Hospital, Otsu, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Takeoka
authors.affiliation: Department of Haematology, Shinko Hospital, Kobe, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akasaka
authors.affiliation: Department of Haematology, Shiga Medical Centre for Adults, Moriyama, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Utsumi
authors.affiliation: Division of Haematology, National Kyushu Cancer Centre, National Hospital Organisation, Fukuoka, Japan.
authors.forename: Naokuni
authors.initials: N
authors.lastname: Uike
authors.affiliation: Fourth Department of Internal Medicine, Sapporo Medical, University School of Medicine, Sapporo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Haematology, Teine Keijinkai Hospital, Sapporo, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ando
authors.affiliation: Division of Haematology, NTT Medical Centre Tokyo, Tokyo, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Usuki
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.affiliation: NPO Epidemiological and Clinical Research Information Network (ECRIN), Okazaki, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakamoto
authors.affiliation: Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: shkimu@cc.saga-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069439:Dasatinib / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007564:Japan; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000069439:Dasatinib