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Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study

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Abstract

The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again; all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan–Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in > 100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan.

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Acknowledgements

The authors would like to thank the investigators and clinical research coordinators of the sites in the JALSG study group and all of the patients who participated in this study. The Ipsogen BCR-ABL1M-BCR IS-PCR kits was provided by Sysmex Co., Ltd., and IS-PCR analysis was performed at the central laboratory of Sysmex Co., Ltd. We thank Ms. Mika Yoshimura and Mr. Yoshiro Ikeuchi at Sysmex Co., Ltd. for their collaboration. We also thank Ms. Saori Takahashi at Akita University for collecting the data and conducting central monitoring of this study. This study was supported by the Practical Research for Innovative Cancer Control program of the Japan Agency for Medical Research and Development (AMED 15ck0106189h0001, 16ck0106189h0002, 17ck0106189h0003).

Author information

Authors and Affiliations

  1. Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, Akita, 010-8543, Japan

    Naoto Takahashi

  2. Department of Hematology, Tokyo Medical University, Tokyo Medical University, Tokyo, Japan

    Tetsuzo Tauchi

  3. Division of Hematology, Ichinomiya Municipal Hospital, Ichinomiya, Japan

    Kunio Kitamura

  4. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Koichi Miyamura

  5. Department of Hematology, Oita Prefectural Hospital, Oita, Japan

    Yoshio Saburi

  6. Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan

    Yoshihiro Hatta

  7. National Hospital Organization, Nagoya Medical Center, Nagoya, Japan

    Yasuhiko Miyata & Tomoki Naoe

  8. Division of Hematology, National Defense Medical College, Tokorozawa, Japan

    Shinichi Kobayashi

  9. Department of Hematology, NTT Medical Center Tokyo, Tokyo, Japan

    Kensuke Usuki

  10. Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan

    Itaru Matsumura

  11. Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan

    Yosuke Minami

  12. Department of Clinical Oncology/Hematology, The Jikei University School of Medicine, Tokyo, Japan

    Noriko Usui

  13. Department of Hematology, Tokyo Medical and Dental University, Tokyo, Japan

    Tetsuya Fukuda

  14. Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan

    Satoru Takada

  15. Department of Hematology, Saitama Medical University International Medical Center, Saitama, Japan

    Maho Ishikawa

  16. Department of Hematology, Fujisawa City Hospital, Fujisawa, Japan

    Katsumichi Fujimaki

  17. Department of Hematology, Hyogo Cancer Center, Akashi, Japan

    Hiroshi Gomyo

  18. Department of Hematology, Miyagi Cancer Center, Natori, Japan

    Osamu Sasaki

  19. Department of Transfusion Medicine and Cell Therapy, Mie University Hospital, Tsu, Japan

    Kohshi Ohishi

  20. Department of Oncology/Hematology, Shimane University Hospital, Izumo, Japan

    Takaaki Miyake

  21. Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan

    Kiyotoshi Imai

  22. Department of Hematology, Kumamoto Shinto General Hospital, Kumamoto, Japan

    Hitoshi Suzushima

  23. Department of Hematology, Otemae Hospital, Osaka, Japan

    Hideki Mitsui

  24. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi, Japan

    Kazuto Togitani

  25. Department of Hematology, Chugoku Central Hospital, Fukuyama, Japan

    Toru Kiguchi

  26. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Yoshiko Atsuta

  27. Kanazawa University, Kanazawa, Japan

    Shigeki Ohtake

  28. Japanese Red Cross Aichi Blood Center, Seto, Japan

    Kazunori Ohnishi

  29. Hematology Division, International University of Health and Welfare, Mita Hospital, Tokyo, Japan

    Yukio Kobayashi

  30. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hitoshi Kiyoi

  31. Department of Hematology, Nagasaki University, Nagasaki, Japan

    Yasushi Miyazaki

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  1. Naoto Takahashi
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  2. Tetsuzo Tauchi
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  3. Kunio Kitamura
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  14. Satoru Takada
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  32. Tomoki Naoe
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The Japan Adult Leukemia Study Group

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Correspondence to Naoto Takahashi.

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Conflict of interest

Naoto Takahashi reports grants from Japan Agency for Medical Research and Development, non-financial support from Sysmex Co., Ltd., personal fees from NPO JALSG, during the conduct of the study; grants and personal fees from Novartis Pharma K.K., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., grants and personal fees from Pfizer Japan Inc., personal fees from Bristol-Myers Squibb K. K., outside the submitted work. Tetsuzo Tauchi reports grants and other from Novartis Pharma K.K., grants and other from Pfizer Japan Inc., other from Bristol-Myers Squibb K. K., other from Otsuka Pharmaceutical Co., Ltd., during the conduct of the study. Koichi Miyamura reports personal fees from Novartis Pharma K.K., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Bristol-Myers Squibb K. K., personal fees from Pfizer Japan Inc., outside the submitted work. Kensuke Usuki reports personal fees from Novartis Pharma K.K., grants from Fujimoto Pharmaceutical, grants from Otsuka Pharmaceutical Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Kyowa Hakko Kirin Co., Ltd., grants from Daiichi Sankyo Co., Ltd., outside the submitted work. Itaru Matsumura reports personal fees from Novartis Pharma K.K., personal fees from Bristol-Myers Squibb K. K., personal fees from Pfizer Japan Inc., personal fees from Otsuka Pharmaceutical Co., Ltd., during the conduct of the study. Yosuke Minami reports grants from Kyowa Hakko Kirin Co., Ltd., grants from Novartis Pharma K.K., grants from Bristol-Myers Squibb K. K., outside the submitted work. Noriko Usui reports personal fees from CIMIC Co., Ltd., personal fees from Takeda Bio Development Center, personal fees from Lilly Japan, personal fees from Pfizer Japan Inc., grants from Pfizer Japan Inc., personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants from Sysmex Co., Ltd., personal fees from Jansen Pharm Co, Ltd., personal fees from Zenyaku Kogyo Co, Ltd., personal fees from Kyowa Hakko Kirin Co., Ltd., grants from Kyowa Hakko Kirin Co., Ltd., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Celgene K. K., personal fees from SymBio Pharm Co, Ltd., personal fees from Huya Bioscience International, personal fees from Astellas Pharma Inc., personal fees from Chugai Pharmaceutical Co. Ltd., grants from Bristol-Myers Squibb K. K., personal fees from Bristol-Myers Squibb K. K., grants from Novartis Pharma K.K., grants from Nippon Shinyaku Co. Ltd., grants from Fujimoto Pharmaceutical, grants from Celgene K. K., outside the submitted work. Tetsuya Fukuda reports personal fees from Novartis Pharma K.K., outside the submitted work. Yoshiko Atsuta reports personal fees and other from Otsuka Pharmaceutical Co., Ltd., personal fees and other from Bristol-Myers Squibb K. K., personal fees from Mochida Pharmaceutical Co., Ltd., personal fees from Kyowa Hakko Kirin Co., Ltd., outside the submitted work. Yukio Kobayashi reports personal fees from Pfizer Japan Inc., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Daiichi Sankyo Co., Ltd., personal fees from CIMIC Co., Ltd., outside the submitted work. Hitoshi Kiyoi reports grants from Japan Agency for Medical Research and Development, during the conduct of the study; grants from Chugai Pharmaceutical Co. Ltd., grants and personal fees from Bristol-Myers Squibb K. K., grants from Kyowa Hakko Kirin Co. Ltd., grants from FUJIFILM Corporation, grants from Nippon Boehringer Ingelheim Co., Ltd., grants and personal fees from Astellas Pharma Inc., grants from Celgene K. K., personal fees from Daiichi Sankyo Co. Ltd., grants and personal fees from Pfizer Japan Inc., grants from Nippon Shinyaku Co. Ltd., grants from Eisai Co. Ltd., grants from Takeda Pharmaceutical Co. Ltd., grants from Ono Pharmaceutical Co. Ltd., grants from Japan Blood Products Organization, outside the submitted work. Yasushi Miyazaki reports personal fees from Sumitomo Dainippon Pharma Co., Ltd., grants and personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from Novartis Pharma K.K., personal fees from Celgene K. K., personal fees from Shinbio, grants from Chugai Pharmaceutical Co. Ltd., grants from Takeda Pharmaceutical Co. Ltd., outside the submitted work. Tomoki Naoe reports grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Fujifilm Corporation, grants from Astellas Pharma Inc., personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., grants from Toyoma Chemical Co., Ltd., outside the submitted work; In addition, TN has a patent Fujifilm Corporation pending. The other authors declare that they have no conflict of interest.

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Takahashi, N., Tauchi, T., Kitamura, K. et al. Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study. Int J Hematol 107, 185–193 (2018). https://doi.org/10.1007/s12185-017-2334-x

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