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Switching to nilotinib is associated with deeper molecular responses in chronic myeloid leukemia chronic phase with major molecular responses to imatinib: STAT1 trial in Japan

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Abstract

The purpose of this clinical trial was to evaluate the efficacy of 2-year consolidation therapy using nilotinib (NIL) for achieving a molecular response (MR4.5, BCR-ABL1IS ≤ 0.0032% on the International Scale) in patients with chronic myeloid leukemia in the chronic phase (CML-CP) who had achieved a major molecular response (MMR, BCR-ABL1IS ≤ 0.1%) with imatinib (IM). We recruited 76 Japanese patients for this trial. Nilotinib 300 mg, twice daily, was administered for 2 years, and 74 patients were evaluated in the study. The median age was 55.0 years. The median duration of IM treatment was 69.0 months. All patients showed MMR at the time of entry into the study; the median time to MMR on IM therapy was 20.4 months. The proportion of patients who achieved MR4.5 increased over time. The rates of MR4.5 in the 74 evaluable patients were 27.0% [90% confidence interval (CI) (18.7–36.8%)] and 44.6% [90% CI (34.7–54.8%)] at 12 and 24 months, respectively. The frequency of ABCG2 421C/A + A/A was an independent predictive biomarker for achieving a 24-month MR4.5. Switching to NIL led to safer, deeper molecular responses in patients with MMR on long-term IM therapy for future treatment-free remission.

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Acknowledgements

This study was supported by research funding from Novartis Pharmaceuticals to N.T. The authors thank all study participants and their families. We also thank Ms. Saori Takahashi and the STAT data center (EPS, Co.) for monitoring the clinical trial, and Dr. Toshihiro Miyamoto, Dr. Yosuke Minami, and Dr. Hidetaka Niitsu for cooperation as members of the data and safety monitoring committee, and all investigators in the STAT study group. The STAT study group (46 institutions and investigators): Akita University Hospital, Dr. Naoto Takahashi; Asahi Hospital, Dr. Masayuki Koizumi; Asahikawa Medical University Hospital, Dr. Motohiro Shindo; Chiba Aoba Municipal Hospital, Dr. Akira Yokota; Chiba Rosai Hospital, Dr. Kenji Kimura; Chiba University Hospital, Dr. Chiaki Nakaseko; Chibaken Saiseikai Narashino Hospital, Dr. Kazuhisa Fujikawa; Dokkyo Medical University Hospital, Dr. Kinuko Mitani; Eiju Hospital, Dr. Masao Hagihara; Fukushima Medical University Hospital, Dr. Hideki Noji; Gumna prefectural Cancer Center, Dr. Tadahiko Igarashi; Gunma University Hospital, Dr. Hiroshi Handa; Hokkaido University Hospital, Dr. Takeshi Kondo; Inoue Memorial Hospital, Dr. Hirotoshi Nakamura; Japanese Red Cross Narita Hospital, Dr. Hisashi Wakita; Jikei University Kashiwa Hospital, Dr. Kaichi Nishiwaki; Jikei University The Third Hospital, Dr. Noriko Usui; Juntendo University Urayasu Hospital, Dr. Masaaki Noguchi; Kameda Medical Center, Dr. Kosei Matsue; Kurokawa Hospital, Dr. Hironao Yokomichi; Mie University Hospital, Dr. Kohshi Ohishi; National Defense Medical College Hospital, Dr. Fumihiko Kimura; Nihonkai General Hospital, Dr. Soichi Saito; Niigata University Hospital, Dr. Masayoshi Masuko; Northern Fukushima Medical Center, Dr. Hideo Kimura; NTT Medical Center Tokyo, Dr. Kensuke Usuki; Odate Municipal General Hospital, Dr. Hitoshi Ogasawara; Okitama Public General Hospital, Dr. Shinji Sato; Omagari Kosei Medical Center, Dr. Mutsuhito Motegi; Saitama Medical Center, Saitama Medical University, Dr. Michihide Tokuhira; Sapporo City General Hospital, Dr. Satoshi Yamamoto; Sapporo Hokuyu Hospital, Dr. Kiyotoshi Imai; Sapporo Medical University Hospital, Dr. Tsutomu Sato; Sendai City Hospital, Dr. Joji Yamamoto; Sendai Medical Center, Dr. Toshiyuki Yokoyama; Shirakawa Kosei General Hosptal, Dr. Masayuki Mita; The Fraternity Memorial Hospital, Dr. Sakae Tanozaki; Tohoku University Hospital, Dr. Hideo Harigae; Tokyo Medical and Dental University Hospital, Dr. Tetsuya Fukuda; Tokyo Medical University Hachioji Medical Center, Dr. Osamu Iwase; Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Dr. Noriko Doki; Tokyo Women’s Medical University Yachiyo Medical Center, Dr. Michihiko Masuda; Yamagata Prefectural Central Hospital, Dr. Eijiro Omoto; Yamagata University Hospital, Dr. Yuichi Kato; Yamanashi University Hospital, Dr. Toru Mitsumori; Yuri General Hospital, Dr. Jun Kuroki.

Author information

Authors and Affiliations

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

    Shinsuke Noguchi & Naoto Takahashi

  2. Department of Hematology, International University of Health and Welfare School of Medicine, Narita, Japan

    Chiaki Nakaseko

  3. Department of Hematology, Chiba University Hospital, Chiba, Japan

    Chiaki Nakaseko

  4. Department of Oncology and Hematology, Jikei University Kashiwa Hospital, Kashiwa, Japan

    Kaichi Nishiwaki

  5. Department of Hematology and Oncology, Odate Municipal Hospital, Odate, Japan

    Hitoshi Ogasawara

  6. Department of Transfusion Service, Mie University Hospital, Tsu, Japan

    Kohshi Ohishi

  7. Department of Hematology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

    Michihide Tokuhira

  8. Department of Hematology, Juntendo University Urayasu Hospital, Urayasu, Japan

    Masaaki Noguchi

  9. Department of Hematology, Northern Fukushima Medical Center, Date, Japan

    Hideo Kimura

  10. Department of Hematology, Gunma University Hospital, Maebashi, Japan

    Hiroshi Handa

  11. Department of Hematology and Oncology, Dokkyo Medical University, Mibu-machi, Japan

    Kinuko Mitani

  12. Department of Pharmacy, Akita University Hospital, Akita, Japan

    Masatomo Miura

  13. Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Narita, Japan

    Hisashi Wakita

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  1. Shinsuke Noguchi
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  2. Chiaki Nakaseko
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  7. Masaaki Noguchi
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  8. Hideo Kimura
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  13. Naoto Takahashi
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Consortia

the STAT study group

  • Naoto Takahashi
  • , Masayuki Koizumi
  • , Motohiro Shindo
  • , Akira Yokota
  • , Kenji Kimura
  • , Chiaki Nakaseko
  • , Kazuhisa Fujikawa
  • , Kinuko Mitani
  • , Masao Hagihara
  • , Hideki Noji
  • , Tadahiko Igarashi
  • , Hiroshi Handa
  • , Takeshi Kondo
  • , Hirotoshi Nakamura
  • , Hisashi Wakita
  • , Kaichi Nishiwaki
  • , Noriko Usui
  • , Masaaki Noguchi
  • , Kosei Matsue
  • , Hironao Yokomichi
  • , Kohshi Ohishi
  • , Fumihiko Kimura
  • , Soichi Saito
  • , Masayoshi Masuko
  • , Hideo Kimura
  • , Kensuke Usuki
  • , Hitoshi Ogasawara
  • , Shinji Sato
  • , Mutsuhito Motegi
  • , Michihide Tokuhira
  • , Satoshi Yamamoto
  • , Kiyotoshi Imai
  • , Tsutomu Sato
  • , Joji Yamamoto
  • , Toshiyuki Yokoyama
  • , Masayuki Mita
  • , Sakae Tanozaki
  • , Hideo Harigae
  • , Tetsuya Fukuda
  • , Osamu Iwase
  • , Noriko Doki
  • , Michihiko Masuda
  • , Eijiro Omoto
  • , Yuichi Kato
  • , Toru Mitsumori
  •  & Jun Kuroki

Corresponding author

Correspondence to Naoto Takahashi.

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Conflict of interest

N.T received grants from Novartis Pharmaceuticals, during the conduct of the study; grants and personal fees from Novartis Pharmaceuticals, grants and personal fees from Otsuka, grants and personal fees from Pfizer, personal fees from Bristol-Myers Squibb, outside the submitted work; C.N received personal fees from Novartis, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Pfizer, grants and personal fees from Takeda pharmaceuticals, grants and personal fees from Kyowa Hakko Kirin, grants and personal fees from Otsuka Pharmaceutical, grants and personal fees from Ono Pharmaceutical, grants and personal fees from Chugai Pharmaceutical, grants and personal fees from Asahi Kasei Pharma, grants and personal fees from Shionogi, personal fees from Shire, personal fees from Jannsen, personal fees from Celgene, outside the submitted work; K.N received grants from Zenyaku Kogyo Company, Limited, grants from Chugai Pharmaceutical, grants from Novartis Pharma K.K., grants from Kyowa Hakko Kirin Co, Ltd, grants from Nippon Shinyaku Co, Ltd, outside the submitted work; M.T. received personal fees from Bristol-Myers Squib, personal fees from Pfizer, outside the submitted work; K.M received grants from Kyowa Hakko Kirin Co. Ltd., grants from Chugai Pharmaceutical Co. Ltd., grants from Takeda Pharmaceutical Co. Ltd., grants from Novartis Pharma K. K., personal fees from Kyowa Hakko Kirin Co. Ltd., personal fees from Celgene Co., personal fees from Pfizer Inc., personal fees from Alexion Pharmaceuticals Inc., personal fees from BML Inc., personal fees from Shire Japan K.K., personal fees from Bristol-Myers Squibb K.K., personal fees from Abbvie Inc., personal fees from Mochida Pharmaceutical Co. Ltd., personal fees from Novartis Pharma K. K., personal fees from Takeda Pharmaceutical Co. Ltd., personal fees from Kyowa Hakko Kirin Co. Ltd., personal fees from Ono Pharmaceutical Co. Ltd., personal fees from Nippon Shinyaku Co. Ltd., outside the submitted work. The other authors declare that they have no conflicts of interest.

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Noguchi, S., Nakaseko, C., Nishiwaki, K. et al. Switching to nilotinib is associated with deeper molecular responses in chronic myeloid leukemia chronic phase with major molecular responses to imatinib: STAT1 trial in Japan. Int J Hematol 108, 176–183 (2018). https://doi.org/10.1007/s12185-018-2459-6

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  • DOI: https://doi.org/10.1007/s12185-018-2459-6

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