Original Article | Published:

Acute lymphoblastic leukemia

High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG

Leukemia volume 32, pages 626632 (2018) | Download Citation


High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

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We thank Masayuki Towatari MD, PhD, Itsuro Jinnai MD, PhD, Daisuke Imanishi MD, PhD and all physicians and staff at the participating centers. We also thank Manami Kira, Midori Fukushima, Saki Amano and Yuko Makino for their secretarial assistance. This work was supported in part by MHLW KAKENHI, MEXT KAKENHI for Programs for Development of Innovative Research on Cancer Therapeutics (P-DIRECT), AMED KAKENHI for Practical Research for Innovative Cancer Control, the National Cancer Center Research and Development Fund (23-A-23) and a grant from the Nonprofit Organization for Support Japan Adult Leukemia Study Group (NPO-JALSG).

Author information


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

    • T Sakura
  2. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    • F Hayakawa
    •  & H Kiyoi
  3. Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan

    • I Sugiura
  4. Department of Hematology, Hyogo Cancer Center, Akashi, Japan

    • T Murayama
  5. Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan

    • K Imai
  6. Department of Clinical Oncology and Hematology, The Jikei University School of Medicine, Tokyo, Japan

    • N Usui
  7. Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan

    • S Fujisawa
  8. Faculty of Medical Sciences, Department of Hematology and Oncology, University of Fukui, Yoshida, Japan

    • T Yamauchi
  9. Third Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Japan

    • T Yujiri
  10. Hematology Division, Tokyo Metropolitan Cancer and Infectious diseases Center, Komagome Hospital, Tokyo, Japan

    • K Kakihana
  11. Department of Hematology, Tokyo Medical University, Tokyo, Japan

    • Y Ito
  12. Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan

    • H Kanamori
  13. Department of Hematology/Oncology, Kurashiki Central Hospital, Kurashiki, Japan

    • Y Ueda
  14. Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    • Y Miyata
  15. Department of Hematology and Oncology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    • M Kurokawa
  16. Department of Hematology, Saitama Medical University International Medical Center, Hidaka, Japan

    • N Asou
  17. Japanese Red Cross Aichi Blood Center, Seto, Japan

    • K Ohnishi
  18. Department of Clinical Laboratory Science, Kanazawa University, Kanazawa, Japan

    • S Ohtake
  19. Department of Hematology and Oncology, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan

    • Y Kobayashi
  20. Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan

    • K Matsuo
  21. Department of Hematology and Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    • Y Miyazaki
  22. National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    • T Naoe


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Competing interests

Employment: TS (Astellas Pharma) and MK (Celgene, Shionogi, Daiichi Sankyo Foundation of Life Science). Consultancy: TS (Astellas Pharma), NU (CIMIC, Takeda Bio Development Center, Lilly Japan, Pfizer, Nippon Boehiringer-Ingleheim, Sysmex, Janssen, Zenyaku Kogyo, Kyowa hakko Kirin, Astellas Pharma, Otsuka Pharmaceutical, Celgene, SymBio Phrmaceuticals, Huya Bioscience International), YK (Boehiringer-Ingleheim, Novartis), H Kiyoi (Daiichi Sankyo, Celgene, Astellas Pharma, Quintiles), Y Miyazaki (Otsuka, Shire) and TN (Astellas Pharma, Otsuka Pharmaceutical Factory, Fujifilm, Nippon Boehiringer-Ingleheim, Celgene, Dainippon Sumitomo Pharma, Kyowa Hakko Kirin, Pfizer, Toyama Chemical). Stock Ownership: none. Honoraria: FH (Nippon Shinyaku, Dainippon Sumitomo Pharma, Asahi Kasei, Kyowa hakko Kirin, Meiji Seika Pharma), TM (Kyowa Hakko Kirin, Nippon Shinyaku, Taiho Pharmaceutical, Janssen, Siemens, Novartis, Celgene, Ono Pharmaceutical, Pfizer, Bristol-Myers Squibb, Eisai), NU (Chugai Pharmaceutical, Bristol-Myers Squibb, Pfizer, Kyowa Hakko Kirin), SF (Bristol-Myers Squibb, Chugai Pharmaceutical, Celgene, Takeda Pharmaceuticals, Ono Phamaceutical, Pfizer, Alexion Phamaceutical, Shire plc, SHIONOGI CO., LTD, Otsuka Phamaceutical, Sumitomo Dainippon Pharma, Nippon Shinyaku, Astellas Pharma, Novartis, Janssen Pharmaceutical, Eisai, Beckman Coulter), KK (Chugai Pharma, Bristol-Myers Squibb, Kyowa Hakko Kirin, Dainippon Sumitomo Pharma, Celgene), YI (Kyowa Hakko Kirin), H Kanamori (Novartis, Chugai Pharma, Kyowa Hakko Kirin), MK (Kagakuhyoronsha, Nankodo, MSD, Kyowa Hakko Kirin, Ketsuekijohohiroba Tsubasa, Nippon Shinyaku, Yakult, Pfizer, Hokuryukan, Shire, Daiichi Sankyo, New Science, Ono Pharmaceutical, Dainippon Sumitomo Pharma, Celgene, Bristol-Myers Squibb, Takeda), H Kiyoi (Kyowa Hakko Kirin, Pfizer, Shire, Ono Pharmaceutical, Dainippon Sumitomo Pharma, Celgene, Bristol-Myers Squibb, Takeda, Astellas Pharma, Mochida Pharmaceutical, Chugai Pharma, Fujifilm, Alexion Pharmaceuticals, Nippon Kayaku, Sysmex, Amgen Astellas Biopharma, Novartis, Otsuka), Y Miyazaki (Kyowa Hakko Kirin, Celgene, Nippon Shinyaku, Chugai Pharma, Astellas Pharma) and TN (Nippon Boehiringer-Ingleheim, Chugai Pharma, Dainippon Sumitomo Pharma, Kyowa Hakko Kirin, Sysmex, Amgen Astellas Biopharma, Alexion Pharmaceuticals, Daiichi Sankyo, Agios, Eisai). Research Funding: TS (Otsuka Pharmaceutical Factory), NU (Bristol-Myers Squibb, Novartis, Nippon Shinyaku, Fujimoto Pharmaceutical, Celgene, Pfizer), SF (Otsuka Pharmaceutical, Kyowa Hakko Kirin, Ono Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical, Pfizer, SHIONOGI CO., LTD, Nippon Shinyaku, Astellas Pharma, MSD), MK (Teijin Pharma, Pfizer, MSD, Toyama Chemical, Astellas Pharma, Kyowa Hakko Kirin, Chugai Pharma), NA (Toyama Chemical, Chugai Pharma), YK (Otsuka Pharmaceutical, Pfizer, Takeda, Astellas Pharma, Daiichi Sankyo) and H Kiyoi (Kyowa Hakko Kirin, Pfizer, Dainippon Sumitomo Pharma, Takeda, Astellas Pharma, Mochida Pharmaceutical, Chugai Pharma, Fujifilm, Alexion Pharmaceuticals, Novartis, Nippon Boehiringer-Ingleheim, Toyama Chemical, Zenyaku Kogyo, Nippon Shinyaku, Yakult, Eisai, MSD, JCR Pharma, Meiji Seika Pharma).Expert Testimony: none. Other potential financial relationships: none.

Corresponding author

Correspondence to F Hayakawa.

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