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Use of unapproved or off-label drugs in Japan for the treatment of graft-versus-host disease and post-transplant viral infection

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Abstract

Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.

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Acknowledgements

The authors thank physicians and staffs at transplant centers for providing clinical data to the registry. They also thank staffs at the JDCHCT for data management. This study was funded in part by JSPS KAKENHI Grant Numbers 26860346 and 17K08911 from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Advanced Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan

    Yachiyo Kuwatsuka

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

    Yoshiko Atsuta

  3. Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta

  4. Division of Biostatistics and Data Science, Clinical Research Center, Tokyo Medical and Dental University, Tokyo, Japan

    Akihiro Hirakawa

  5. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospsital, Tokyo, Japan

    Naoyuki Uchida

  6. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

    Yoshihiro Inamoto & Takahiro Fukuda

  7. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Yuho Najima

  8. Department of Hematology, Hyogo College of Medicine Hospital, Nishinomiya, Japan

    Kazuhiro Ikegame

  9. Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan

    Tetsuya Eto

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

    Yukiyasu Ozawa & Koichi Miyamura

  11. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Tatsuo Ichinohe

  12. Department of Hematology/Oncology, Osaka Women’s and Children’s Hospital, Izumi, Japan

    Masami Inoue

  13. Preparation Department, Japanese Red Cross Kinki Block Blood Center, Ibaraki, Japan

    Takafumi Kimura

  14. Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

    Shinichiro Okamoto

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  1. Yachiyo Kuwatsuka
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Corresponding author

Correspondence to Yachiyo Kuwatsuka.

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Conflict of interest

YK reports grants from Japan Society for the Promotion of Science, during the conduct of the study; YA reports personal fees from Astellas Pharma Inc., Mochida Pharmaceutical Co., Ltd., Meiji Seika Pharma Co, Ltd., CHUGAI PHARMACEUTICAL CO., LTD., Kyowa Kirin Co., Ltd, Janssen Pharmaceutical K.K., outside the submitted work; AH reports grants and personal fees from Ono Pharmaceutical, personal fees from Astellas Pharma, Abbvie, Nippon Boehringer Ingelheim, Kissei Pharmaceutical, Pfizer, Nippon Shinyaku, Chugai Pharmaceutical, Taiho Pharmaceutical, Torii Pharmaceutical, Sumitomo Dainippon Pharma, Teijin Pharma, Fuji Pharma, Japan Tabacco, HEALIOS K.K, Life Science Institute, Inc., Novartis Japan, outside the submitted work; NU reports and personal fees from Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Otsuka Pharmaceeutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., and Novartis Pharma Inc, outside the submitted work; YI reports personal fees from Kyowa Kirin Co., Ltd, Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd., Novartis, outside the submitted work; YN received personal fees from Pfizer; YO reports personal fees from Pfizer Japan, Astellas Pharma, Novartis Pharma, Kyowa Hakko Kirin, outside the submitted work; TI reports grants from Chugai Pharmaceutical Co., Pfizer, Astellas Pharma, Zenyaku Kogyo Co., and personal fees from Novartis, outside the submitted work; SO reports grants from Asahi Kasei Pharma, Astellas, Eisai, Otsuka, Ono, Kyowa Kirin, Sanofi, Shionogi, Daiichi Sankyo, Takeda, Dainihon Sumitomo, Chugai, Teijin Pharma, Novartis, Mochida, JCR Pharma, Pfizer, personal fees from Astellas, Eisai, Otsuka, Ono, Kyowa Kirin, Sanofi, Daiichi Sankyo, Takeda, Chugai, Nihon Shinyaku, Novartis, BMS, Mochida, JCR Pharma, Pfizer, outside the submitted work; KM reports personal fees from Bristol-Myers Squibb, Novartis, Pfizer, Otsuka, Takeda, Kyowa-Hakko Kirin, Chugai, Astellas Pharmaceuticals, Celgene, Daiichi-Sankyo, Mochida, outside the submitted work. The other authors declare no competing financial interests regarding this paper.

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Kuwatsuka, Y., Atsuta, Y., Hirakawa, A. et al. Use of unapproved or off-label drugs in Japan for the treatment of graft-versus-host disease and post-transplant viral infection. Int J Hematol 112, 841–850 (2020). https://doi.org/10.1007/s12185-020-02972-0

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