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Clinical effects of recombinant thrombomodulin and defibrotide on sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 54, pages 674–680 (2019)Cite this article

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Abstract

Sinusoidal obstruction syndrome (SOS) is a lethal complication after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is the only drug internationally recommended for SOS treatment in Western countries. Recombinant human soluble thrombomodulin (rhTM), which is promising for the treatment of patients with disseminated intravascular coagulation, is also reported to be potentially effective for SOS. To clarify the safety and efficacy of DF and rhTM, we conducted a retrospective survey of these agents in Japan. Data from 65 patients who underwent allogeneic HSCT and received DF (n  =  24) or rhTM (n  =  41) for SOS treatment were collected. The complete response rates for SOS on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100-day overall survival rates were 50% in the DF group, and 48% in the rhTM group. Several severe hemorrhagic adverse events were observed in one patient in the DF group and five patients in the rhTM group. The main causes of death were SOS-related death, and no patient died of direct adverse events of DF or rhTM. Our results suggest that rhTM, as well as DF, can be effective as a novel treatment option for SOS.

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Acknowledgements

We would like to thank all patients and their families in our study, the medical staffs in the participating centers, and collaborators Dr. Nozomu Kawashima (Nagoya University Hospital), Dr. Kai Yamasaki (Osaka City General Hospital), Dr. Yuichi Kato (Yamagata University Hospital), Dr. Hideo Yagi (Kindai University Nara Hospital), Dr. Shotaro Tatekawa (Konan Kosei Hospital), Dr. Taichi Ikebe (Oita University Hospital), and Dr. Yoshihisa Morishita (Konan Kosei Hospital).

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Authors and Affiliations

  1. Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan

    Kimikazu Yakushijin & Atsuo Okamura

  2. Department of Hematology, Fukushima Medical School, Fukushima, Japan

    Takayuki Ikezoe

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

    Chikako Ohwada

  4. Department of Pediatrics, Fujita Health University School of Medicine, Aichi, Japan

    Kazuko Kudo

  5. Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Hiroshi Okamura

  6. Division of Hemato-Oncology and Regenerative Medicine, Kanagawa Children’s Medical Center, Yokohama, Japan

    Hiroaki Goto

  7. Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan

    Hiromasa Yabe

  8. Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Atsushi Yasumoto

  9. Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan

    Hideyuki Kuwabara

  10. Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan

    Shiro Fujii & Kumiko Kagawa

  11. Department of Hematology, Oita University Hospital, Oita, Japan

    Masao Ogata

  12. Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan

    Yasushi Onishi

  13. Department of Hematology and Oncology, Konan Kosei Hospital, Aichi, Japan

    Akio Kohno & Koichi Watamoto

  14. Department of Hematology, Matsushita Memorial Hospital, Osaka, Japan

    Nobuhiko Uoshima

  15. Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan

    Daisuke Nakamura

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

    Shuichi Ota

  17. Department of Hematology/Oncology, Kurashiki Central Hospital, Kurashiki, Japan

    Yasunori Ueda

  18. Department of Hematology and Oncology, Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan

    Tatsuo Oyake

  19. Division of Pediatric Hematology and Oncology, Ibaraki Children’s Hospital, Mito, Japan

    Kazutoshi Koike

  20. Department of Hematology, Hyogo Cancer Center, Hyogo, Japan

    Ishikazu Mizuno

  21. Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Hiroatsu Iida

  22. Division of Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

    Yoshio Katayama

  23. Department of Hematology and Oncology, Shimane Prefectural Central Hospital, Izumo, Japan

    Hiroatsu Ago

  24. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Koji Kato

  25. Department of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan

    Atsushi Kikuta

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

    Takahiro Fukuda

Authors
  1. Kimikazu Yakushijin
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  13. Yasushi Onishi
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  16. Nobuhiko Uoshima
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  17. Daisuke Nakamura
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  19. Yasunori Ueda
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  20. Tatsuo Oyake
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  21. Kazutoshi Koike
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  22. Ishikazu Mizuno
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  23. Hiroatsu Iida
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  26. Koji Kato
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  27. Atsuo Okamura
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  28. Atsushi Kikuta
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  29. Takahiro Fukuda
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Corresponding author

Correspondence to Kimikazu Yakushijin.

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Conflict of interest

KY received honoraria from Asahi-kasei Pharma, JAZZ Pharmaceuticals, and Pfizer Inc. TI received grant/research support from Asahi-kasei Pharma. YU received research funding and travel expense fee from Kainos Laboratories Inc., Ablynx NV., and Eli Lilly Japan, outside submitted work. AK received grant/research support from JAZZ Pharmaceuticals and Nippon Shinyaku Co., Ltd. The remaining authors declare that they have no conflict of interest.

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Yakushijin, K., Ikezoe, T., Ohwada, C. et al. Clinical effects of recombinant thrombomodulin and defibrotide on sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 54, 674–680 (2019). https://doi.org/10.1038/s41409-018-0304-4

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