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Phase II study of tacrolimus and methotrexate for prophylaxis of acute graft-versus-host disease after HLA-A, B, and DRB1 genotypically mismatched unrelated bone marrow transplantation among Japanese patients

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Abstract

Bone marrow transplantation from unrelated donors (UR-BMT) has been considered to be effective for patients with hematological malignancies who have no suitable related donor. However, disparities of HLA between a recipient and a donor increase the risk of severe acute graft-versus-host disease (GVHD). We evaluated GVHD prophylaxis using tacrolimus and methotrexate for HLA-A, B, or DRB1 genotypically mismatched UR-BMT. Fifty-five patients were enrolled in this study. The incidence of grade III to IV acute GVHD was 23.6% for all patients. No significant difference in the incidence of grade III to IV acute GVHD was observed between HLA-A or B 1 locus mismatch transplantation (18.8%) and HLA-DRB1 1 locus mismatch transplantation (16.7%) (P = 0.96). The incidence of chronic GVHD was 71.7%. Disease-free survival at 5 years was 53.2% for patients with standard risk disease and 24.5% for patients with high-risk disease. Patients with chronic GVHD exhibited better disease-free survival than those without chronic GVHD (53.2 vs. 30.9%, P = 0.011). Twenty patients (36.4%) had a relapse of leukemia and 14 of them died of recurrent leukemia. This study indicates tacrolimus and methotrexate can lower the risk of severe acute GVHD after HLA-A, B, or DRB1 genotypically 1 locus mismatched UR-BMT.

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Acknowledgments

This study was supported by Health and Labour Sciences Research Grants, Research on Human Genome, Tissue Engineering, Ministry of Health, Labour and Welfare. We thank the physicians, nurses, and staff of the transplant centers who participated in this study, and the JMDP. We are also grateful to Center for Supporting Hematology–Oncology Trials (C-SHOT), to Ms. Ryouko Yamauchi for the data management, and to Ms. Haruko Nakamura and Ms. Yumi Ohashi for secretarial assistance.

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Authors and Affiliations

  1. Department of Internal Medicine, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Tetsuya Nishida & Yoshihisa Kodera

  2. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan

    Tetsuya Nishida

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

    Tohru Murayama

  4. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Hisamaru Hirai

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

    Shinichiro Okamoto

  6. Department of Hematology, Meitetsu Hospital, Nagoya, Japan

    Hiroshi Sao

  7. Division of Hematology, Ehime Prefectural Central Hospital, Matsuyama, Japan

    Masamichi Hara

  8. Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Heiwa Kanamori

  9. Department of Preventive Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta

  10. Division of Epidemiology and Prevention, Aichi Cancer Center, Nagoya, Japan

    Keitaro Matsuo

  11. Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan

    Yasuo Morishima

Authors
  1. Tetsuya Nishida
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  2. Tohru Murayama
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  3. Hisamaru Hirai
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  4. Shinichiro Okamoto
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  5. Hiroshi Sao
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  6. Masamichi Hara
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  7. Heiwa Kanamori
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  8. Yoshiko Atsuta
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  9. Keitaro Matsuo
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  10. Yasuo Morishima
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  11. Yoshihisa Kodera
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Corresponding author

Correspondence to Tetsuya Nishida.

Appendix

Appendix

Institutions participating in this study

First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan; Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan; Third Department of Internal Medicine, Akita University School of Medicine, Akita, Japan; Division of Hematology, Jichi Medical University, Tochigi, Japan; Department of Hematology, Dokkyo Medical School of Medicine, Tochigi, Japan; Division of Hematology, Saiseikai Maebashi Hospital, Maebashi, Japan; Division of Hematology, Second Department of Internal Medicine, Chiba University Graduate School of Medicine, Chiba, Japan; Division of Hematology, Chiba Municipal Hospital, Chiba, Japan; Hematology Division, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Department of Cell Therapy and Transplantation Medicine, University of Tokyo, Tokyo, Japan; Department of Hematology, Toranomon Hospital, Tokyo, Japan; Department of Hematology, Tokyo Women’s Medical University, Tokyo, Japan; Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan; Department of Hematology, Oncology and Rheumatology, Tokai University School of Medicine, Isehara, Japan; Department of Cellular Transplantation Biology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; Division of Hematology, Shizuoka General Hospital, Shizuoka, Japan; Division of Hematology, Department of Internal Medicine, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan; Department of Hematology, Meitetsu Hospital, Nagoya, Japan; Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan; First Department of Internal Medicine, Kansai Medical University, Osaka, Japan; Second Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan; Department of Transfusion Medicine, Hyogo College of Medicine, Nishinomiya, Japan; Division of Hematology and Oncology, Department of Medicine, Hyogo Medical Center for Adults, Akashi, Japan; Department of Hematology, Tenri Hospital, Tenri, Japan; Division of Hematology, Ehime Prefectural Central Hospital, Matsuyama, Japan.

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Nishida, T., Murayama, T., Hirai, H. et al. Phase II study of tacrolimus and methotrexate for prophylaxis of acute graft-versus-host disease after HLA-A, B, and DRB1 genotypically mismatched unrelated bone marrow transplantation among Japanese patients. Int J Hematol 89, 98–105 (2009). https://doi.org/10.1007/s12185-008-0219-8

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