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Improved survival after single-unit cord blood transplantation using fludarabine and melphalan-based reduced-intensity conditioning for malignant lymphoma: impact of melphalan dose and graft-versus-host disease prophylaxis with mycophenolate mofetil

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Abstract

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m2) and FM140 (melphalan dose: 140 mg/m2), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.

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For anonymized clinical data without patient sensitive information, please contact the corresponding author with reasonable request.

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Funding

This work was supported by a grant from the National Cancer Research and Development Fund (2020-A-15).

Author information

Authors and Affiliations

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

    Kazuki Sakatoku & Hiroshi Okamura

  2. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Sung-Won Kim & Takahiro Fukuda

  3. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

    Minoru Kanaya

  4. Department of Hematology, Hokkaido University Hospital, Sapporo, Japan

    Minoru Kanaya

  5. Hematology, Oncology & Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan

    Koji Kato & Toshihiro Miyamoto

  6. Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan

    Satoshi Yamasaki

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

    Naoyuki Uchida

  8. Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan

    Hikaru Kobayashi

  9. Department of Hematology, Kyorin University Faculty of Medicine, Tokyo, Japan

    Nobuyuki Takayama

  10. Department of Hematology, Osaka International Cancer Institute, Osaka, Japan

    Jun Ishikawa

  11. Department of Hematology, Shinshu University School of Medicine, Matsumoto, Japan

    Hideyuki Nakazawa

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

    Masatoshi Sakurai

  13. Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, Shizuoka, Japan

    Takashi Ikeda

  14. Department of Hematology, Kyoto University Hospital, Kyoto, Japan

    Tadakazu Kondo

  15. Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan

    Satoshi Yoshioka

  16. Preparation Department, Japanese Red Cross Kinki Block Blood Center, Osaka, Japan

    Takafumi Kimura

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

    Tatsuo Ichinohe

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

    Yoshiko Atsuta

  19. Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan

    Yoshiko Atsuta

  20. Department of Hematology, Kawasaki Medical School, Kurashiki, Japan

    Eisei Kondo

Authors
  1. Kazuki Sakatoku
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  2. Sung-Won Kim
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  4. Minoru Kanaya
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Contributions

K.S. designed the research, analyzed the data, performed the statistical analysis, and wrote the first draft of the manuscript. S.W.K. designed the research and contributed to the critical review of the manuscript. H.O. analyzed the data and performed the statistical analysis. M.K., K.K., and S.Y. contributed to the critical review of the manuscript. All the other authors contributed to data collection. All authors approved the final version.

Corresponding author

Correspondence to Sung-Won Kim.

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Ethics approval

This study was approved by the data management committee of the Japanese Society for Transplantation and Cellular Therapy and by the institutional review board of Osaka City University (Osaka, Japan). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate

The Transplant Registry Unified Management Program (TRUMP) database of the Japanese Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation includes physician-reviewed data. Observational studies based on the TRUMP database are performed with informed consent.

Competing interests

K.K. received honoraria from MSD K.K., Chugai Pharmaceutical Co., Ltd. N.T. received honoraria from Chugai Pharmaceutical Co., Ltd. and Pfizer Inc., Sanofi S.A., and research funding from Chugai Pharmaceutical Co., Ltd. The remaining authors declare no competing financial interests.

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Sakatoku, K., Kim, SW., Okamura, H. et al. Improved survival after single-unit cord blood transplantation using fludarabine and melphalan-based reduced-intensity conditioning for malignant lymphoma: impact of melphalan dose and graft-versus-host disease prophylaxis with mycophenolate mofetil. Ann Hematol 101, 2743–2757 (2022). https://doi.org/10.1007/s00277-022-04990-w

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