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Early administration of cyclosporine may reduce the incidence of cytokine release syndrome after HLA-haploidentical hematopoietic stem-cell transplantation with post-transplant cyclophosphamide

Annals of Hematology volume 100, pages 1295–1301 (2021)Cite this article

Abstract

Cytokine release syndrome (CRS), occurring in more than 70% of HLA-haploidentical hematopoietic stem-cell transplantations with post-transplant cyclophosphamide (PT/CY-haplo), can lead to hemodynamic instability and worsen clinical outcomes. A calcineurin inhibitor is initiated after cyclophosphamide administration in the commonly used PT/CY regimens. Here, we conducted a phase I/II, prospective, single-center trial of PT/CY-haplo to evaluate the safety and efficacy of cyclophosphamide on days 3 and 5 along with cyclosporin and mycophenolate mofetil started from day − 1. Thirty-five adults with hematologic malignancies were enrolled. Myeloablative and reduced-intensity conditioning were used in 25 and 10 patients, respectively. Graft sources were bone marrow in 11 patients and mobilized peripheral blood stem cells in 24 patients. Disease-free survival on day 100, the primary endpoint, was 86% (95% confidence interval (CI), 69–94), which was over the predefined threshold of 50%. Unexpectedly, only 20% (95% CI, 8.4–37) of patients developed fever of > 38 °C early after graft infusion, all CRS grade 1, and all of which resolved just after cyclophosphamide administration. The cumulative incidences of grades II–IV acute graft-versus-host disease (GVHD), III–IV acute GVHD, and moderate-severe chronic GVHD were 23% (95% CI, 11–38), 6% (95% CI, 1–17), and 11% (95% CI, 4–25), respectively. The 3-year overall survival rate was 49% (95% CI, 31–64). Our results suggest that administration of cyclosporine and mycophenolate mofetil prior to PT/CY can reduce the frequency and severity of CRS without increasing GVHD. UMIN Clinical Trial Registry numbers: 000006631 and 000015694

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Bryan J. Mathis (Medical English Communications Center, University of Tsukuba) for grammatical review and advice.

Funding

This work was supported by Japan Agency for Medical Research and Development (AMED), under Grant Number JP15Aek0510005.

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Authors and Affiliations

  1. Department of Hematology, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8575, Japan

    Naoki Kurita, Tatsuhiro Sakamoto, Takayasu Kato, Manabu Kusakabe, Yasuhisa Yokoyama, Hidekazu Nishikii, Mamiko Sakata-Yanagimoto, Naoshi Obara, Yuichi Hasegawa & Shigeru Chiba

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  1. Naoki Kurita
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  2. Tatsuhiro Sakamoto
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  3. Takayasu Kato
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  6. Hidekazu Nishikii
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  7. Mamiko Sakata-Yanagimoto
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Contributions

NK designed and conducted the study, interpreted the data, and wrote the manuscript. TS, TK, MK, YY, HN, NO, MS-Y, and YH conducted the study and reviewed the manuscript. SC supervised the project, discussed data analysis, and reviewed the manuscript.

Corresponding author

Correspondence to Shigeru Chiba.

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Ethics approval and consent to participate

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. The study was approved by the Institutional Review Board of University of Tsukuba Hospital (approval #H23-081 and #H26-184). Informed consent was obtained from all individual participants included in the study.

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Kurita, N., Sakamoto, T., Kato, T. et al. Early administration of cyclosporine may reduce the incidence of cytokine release syndrome after HLA-haploidentical hematopoietic stem-cell transplantation with post-transplant cyclophosphamide. Ann Hematol 100, 1295–1301 (2021). https://doi.org/10.1007/s00277-021-04439-6

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  • DOI: https://doi.org/10.1007/s00277-021-04439-6

Keywords

  • Post-transplant cyclophosphamide
  • HLA-haploidentical transplantation
  • Cytokine release syndrome
  • Graft-versus-host disease