Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis

Abstract

Posttransplant high-dose cyclophosphamide (PTCY) has been increasingly used as graft-versus-host disease (GVHD) prophylaxis after HLA-haploidentical or matched hematopoietic stem cell transplantation (SCT). However, PTCY alone is insufficient and requires additional immunosuppressants such as calcineurin inhibitors. In the current study, we evaluated effects of a novel GVHD prophylaxis with PTCY in combination with short-term KRP203, a selective agonist of sphingosine-1-phosphate receptor 1 that regulates egress of lymphocytes from the secondary lymphoid organs (SLOs) in mice. Short-term oral administration of KRP203 alone induced apoptosis of donor T cells in the SLOs and ameliorated GVHD. Administration of KRP203 significantly preserved graft-versus-leukemia effects compared to cyclosporin. A combination of KRP203 on days 0 to +4 and PTCY on day +3 synergistically suppressed donor T-cell migration into the intestine and skin, and ameliorated GVHD more potently than PTCY alone. A combination of short-term KRP203 and PTCY is a promising novel calcineurin-free GVHD prophylaxis in HLA-haploidentical SCT.

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Acknowledgements

This study was supported by JSPS KAKENHI (17K19641 and 17H04206 to TT, 17K09945 to DH), Japan Society of Hematology Research Fund (TT), the Center of Innovation Program from JST (TT), and research grants from the Mochida Memorial Foundation for Medical and Pharmaceutical Research (DH).

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Correspondence to Daigo Hashimoto or Takanori Teshima.

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TT is a consultant of Novartis Pharma AG and received a research grant from Novartis Pharma AG.

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Yokoyama, E., Hashimoto, D., Hayase, E. et al. Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis. Bone Marrow Transplant (2019). https://doi.org/10.1038/s41409-019-0733-8

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