Skip to main content

Advertisement

SpringerLink
Log in

A comparison of tacrolimus and cyclosporine combined with methotrexate for graft-versus-host disease prophylaxis, stratified by stem cell source: a retrospective nationwide survey

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

This nationwide, retrospective study compared the efficacy of cyclosporine and tacrolimus with methotrexate (CsA/MTX and TAC/MTX) for acute graft-versus-host disease (aGVHD) prevention and transplant-related outcomes. Data were obtained from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation for ≥16-year-old leukemia patients who received CsA/MTX or TAC/MTX after bone marrow transplantation and peripheral blood stem cell transplantation from serological HLA-matched related donors (MRD), HLA 8/8 allele-matched, or one allele-mismatched unrelated bone marrow (UBM), or 0–2 antigen-mismatched unrelated cord blood (UCB) transplantation between January 2005 and December 2009. Separate analyses were performed for each cohort. Adjusted multivariate analyses indicated that in the MRD (n = 1524) and the UBM (n = 1466) cohorts, TAC/MTX significantly reduced grade II–IV aGVHD risk (HR 0.58, P = 0.006 and HR 0.77, P = 0.015, respectively) without affecting the other transplant-related outcomes. In the UCB cohort (n = 925), TAC/MTX significantly reduced the risk of non-relapse mortality (HR 0.63, P = 0.027) and chronic GVHD (HR 0.60, P = 0.02) without significant effects on grade II–IV aGVHD (HR 0.83, P = 0.21). Our results may provide the most up-to-date data regarding GVHD prevention in Japan.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998;92:2303–14.

    CAS  PubMed  Google Scholar 

  2. Horowitz MM, Przepiorka D, Bartels P, Bartels P, Buell DN, Zhang MJ, et al. Tacrolimus vs. cyclosporine immunosuppression: results in advanced-stage disease compared with historical controls treated exclusively with cyclosporine. Biol Blood Marrow Transplant. 1999;5:180–6.

    Article  CAS  PubMed  Google Scholar 

  3. Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000;96:2062–8.

    CAS  PubMed  Google Scholar 

  4. Hiraoka A, Ohashi Y, Okamoto S, Moriyama Y, Nagao T, Kodera Y, et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2001;28:181–5.

    Article  CAS  PubMed  Google Scholar 

  5. Yanada M, Emi N, Naoe T, Sakamaki H, Takahashi S, Hirabayashi N, et al. Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan. Bone Marrow Transplant. 2004;34:331–7.

    Article  CAS  PubMed  Google Scholar 

  6. Morishima Y, Sasazuki T, Inoko H, Juji T, Akaza T, Yamamoto K, et al. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002;99:4200–6.

    Article  CAS  PubMed  Google Scholar 

  7. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110:4576–83.

    Article  CAS  PubMed  Google Scholar 

  8. Kanda Y, Kanda J, Atsuta Y, Maeda Y, Ichinohe T, Ohashi K, et al. Impact of a single human leucocyte antigen (HLA) allele mismatch on the outcome of unrelated bone marrow transplantation over two time periods. A retrospective analysis of 3003 patients from the HLA working group of the Japan society for blood and marrow transplantation. Br J Haematol. 2013;161:566–77.

    Article  CAS  PubMed  Google Scholar 

  9. Kanda Y, Kanda J, Atsuta Y, Fuji S, Maeda Y, Ichinohe T, et al. Changes in the clinical impact of high-risk human leukocyte antigen allele mismatch combinations on the outcome of unrelated bone marrow transplantation. Biol Blood Marrow Transplant. 2014;20:526–35.

    Article  CAS  PubMed  Google Scholar 

  10. Atsuta Y, Morishima Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S, et al. Comparison of unrelated cord blood transplantation and HLA-mismatched unrelated bone marrow transplantation for adults with leukemia. Biol Blood Marrow Transplant. 2012;18:780–7.

    Article  PubMed  Google Scholar 

  11. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP system. Int J Hematol. 2007;86:269–74.

    Article  PubMed  Google Scholar 

  12. Klein JP, Rizzo JD, Zhang MJ, Keiding N. Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part I: unadjusted analysis. Bone Marrow Transplant. 2001;28:909–15.

    Article  CAS  PubMed  Google Scholar 

  13. Gray RJ. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Statist. 1988;16:1141–54.

    Article  Google Scholar 

  14. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  15. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1994;15:825–8.

    Google Scholar 

  16. Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol. 1991;28:250–9.

    CAS  PubMed  Google Scholar 

  17. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15:367–9.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628–33.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Inamoto Y, Flowers ME, Appelbaum FR, Carpenter PA, Deeg HJ, Furlong T, et al. A retrospective comparison of tacrolimus versus cyclosporine with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation with mobilized blood cells. Biol Blood Marrow Transplant. 2011;17:1088–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Nishida T, Murayama T, Hirai H, Okamoto S, Sao H, Hara M, 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. 2009;89:98–105.

    Article  CAS  PubMed  Google Scholar 

  21. Kanda J, Nakasone H, Atsuta Y, Toubai T, Yokoyama H, Fukuda T, et al. Risk factors and organ involvement of chronic GVHD in Japan. Bone Marrow Transplant. 2014;49:228–35.

    Article  CAS  PubMed  Google Scholar 

  22. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351:2276–85.

    Article  CAS  PubMed  Google Scholar 

  23. Kishi Y, Kami M, Miyakoshi S, Kanda Y, Murashige N, Teshima T, et al. Early immune reaction after reduced-intensity cord-blood transplantation for adult patients. Transplantation. 2005;80:34–40.

    Article  PubMed  Google Scholar 

  24. Uchida N, Wake A, Takagi S, Yamamoto H, Kato D, Matsuhashi Y, et al. Umbilical cord blood transplantation after reduced-intensity conditioning for elderly patients with hematologic diseases. Biol Blood Marrow Transplant. 2008;14:583–90.

    Article  PubMed  Google Scholar 

  25. Miyakoshi S, Kami M, Tanimoto T, Yamaguchi T, Narimatsu H, Kusumi E, et al. Tacrolimus as prophylaxis for acute graft-versus-host disease in reduced intensity cord blood transplantation for adult patients with advanced hematologic diseases. Transplantation. 2007;84:316–22.

    Article  CAS  PubMed  Google Scholar 

  26. Narimatsu H, Terakura S, Matsuo K, Oba T, Uchida T, Iida H, et al. Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults. Bone Marrow Transplant. 2007;39:31–9.

    Article  CAS  PubMed  Google Scholar 

  27. Kanda J, Kaynar L, Kanda Y, Prasad VK, Parikh SH, Lan L, et al. Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment. Bone Marrow Transplant. 2013;48:926–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Kanda Y, Hyo R, Yamashita T, Fujimaki K, Oshima K, Onoda M, et al. Effect of blood cyclosporine concentration on the outcome of hematopoietic stem cell transplantation from an HLA-matched sibling donor. Am J Hematol. 2006;81:838–44.

    Article  CAS  PubMed  Google Scholar 

  29. Oshima K, Kanda Y, Nakasone H, Arai S, Nishimoto N, Sato H, et al. Decreased incidence of acute graft-versus-host disease by continuous infusion of cyclosporine with a higher target blood level. Am J Hematol. 2008;83:226–32.

    Article  CAS  PubMed  Google Scholar 

  30. Bensinger W. Individual patient data meta-analysis of allogeneic peripheral blood stem cell transplant vs bone marrow transplant in the management of hematological malignancies: indirect assessment of the effect of day 11 methotrexate administration. Bone Marrow Transplant. 2006;38:539–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Mori T, Kato J, Shimizu T, Aisa Y, Nakazato T, Yamane A, et al. Effect of early posttransplantation tacrolimus concentration on the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from unrelated donors. Biol Blood Marrow Transplant. 2012;18:229–34.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank all of the physicians and data managers who provided valuable transplantation data to the Japan Society for Hematologic Cell Transplantation, the Japan Cord Blood Bank Network, and the Japan Marrow Donor Program. We also thank all members of the data management committees of the above-mentioned centers for their assistance.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-0815, Japan

    Rika Sakai

  2. Department of Biostatistics and Epidemiology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan

    Masataka Taguri & Satoshi Morita

  3. Division of Hematology and Oncology, St. Luke International Hospital, Tokyo, Japan

    Kumi Oshima

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

    Takehiko Mori

  5. Division of Hematology and Oncology, Shimane Prefectural Central Hospital, Matsue, Japan

    Hiroatsu Ago

  6. Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Souichi Adachi

  7. Department of Hematology, Toranomon Hospital, Tokyo, Japan

    Shuichi Taniguchi

  8. Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

    Takahiro Fukuda

  9. Division of Hematology, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan

    Kazuteru Ohashi & Tokiko Nagamura-Inoue

  10. Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan

    Tetsuya Eto

  11. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Koichi Miyamura

  12. Department of Hematology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan

    Koji Iwato

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

    Naoki Kobayashi

  14. Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan

    Heiwa Kanamori

  15. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan

    Yasuo Morishima

  16. Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Hisashi Sakamaki

  17. Department of Hematopoietic Stem Cell Transplantation Data Management and Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta

  18. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Makoto Murata

Authors
  1. Rika Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masataka Taguri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kumi Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takehiko Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroatsu Ago
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Souichi Adachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Satoshi Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shuichi Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takahiro Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kazuteru Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tetsuya Eto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Koichi Miyamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Koji Iwato
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Naoki Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Heiwa Kanamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yasuo Morishima
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Tokiko Nagamura-Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hisashi Sakamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Yoshiko Atsuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Makoto Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rika Sakai.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

On behalf of the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sakai, R., Taguri, M., Oshima, K. et al. A comparison of tacrolimus and cyclosporine combined with methotrexate for graft-versus-host disease prophylaxis, stratified by stem cell source: a retrospective nationwide survey. Int J Hematol 103, 322–333 (2016). https://doi.org/10.1007/s12185-016-1939-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-016-1939-9

Keywords

Search

Navigation