Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Post-transplant cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil compared to anti-thymocyte globulin, calcineurin inhibitor, and methotrexate combinations as graft-versus-host disease prophylaxis post allogeneic stem cell transplantation from sibling and unrelated donors in patients with acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Bone Marrow Transplantation volume 59, pages 1012–1021 (2024)Cite this article

Subjects

Abstract

Post-transplant cyclophosphamide plus calcineurin inhibitor (CNI)(tacrolimus or cyclosporine A) plus mycophenolate mofetil (PTCy/TAC or CSA/MMF) and anti-thymocyte globulin plus CNI (tacrolimus or cyclosporine A) plus methotrexate (ATG/TAC or CSA/MTX) are common graft-versus-host disease (GVHD) prophylaxis regimens. We compared the two regimens in patients with acute myeloid leukemia (AML) undergoing allogeneic transplantation from matched siblings or unrelated donors. 402 received PTCy/TAC or CSA/MMF and 5648 received ATG/TAC or CSA/MTX. Patients in the PTCy-based group were younger (48.7 vs. 51.5 years, p = 0.024) and there was a higher frequency of patient cytomegalovirus seropositivity and female donor to male patient combination in this group (77.8% vs. 71.8%, p = 0.009 and 18.4% vs. 14.4%, p = 0.029, respectively). More patients in the PTCy-based group received reduced-intensity conditioning (51.5% vs. 41%, p < 0.0001). No differences were observed in the incidence of acute GVHD grade II–IV and III–IV (21.2% vs. 20.4%, p = 0.92 and 8.1% vs. 6%, p = 0.1) or 2-year total and extensive chronic GVHD (33.7% vs. 30%, p = 0.09 and 10.7% vs. 11.2%, p = 0.81) between the groups. In the multivariate analysis, all transplant outcomes did not differ between the groups. PTCy/CNI/MMF and ATG/CNI/MTX are alternative regimens for GVHD prophylaxis in AML patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

AN, ML, FC, and MM had full access to all study data (available upon data-specific request).

References

  1. Zeiser R, Blazar BR. Acute graft-versus-host disease—biologic process, prevention, and therapy. N. Engl J Med. 2017;377:2167–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Malard F, Holler E, Sandmaier BM, Huang H, Mohty M. Acute graft-versus-host disease. Nat Rev Dis Prim. 2023;9:27.

    PubMed  Google Scholar 

  3. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N. Engl J Med. 2017;377:2565–79.

    CAS  PubMed  Google Scholar 

  4. Penack O, Marchetti M, Aljurf M, Arat M, Bonifazi F, Duarte RF, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2024;11:e147–e159.

  5. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, et al. ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855–64.

    CAS  PubMed  Google Scholar 

  6. Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001;98:2942–7.

    CAS  PubMed  Google Scholar 

  7. Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Cell Therapy Transplant Canada. Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2020;7:e100–e111.

    PubMed  Google Scholar 

  8. Soiffer RJ, Kim HT, McGuirk J, Horwitz ME, Johnston L, Patnaik MM, et al. Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation. J Clin Oncol. 2017;35:4003–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Anti-lymphocyte globulin for prevention of chronic graft-versus-host disease. N. Engl J Med. 2016;374:43–53.

    PubMed  Google Scholar 

  10. Luznik L, O’Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol. 2012;39:683–93.

    CAS  PubMed  Google Scholar 

  11. Nagler A, Labopin M, Blaise D, Raiola AM, Corral LL, Bramanti S, et al. Non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary versus de novo AML in first complete remission: a study from the ALWP/EBMT. J Hematol Oncol. 2023;16:58.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Sanz J, Galimard JE, Labopin M, Afanasyev B, Angelucci E, Ciceri F, et al. Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT. J Hematol Oncol. 2020;13:46.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Battipaglia G, Labopin M, Kröger N, Vitek A, Afanasyev B, Hilgendorf I, et al. Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood. 2019;134:892–9.

    CAS  PubMed  Google Scholar 

  14. Lorentino F, Labopin M, Ciceri F, Vago L, Fleischhauer K, Afanasyev B, et al. Post-transplantation cyclophosphamide GvHD prophylaxis after hematopoietic stem cell transplantation from 9/10 or 10/10 HLA-matched unrelated donors for acute leukemia. Leukemia. 2021;35:585–94.

    CAS  PubMed  Google Scholar 

  15. Bailén R, Kwon M, Pascual-Cascón MJ, Ferrà C, Sanz J, Gallardo-Morillo A, et al. Post-transplant cyclophosphamide for GVHD prophylaxis compared to ATG-based prophylaxis in unrelated donor transplantation. Ann Hematol. 2021;100:541–53.

    PubMed  Google Scholar 

  16. Brissot E, Labopin M, Moiseev I, Cornelissen JJ, Meijer E, Van Gorkom G, et al. Post-transplant cyclophosphamide versus anti-thymocyte globulin in patients with acute myeloid leukemia in first complete remission undergoing allogeneic stem cell transplantation from 10/10 HLA-matched unrelated donors. J Hematol Oncol. 2020;13:87.

    PubMed  PubMed Central  Google Scholar 

  17. Soltermann Y, Heim D, Medinger M, Baldomero H, Halter JP, Gerull S, et al. Reduced dose of post-transplantation cyclophosphamide compared to ATG for graft-versus-host disease prophylaxis in recipients of mismatched unrelated donor hematopoietic cell transplantation: a single-center study. Ann Hematol. 2019;98:1485–93.

    CAS  PubMed  Google Scholar 

  18. Bolaños-Meade J, Reshef R, Fraser R, Fei M, Abhyankar S, Al-Kadhimi Z, et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomized phase 2 trial with a non-randomized contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019;6:e132–e143.

    PubMed  PubMed Central  Google Scholar 

  19. Bolaños-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N. Engl J Med. 2023;388:2338–48.

    PubMed  PubMed Central  Google Scholar 

  20. 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 Transpl. 2009;15:1628–33.

    Google Scholar 

  21. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15:825–8.

    CAS  Google Scholar 

  22. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204–17.

    CAS  PubMed  Google Scholar 

  23. Ruggeri A, Labopin M, Ciceri F, Mohty M, Nagler A. Definition of GvHD-free, relapse-free survival for registry-based studies: an ALWP-EBMT analysis on patients with AML in remission. Bone Marrow Transpl. 2016;51:610–1.

    CAS  Google Scholar 

  24. Kanate AS, Nagler A, Savani B. Summary of scientific and statistical methods, study endpoints and definitions for observational and registry-based studies in hematopoietic cell transplantation. Clin Hematol Int. 2019;2:2–4.

    PubMed  PubMed Central  Google Scholar 

  25. Andersen PK, Klein JP, Zhang MJ. Testing for center effects in multi-center survival studies: a Monte Carlo comparison of fixed and random effects tests. Stat Med. 1999;18:1489–500.

    CAS  PubMed  Google Scholar 

  26. McCafrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med. 2013;32:3388–414.

    Google Scholar 

  27. R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing; 2020. https://www.R-project.org/.

  28. Al Malki MM, Tsai NC, Palmer J, Mokhtari S, Tsai W, Cao T, et al. Posttransplant cyclophosphamide as GVHD prophylaxis for peripheral blood stem cell HLA-mismatched unrelated donor transplant. Blood Adv. 2021;5:2650–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bacigalupo A, Jones R. PTCy the “new” standard for GVHD prophylaxis. Blood Rev. 2023;62:101096.

    PubMed  Google Scholar 

  30. Leick M, Bin Chen Y. A glimpse into what happens after PTCy. Blood. 2022;139:479–81.

    CAS  PubMed  Google Scholar 

  31. Mielcarek M, Furlong T, O’Donnell PV, Storer BE, McCune JS, Storb R, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127:1502–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ruggeri A, Labopin M, Bacigalupo A, Afanasyev B, Cornelissen JJ, Elmaagacli A, et al. Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT. J Hematol Onco. 2018;11:40.

    Google Scholar 

  33. Carnevale-Schianca F, Caravelli D, Gallo S, Becco P, Paruzzo L, Poletto S, et al. Post-transplant cyclophosphamide and tacrolimus–mycophenolate mofetil combination governs GVHD and immunosuppression need, reducing late toxicities in allogeneic peripheral blood hematopoietic cell transplantation from HLA-matched donors. J Clin Med. 2021;10:1173.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mehta RS, Saliba, et al. Post-transplantation cyclophosphamide versus tacrolimus and methotrexate graft-versus-host disease prophylaxis for HLA-matched donor transplantation. Transpl Cell Ther. 2022;28:695.e1–695.e10.

    CAS  Google Scholar 

  35. Broers AEC, de Jong CN, Bakunina K, Hazenberg MD, van Marwijk Kooy M, de Groot MR, et al. Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial. Blood Adv. 2022;6:3378–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Luznik L, Pasquini MC, Logan B, Soiffer RJ, Wu, et al. Randomized phase III BMT CTN trial of calcineurin inhibitor-free chronic graft-versus-host disease interventions in myeloablative hematopoietic cell transplantation for hematologic malignancies. J Clin Oncol. 2022;40:356–68.

    CAS  PubMed  Google Scholar 

  37. Modi D, Kondrat K, Kim S, Deol A, Ayash L, Ratanatharathorn V, et al. Post-transplant cyclophosphamide versus thymoglobulin in HLA-mismatched unrelated donor transplant for acute myelogenous leukemia and myelodysplastic syndrome. Transpl Cell Ther. 2021;27:760–7.

    CAS  Google Scholar 

  38. Berro M, Rivas M, Trucco J, Paganini I, Ravchina I, Kusminsky G. Post-transplant cyclophosphamide demonstrates lower non-relapse mortality and better graft-versus-host disease/relapse-free survival compared with antithymocyte globulin in unrelated donor hematopoietic stem cell transplantation. A single-center experience. Bone Marrow Transpl. 2021;56:986–8.

    CAS  Google Scholar 

  39. Dachy F, Furst S, Calmels B, Pagliardini T, Harbi S, Bouchacourt B, et al. GVHD prophylaxis with post-transplant cyclophosphamide results in lower incidence of GVHD and allows faster immunosuppressive treatment reduction compared to antithymocyte globulin in 10/10 HLA-matched unrelated allogeneic hematopoietic cell transplantation. Bone Marrow Transpl. 2023;58:1179–81.

    CAS  Google Scholar 

  40. Moiseev IS, Pirogova OV, Alyanski AL, Babenko EV, Gindina TL, Darskaya EI, et al. Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Biol Blood Marrow Transpl. 2016;22:1037–42.

    CAS  Google Scholar 

  41. Massoud R, Gagelmann N, Fritzsche-Friedland U, Zeck G, Heidenreich S, Wolschke C, et al. Comparison of immune reconstitution between anti-T-lymphocyte globulin and posttransplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation. Haematologica. 2022;107:857–67.

    CAS  PubMed  Google Scholar 

  42. Tang, Liu L, Li Z, Dong T, Wu T, Niu Q, et al. Post-transplant cyclophosphamide versus anti-thymocyte globulin in allogeneic hematopoietic stem cell transplantation from unrelated donors: a systematic review and meta-analysis. Front Oncol. 2023;13:1071268.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Greinix HT, Eikema DJ, Koster L, Penack O, Yakoub-Agha I, Montoto S, et al. Improved outcome of patients with graft-versus-host disease after allogeneic hematopoietic cell transplantation for hematologic malignancies over time: an EBMT mega-file study. Haematologica. 2022;107:1054–63.

    CAS  PubMed  Google Scholar 

  44. Turki AT, Tsachakis-Mück N, Leserer S, Crivello P, Liebregts T, Betke L, et al. Impact of CMV reactivation on relapse of acute myeloid leukemia after HCT is dependent on disease stage and ATG. Blood Adv. 2022;6:28–36.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the EBMT centers and national registries for contributing patients to this study (Supplementary appendix material). We also thank the data managers for their excellent work.

Author information

Authors and Affiliations

  1. Division of Hematology, Chaim Sheba Medical Center, Tel Hashomer, Israel

    Arnon Nagler

  2. EBMT Paris Study Office; Department of Haematology, Saint Antoine Hospital; INSERM UMR 938, Sorbonne University, Paris, France

    Myriam Labopin & Mohamad Mohty

  3. Department of Haematology, Saint Antoine Hospital, Sorbonne University; INSERM UMR 938, Paris, France

    Myriam Labopin, Eolia Brissot & Mohamad Mohty

  4. Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

    Ryszard Swoboda

  5. University Hospital of Essen, Essen, Germany

    Thomas Schroeder

  6. Centre Pierre et Marie Curie, Alger, Algeria

    Rose-Marie Hamladji

  7. Hospital Santaros Klinikos, Vilnius University, Vilnius, Lithuania

    Laimonas Griskevicius

  8. HUCH Comprehensive Cancer Center, Helsinki, Finland

    Urpu Salmenniemi

  9. Department of Oncology and Hematology, University of Milan and Azienda Socio-Sanitaria Territoriale, Papa Giovanni XXIII, Bergamo, Italy

    Alessandro Rambaldi

  10. Karolinska University Hospital, Stockholm, Sweden

    Stephan Mielke

  11. RM Gorbacheva Research Institute, Pavlov University, Petersburg, Russia

    Alexander Kulagin

  12. University Hospital of Basel, Basel, Switzerland

    Jakob Passweg

  13. University of Heidelberg, Heidelberg, Germany

    Thomas Luft

  14. Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Tobias Gedde-Dahl

  15. Hôpital Haut-Leveque, CHU Bordeaux, Pessac, France

    Edouard Forcade

  16. Silesian Medical Academy, Katowice, Poland

    Grzegorz Helbig

  17. University of Muenster, Muenster, Germany

    Matthias Stelljes

  18. Gustave Roussy Cancer Campus, Villejuif, France

    Cristina Castilla-Llorente

  19. Department of Internal Medicine, Bone Marrow Transplantation Unit, University Hospital of Patras, Patras, Greece

    Alexandros Spyridonidis

  20. Department of Haematology and BMT, IRCCS Osspedale San Raffaele; Vita-Salute San Raffaele University, Milano, Italy

    Fabio Ciceri

Authors
  1. Arnon Nagler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myriam Labopin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryszard Swoboda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Schroeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rose-Marie Hamladji
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laimonas Griskevicius
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Urpu Salmenniemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alessandro Rambaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephan Mielke
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alexander Kulagin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jakob Passweg
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Thomas Luft
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tobias Gedde-Dahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Edouard Forcade
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Grzegorz Helbig
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Matthias Stelljes
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Cristina Castilla-Llorente
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Alexandros Spyridonidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Eolia Brissot
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Fabio Ciceri
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Mohamad Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AN wrote the manuscript, designed the study, and interpreted the data. ML and MM designed the study, performed the statistical analyses, interpreted the data, and edited the manuscript. RS helped with writing the first draft of the manuscript. TS, RMH, LG, US, AR, SM, AK, JP, PD, TGD, EF, GH, MS, CCL, AS, EB, and FC reviewed the manuscript and provided clinical data. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Arnon Nagler.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The scientific boards of the ALWP of the EBMT approved this study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagler, A., Labopin, M., Swoboda, R. et al. Post-transplant cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil compared to anti-thymocyte globulin, calcineurin inhibitor, and methotrexate combinations as graft-versus-host disease prophylaxis post allogeneic stem cell transplantation from sibling and unrelated donors in patients with acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant 59, 1012–1021 (2024). https://doi.org/10.1038/s41409-024-02284-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-024-02284-5

This article is cited by

Search

Advanced search

Quick links