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:

First-line steroid-free systemic treatment of acute and chronic graft-versus-host disease after novel prophylaxis regimens

Bone Marrow Transplantation volume 58, pages 257–264 (2023)Cite this article

Subjects

Abstract

In the early randomized trials the efficacy of calcineurin inhibitors (CNI) in the treatment of graft-versus-host disease (GVHD) was comparable to corticosteroids (CS), but these results became obsolete with the introduction of CNIs in prophylaxis. Recently several effective CNI-free GVHD prophylaxis regimens were introduced based on posttransplantation cyclophosphamide (PTCY) and αβ ex vivo T-cell depletion (αβ-TCD). Among patients treated under these protocols 34 patients with grade II-IV acute (aGVHD) and 40 with moderate and severe chronic (cGVHD) disease were treated with CNIs or other CS-free regimens as the first line. Overall response rate (ORR) was significantly higher in cGVHD than in aGVHD: 80% (95% CI 68–92) vs 47% (95% CI 30–64%), p = 0.0031. In aGVHD it was almost completely restricted to isolated stage III skin GVHD. In cGVHD patients with moderate disease ORR was higher than in severe: 96% (95% CI 88–100%) vs 56% (95%CI 32–81%), p = 0.0022. Two-year overall survival was 76% (95% CI 58–87%) in aGVHD and 95% (95% CI 81–99%) in cGVHD. Failure-free survival was 21% (95% CI 9–37%) in aGVHD and 81% (95% CI 64–91%) in cGVHD. Patients responding to steroid-free regimens had lower use of systemic antibiotics (p = 0.0095), antifungals (p = 0.0319) and antivirals (p < 0.0001).

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: The response to immunosuppressive to 1st-line steroid-free treatments and 2nd line corticosteroids.
Fig. 2: Failure-free survival (left panel) and discontinuation of systemic immunosuppression (right panel).
Fig. 3: Individual organ responses at last follow up in chronic graft-versus-host disease patients treated with steroid-free regimens in the 1st line.

Similar content being viewed by others

Data availability

Primary study data is available through request to Ethical Committee of Pavlov University according to standard operating procedures, e-mail: spbgmutrials@yandex.ru.

References

  1. Doney KC, Weiden PL, Storb R, Thomas ED. Treatment of graft-versus-host disease in human allogeneic marrow graft recipients: a randomized trial comparing antithymocyte globulin and corticosteroids. Am J Hematol. 1981;11:1–8. https://doi.org/10.1002/ajh.2830110102.

    Article  CAS  PubMed  Google Scholar 

  2. Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB, et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood. 1981;57:267–76.

    Article  CAS  PubMed  Google Scholar 

  3. Kennedy MS, Deeg HJ, Storb R, Doney K, Sullivan KM, Witherspoon RP, et al. Treatment of acute graft-versus-host disease after allogeneic marrow transplantation. Randomized study comparing corticosteroids and cyclosporine. Am J Med. 1985;78:978–83. https://doi.org/10.1016/0002-9343(85)90221-9.

    Article  CAS  PubMed  Google Scholar 

  4. Storb R, Deeg HJ, Farewell V, Doney K, Appelbaum F, Beatty P, et al. Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood. 1986;68:119–25.

    Article  CAS  PubMed  Google Scholar 

  5. Cragg L, Blazar BR, Defor T, Kolatker N, Miller W, Kersey J, et al. A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease. Biol Blood Marrow Transplant. 2000;6:441–7. https://doi.org/10.1016/s1083-8791(00)70036-x.

    Article  CAS  PubMed  Google Scholar 

  6. Lee SJ, Zahrieh D, Agura E, MacMillan ML, Maziarz RT, McCarthy PL Jr, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood. 2004;104:1559–64. https://doi.org/10.1182/blood-2004-03-0854.

    Article  CAS  PubMed  Google Scholar 

  7. Alousi AM, Weisdorf DJ, Logan BR, Bolaños-Meade J, Carter S, Difronzo N, et al. Blood and Marrow Transplant Clinical Trials Network. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood. 2009;114:511–7. https://doi.org/10.1182/blood-2009-03-212290. Epub 2009 May 14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bolaños-Meade J, Logan BR, Alousi AM, Antin JH, Barowski K, Carter SL, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014;124:3221–7. https://doi.org/10.1182/blood-2014-06-577023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sullivan KM, Witherspoon RP, Storb R, Weiden P, Flournoy N, Dahlberg S, et al. Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation. Blood. 1988;72:546–54.

    Article  CAS  PubMed  Google Scholar 

  10. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, et al. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood. 2000;96:3995–6.

    Article  CAS  PubMed  Google Scholar 

  11. Arora M, Wagner JE, Davies SM, Blazar BR, Defor T, Enright H, et al. Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2001;7:265–73. https://doi.org/10.1053/bbmt.2001.v7.pm11400948.

    Article  CAS  PubMed  Google Scholar 

  12. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, et al. Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 2002;100:48–51. https://doi.org/10.1182/blood.v100.1.48.

    Article  CAS  PubMed  Google Scholar 

  13. Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, et al. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood. 2009;113:5074–82. https://doi.org/10.1182/blood-2009-02-202937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pidala J, Hamadani M, Dawson P, Martens M, Alousi AM, Jagasia M, et al. Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial. Blood 2020;135:97–107. https://doi.org/10.1182/blood.2019003125.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Luznik L, Bolaños-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010;115:3224–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 Oncol. 2018;11:40. https://doi.org/10.1186/s13045-018-0586-4.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sanz J, Galimard JE, Labopin M, Afanasyev B, Moiseev I, Angelucci E, et al. Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT. J Hematol Oncol. 2021;14:84. https://doi.org/10.1186/s13045-021-01094-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019;6:e132–e143. https://doi.org/10.1016/S2352-3026(18)30221-7.

    Article  PubMed  PubMed Central  Google Scholar 

  20. de Witte MA, Janssen A, Nijssen K, Karaiskaki F, Swanenberg L, van Rhenen A, et al. αβ T-cell graft depletion for allogeneic HSCT in adults with hematological malignancies. Blood Adv 2021;5:240–9. https://doi.org/10.1182/bloodadvances.2020002444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shekhovtsova Z, Shelikhova L, Balashov D, Zakharova V, Ilushina M, Voronin K, et al. Control of graft-versus-host disease with rabbit anti-thymocyte globulin, rituximab, and bortezomib in TCRαβ/CD19-depleted graft transplantation for leukemia in children: a single-center retrospective analysis of two GVHD-prophylaxis regimens. Pediatr Transpl. 2020;24:e13594. https://doi.org/10.1111/petr.13594.

    Article  Google Scholar 

  22. Shelikhova L, Glushkova S, Nikolaev R, Dunaikina M, Zhekhovtsova Z, Blagov S, et al. Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of αβ TCell-Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia. Transpl Cell Ther. 2021;27:330.e1–330.e9. https://doi.org/10.1016/j.jtct.2021.01.010.

    Article  CAS  Google Scholar 

  23. Morozova EV, Barabanshikova MV, Moiseev IS, Shakirova AI, Barhatov IM, Ushal IE, et al. A prospective pilot study of graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide and ruxolitinib in patients with myelofibrosis. Acta Haematol. 2021;144:158–65. https://doi.org/10.1159/000506758.

    Article  CAS  PubMed  Google Scholar 

  24. Greco R, Lorentino F, Albanese S, Lupo Stanghellini MT, Giglio F, Piemontese S, et al. Posttransplantation cyclophosphamide- and sirolimus-based graft-versus-host-disease prophylaxis in allogeneic stem cell transplant. Transplant Cell Ther. 2021;27:776.e1–776.e13. https://doi.org/10.1016/j.jtct.2021.05.023.

    Article  CAS  PubMed  Google Scholar 

  25. Moiseev IS, Pirogova OV, Alyanski AL, Babenko EV, Gindina TL, Darskaya EI, et al. Risk-adapted GVHD prophylaxis with post-transplantation cyclophosphamide in adults after related, unrelated, and haploidentical transplantations. Eur J Haematol 2018;100:395–402. https://doi.org/10.1111/ejh.13030.

    Article  CAS  PubMed  Google Scholar 

  26. Ruutu T, Gratwohl A, de Witte T, Afanasyev B, Apperley J, Bacigalupo A, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014;49:168–73.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–56.

    Article  PubMed  Google Scholar 

  29. Martin PJ, Bachier CR, Klingemann HG, McCarthy PL, Szabolcs P, Uberti JP, et al. Endpoints for clinical trials testing treatment of acute graft-versus-host disease: a joint statement. Biol Blood Marrow Transplant. 2009;15:777–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015;21:984–99.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kanakry CG, Ganguly S, Zahurak M, Bolaños-Meade J, Thoburn C, Perkins B, et al. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med. 2013;5:211ra157 https://doi.org/10.1126/scitranslmed.3006960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ikegawa S, Meguri Y, Mizuhara K, Fukumi T, Kobayashi H, Sumii Y, et al. Pretransplant nivolumab further enhanced Treg expansion after posttransplant cyclophosphamide; another aspect for immune tolerance by PTCy after nivolumab. Leukemia. 2021;35:929–31. https://doi.org/10.1038/s41375-021-01167-8.

    Article  CAS  PubMed  Google Scholar 

  33. Saliba RM, Couriel DR, Giralt S, Rondon G, Okoroji GJ, Rashid A, et al. Prognostic value of response after upfront therapy for acute GVHD. Bone Marrow Transplant. 2012;47:125–31. https://doi.org/10.1038/bmt.2011.41.

    Article  CAS  PubMed  Google Scholar 

  34. Chaleff S, Otto M, Barfield RC, Leimig T, Iyengar R, Martin, et al. A large-scale method for the selective depletion of alphabeta T lymphocytes from PBSC for allogeneic transplantation. Cytotherapy. 2007;9:746–54. https://doi.org/10.1080/14653240701644000.

    Article  CAS  PubMed  Google Scholar 

  35. Luznik L, Pasquini MC, Logan B, Soiffer RJ, Wu J, Devine SM, 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. https://doi.org/10.1200/JCO.21.02293.

    Article  CAS  PubMed  Google Scholar 

  36. Cooper DL, Manago J, Patel V, Schaar D, Krimmel T, McGrath MK, et al. Incorporation of posttransplant cyclophosphamide as part of standard immunoprophylaxis for all allogeneic transplants: a retrospective, single institution study. Bone Marrow Transplant. 2021;56:1099–105. https://doi.org/10.1038/s41409-020-01144-2.

    Article  CAS  PubMed  Google Scholar 

  37. Bolaños-Meade J, Logan BR, Alousi AM, Antin JH, Barowski K, Carter SL, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014;124:3221–335. https://doi.org/10.1182/blood-2014-06-577023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Franco LM, Gadkari M, Howe KN, Sun J, Kardava L, Kumar P, et al. Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses. J Exp Med. 2019;216:384–406. https://doi.org/10.1084/jem.20180595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Youssef J, Novosad SA, Winthrop KL. Infection risk and safety of corticosteroid use. Rheum Dis Clin N Am. 2016;42:157-x. https://doi.org/10.1016/j.rdc.2015.08.004.

    Article  Google Scholar 

  40. Cao W, Manicassamy S, Tang H, Kasturi SP, Pirani A, Murthy N, et al. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol. 2008;9:1157–64. https://doi.org/10.1038/ni.1645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mattson E, Xu L, Li L, Liu GE, Xiao Z. Transcriptome profiling of CTLs regulated by rapamycin using RNA-Seq. Immunogenetics. 2014;66:625–33. https://doi.org/10.1007/s00251-014-0790-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385:228–38. https://doi.org/10.1056/NEJMoa2033122.

    Article  CAS  PubMed  Google Scholar 

  43. Escamilla Gómez V, García-Gutiérrez V, López Corral L, García Cadenas I, Pérez Martínez A, Márquez Malaver FJ, et al. Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study. Bone Marrow Transplant. 2020;55:641–8. https://doi.org/10.1038/s41409-019-0731-x.

    Article  CAS  PubMed  Google Scholar 

  44. Pidala J, Onstad L, Martin PJ, Hamilton BK, Cutler C, Kitko CL, et al. Initial therapy for chronic graft-versus-host disease: analysis of practice variation and failure-free survival. Blood Adv. 2021;5:4549–59. https://doi.org/10.1182/bloodadvances.2021005286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bachier CR, Aggarwal SK, Hennegan K, Milgroom A, Francis K, Dehipawala S, et al. Epidemiology and treatment of chronic graft-versus-host disease post-allogeneic hematopoietic cell transplantation: a US claims analysis. Transplant Cell Ther. 2021;27:504.e1–504.e6. https://doi.org/10.1016/j.jtct.2020.12.027.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the significant input in this work and support of this steroid-free approach of our former director, Boris Afanasyev, who passed away in 2020. We thank Michael Maschan for organizing multicenter validation of αβ-TCD prophylaxis.

Funding

This study is supported by Russian Science Fund grant 17-75-20145-P.

Author information

Authors and Affiliations

  1. RM Gorbacheva Research Institute, Pavlov University, Lva Tolstogo St., 6/8, St. Petersburg, Russian Federation

    Ivan Moiseev, Maria Barabanshikova, Anna Dotsenko, Anna Smirnova, Yulia Vlasova, Elena Morozova, Sergey Bondarenko & Alexander Kulagin

Authors
  1. Ivan Moiseev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Barabanshikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Dotsenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Smirnova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yulia Vlasova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elena Morozova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sergey Bondarenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alexander Kulagin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

IM: conceptualization, methodology, project administration, writing - original draft, visualization, funding acquisition; MB: formal analysis, writing - original draft, AD, AS, YV: investigation, data curation; EM: methodology, writing - review & editing; SB: methodology, writing - review & editing; AK: supervision, writing - review & editing.

Corresponding author

Correspondence to Ivan Moiseev.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Moiseev, I., Barabanshikova, M., Dotsenko, A. et al. First-line steroid-free systemic treatment of acute and chronic graft-versus-host disease after novel prophylaxis regimens. Bone Marrow Transplant 58, 257–264 (2023). https://doi.org/10.1038/s41409-022-01879-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-022-01879-0

Search

Advanced search

Quick links