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.

  • Original Article
  • Published:

Graft-Versus-Host Disease

Lower dose anti-thymocyte globulin for GvHD prophylaxis results in improved survival after allogeneic stem cell transplantation

Abstract

In vivo T-cell depletion with anti-thymocyte globulin (ATG) can attenuate GvHD but may increase infection and relapse risks. ATG-Fresenius (ATG-F) at a dose of 60 mg/kg was standard GvHD prophylaxis in unrelated donor hematopoietic stem cell transplantation (HSCT) at our institution. We changed to an incremental reduced dose regimen of 35 mg/kg and extended ATG prophylaxis to include older matched-related donor transplants considered to be at higher risk of GvHD. A total of 265 adults with hematological malignancies receiving a first allogeneic HSCT after myeloablative conditioning between 2009 and 2014 were analyzed in this cohort study. Patients had either received higher dose (n=32) or lower dose ATG-F (n=88) or no ATG (n=145). ATG-F was associated with slower engraftment and less chronic GvHD, whereas no effect was noted on acute grade II–IV GvHD and relapse incidence. Transplant-related mortality (TRM) was lower and survival higher with lower dose, but not with higher dose ATG-F. Both ATG-F groups were associated with more viral reactivation, viral disease and bacterial blood stream infection, but not invasive fungal infection, and with slower immune reconstitution. The recently adopted strategy of using lower doses of ATG-F in unrelated and older age-related donor HSCT appears to reduce TRM without increasing disease relapse, leading to slightly enhanced survival.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Copelan EA . Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354: 1813–1826.

    Article  CAS  Google Scholar 

  2. Ljungman P, Bregni M, Brune M, Cornelissen J, de Witte T, Dini G et al. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe 2009. Bone Marrow Transplant 2010; 45: 219–234.

    Article  CAS  Google Scholar 

  3. Hahn T, McCarthy PL, Hassebroek A, Bredeson C, Gajewski JL, Hale GA et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol 2013; 31: 2437–2449.

    Article  Google Scholar 

  4. Ho VT, Soiffer RJ . The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001; 98: 3192–3204.

    Article  CAS  Google Scholar 

  5. Fehse N, Fehse B, Kroger N, Zabelina T, Freiberger P, Kruger W et al. Influence of anti-thymocyte globulin as part of the conditioning regimen on immune reconstitution following matched related bone marrow transplantation. J Hematother Stem Cell Res 2003; 12: 237–242.

    Article  Google Scholar 

  6. Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med 1988; 108: 806–814.

    Article  CAS  Google Scholar 

  7. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR et al. 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: 855–864.

    Article  CAS  Google Scholar 

  8. Socie G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR et al. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood 2011; 117: 6375–6382.

    Article  CAS  Google Scholar 

  9. Kroger N, Zabelina T, Kruger W, Renges H, Stute N, Rischewski J et al. In vivo T cell depletion with pretransplant anti-thymocyte globulin reduces graft-versus-host disease without increasing relapse in good risk myeloid leukemia patients after stem cell transplantation from matched related donors. Bone Marrow Transplant 2002; 29: 683–689.

    Article  CAS  Google Scholar 

  10. 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: 2942–2947.

    Article  CAS  Google Scholar 

  11. Bonifazi F, Solano C, Wolschke C . Prevention of chronic GvHD after HLA-identical sibling peripheral hematopoietic stem cell transplantation with or without anti-lymphocyte globulin (ATG). Results from a prospective, multicenter randomized phase III trial (ATG family study). Am Soc Hematol Annu Meet 2014 Abstract 37.

  12. Walker I, Schultz K, Toze C . Thymoglobulin decreases the need for immunosuppression at 12 months after myeloablative and nonmyeloablative unrelated donor transplantation: CBMTG 0801, a randomized, controlled trial. Am Soc Hematol Annu Meet 2014 Abstract 38.

  13. Wang Y, Fu H-X, Liu D-H, Xu L-P, Zhang X-H, Chang Y-J et al. Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial. Bone Marrow Transplant 2014; 49: 426–433.

    Article  CAS  Google Scholar 

  14. Finke J, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR et al. Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial. Biol Blood Marrow Transplant 2012; 18: 1716–1726.

    Article  Google Scholar 

  15. Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG et al. Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 2015; 125: 1333–1338.

    Article  CAS  Google Scholar 

  16. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  17. Cox DR . Regression models and life tables. J R Stat Soc B 1972; 34: 87–220.

    Google Scholar 

  18. Robin M, Porcher R, Ades L, Boissel N, Raffoux E, Xhaard A et al. Matched unrelated or matched sibling donors result in comparable outcomes after non-myeloablative HSCT in patients with AML or MDS. Bone Marrow Transplant 2013; 48: 1296–1301.

    Article  CAS  Google Scholar 

  19. Warlick ED, Peffault de Latour R, Shanley R, Robin M, Bejanyan N, Xhaard A et al. Allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia: similar outcomes regardless of donor type. Biol Blood Marrow Transplant 2015; 21: 357–363.

    Article  Google Scholar 

  20. Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N, Milpied N et al. Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French. J Clin Oncol 2006; 24: 5695–5702.

    Article  Google Scholar 

  21. Russell JA, Turner AR, Larratt L, Chaudhry A, Morris D, Brown C et al. Adult recipients of matched related donor blood cell transplants given myeloablative regimens including pretransplant antithymocyte globulin have lower mortality related to graft-versus-host disease: a matched pair analysis. Biol Blood Marrow Transplant 2007; 13: 299–306.

    Article  CAS  Google Scholar 

  22. Wolschke C, Zabelina T, Ayuk F, Alchalby H, Berger J, Klyuchnikov E et al. Effective prevention of GVHD using in vivo T-cell depletion with anti-lymphocyte globulin in HLA-identical or -mismatched sibling peripheral blood stem cell transplantation. Bone Marrow Transplant 2014; 49: 126–130.

    Article  CAS  Google Scholar 

  23. Bonifazi F, Bandini G, Arpinati M, Tolomelli G, Stanzani M, Motta MR et al. Intensification of GVHD prophylaxis with low-dose ATG-F before allogeneic PBSC transplantation from HLA-identical siblings in adult patients with hematological malignancies: results from a retrospective analysis. Bone Marrow Transplant 2012; 47: 1105–1111.

    Article  CAS  Google Scholar 

  24. Brodska H, Drabek T, Malickova K, Kazda A, Vitek A, Zima T et al. Marked increase of procalcitonin after the administration of anti-thymocyte globulin in patients before hematopoietic stem cell transplantation does not indicate sepsis: a prospective study. Crit Care 2009; 13: R37.

    Article  Google Scholar 

  25. Liu D, Liu J, Liu K, Xu L, Chen H, Chen Y et al. A comparative study on early toxicity of conditioning regimen with or without antithymocyte globulin. Zhonghua Xue Ye Xue Za Zhi 2009; 30: 519–523.

    Google Scholar 

  26. Storek J, Mohty M, Boelens JJ . Rabbit anti-T cell globulin in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2014; 21: 959–970.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J R Passweg.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

This study will be presented in part at the Swiss Society of Hematology annual Meeting in May 2015.

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Binkert, L., Medinger, M., Halter, J. et al. Lower dose anti-thymocyte globulin for GvHD prophylaxis results in improved survival after allogeneic stem cell transplantation. Bone Marrow Transplant 50, 1331–1336 (2015). https://doi.org/10.1038/bmt.2015.148

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.148

This article is cited by

Search

Quick links