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:

Stem cell transplantation

The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation

Leukemia volume 34, pages 1144–1153 (2020)Cite this article

Subjects

Abstract

Measurable residual disease (MRD) status pre-allogeneic hematopoietic cell transplantation (allo-HCT) has been shown to predict transplant outcomes. We investigated the effect of Anti-Thymocyte Globulin (ATG) on acute myelogenous leukemia (AML) relapse by pretransplant MRD status. AML patients undergoing allo-HCT in first complete remission from either a matched sibling or unrelated donor during the 2006–2017 period were selected. Outcomes of 1509 patients (MRD+, n = 426) were studied. ATG was used in 561 (52%) and 239 (58%) patients within the MRD− and MRD+ cohorts, respectively. In MRD− patients, ATG did not affect relapse incidence (RI) (HR = 0.80, p = 0.17), but was associated with reduced incidence of grade II–IV acute GVHD, grade II–IV and chronic GVHD, reduced nonrelapse mortality (HR = 0.66, p = 0.05), improved leukemia-free survival (HR = 0.74, p = 0.02), overall survival (HR = 0.69, p = 0.01), and GVHD-relapse free survival (HR = 0.62, p < 0.01). In MRD+ patients, ATG was associated with a lower incidence of chronic GVHD (total, HR 0.56 p = 0.03; extensive, HR 0.40 P = 0.01), without an impact on other allo-HCT outcome parameters, including RI(HR = 1.02, p = 0.92). The use of ATG was associated with reduced risk for GVHD. ATG did not increase RI, even in high-risk AML patients who were MRD+ before allo-HCT.

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
Fig. 2

Similar content being viewed by others

References

  1. Goerner M, Gooley T, Flowers ME, Sullivan KM, Kiem HP, Sanders JE, et al. Morbidity and mortality of chronic GVHD after hematopoietic stem cell transplantation from HLA-identical siblings for patients with aplastic or refractory anemias. Biol Blood Marrow Transplant. 2002;8:47–56.

    Article  CAS  Google Scholar 

  2. Khera N, Zeliadt SB, Lee SJ. Economics of hematopoietic cell transplantation. Blood. 2012;120:1545–51.

    Article  CAS  Google Scholar 

  3. Gagelmann N, Ayuk F, Wolschke C, Kroger N. Comparison of different rabbit anti-thymocyte globulin formulations in allogeneic stem cell transplantation: systematic literature review and network meta-analysis. Biol Blood Marrow Transplant. 2017;23:2184–91.

    Article  CAS  Google Scholar 

  4. Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016;17:164–73.

    Article  CAS  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. 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;10:855–64.

    Article  CAS  Google Scholar 

  7. Rubio MT, D’Aveni-Piney M, Labopin M, Hamladji RM, Sanz MA, Blaise D, et al. Impact of in vivo T cell depletion in HLA-identical allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission conditioned with a fludarabine iv-busulfan myeloablative regimen: a report from the EBMT Acute Leukemia Working Party. J Hematol Oncol. 2017;10:31.

    Article  Google Scholar 

  8. Oostenbrink LVE, Jol-van der Zijde CM, Kielsen K, Jansen-Hoogendijk AM, Ifversen M, Muller KG, et al. Differential elimination of anti-thymocyte globulin of fresenius and genzyme impacts t-cell reconstitution after hematopoietic stem cell transplantation. Front Immunol. 2019;10:315.

    Article  CAS  Google Scholar 

  9. Devillier R, Labopin M, Chevallier P, Ledoux MP, Socie G, Huynh A, et al. Impact of antithymocyte globulin doses in reduced intensity conditioning before allogeneic transplantation from matched sibling donor for patients with acute myeloid leukemia: a report from the acute leukemia working party of European group of Bone Marrow Transplantation. Bone Marrow Transplant. 2018;53:431–7.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  11. Buckley SA, Wood BL, Othus M, Hourigan CS, Ustun C, Linden MA, et al. Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis. Haematologica. 2017;102:865–73.

    Article  CAS  Google Scholar 

  12. Canaani J, Labopin M, Huang XJ, Ciceri F, Van Lint MT, Bruno B, et al. Minimal residual disease status predicts outcome of acute myeloid leukaemia patients undergoing T-cell replete haploidentical transplantation. An analysis from the Acute Leukaemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Br J Haematol. 2018;183:411–20.

    Article  CAS  Google Scholar 

  13. Di Grazia C, Pozzi S, Geroldi S, Grasso R, Miglino M, Colombo N, et al. Wilms Tumor 1 Expression and Pre-emptive Immunotherapy in Patients with Acute Myeloid Leukemia Undergoing an Allogeneic Hemopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2016;22:1242–6.

    Article  Google Scholar 

  14. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354–65.

    Article  CAS  Google Scholar 

  15. Gilleece MH, Labopin M, Yakoub-Agha I, Volin L, Socie G, Ljungman P, et al. Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: A registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation. Am J Hematol. 2018;93:1142–52.

    Article  Google Scholar 

  16. 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  Google Scholar 

  17. 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 

  18. 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.

    Article  CAS  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. Andersen PK, Klein JP, Zhang MJ. Testing for centre effects in multi-centre survival studies: a Monte Carlo comparison of fixed and random effects tests. Stat Med. 1999;18:1489–1500.

    Article  CAS  Google Scholar 

  21. Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, et al. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017;4:e293–e301.

    Article  Google Scholar 

  22. Rubio MT, D’Aveni-Piney M, Labopin M, Hamladji RM, Sanz MA, Blaise D, et al. Impact of in vivo T cell depletion in HLA-identical allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission conditioned with a fludarabine iv-busulfan myeloablative regimen: a report from the EBMT Acute Leukemia Working Party. J Hematol Oncol. 2017;10:31.

  23. Mohty M, Labopin M, Balere ML, Socie G, Milpied N, Tabrizi R, et al. Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Leukemia. 2010;24:1867–74.

    Article  CAS  Google Scholar 

  24. Kennedy VE, Chen H, Savani BN, Greer J, Kassim AA, Engelhardt BG, et al. Optimizing antithymocyte globulin dosing for unrelated donor allogeneic hematopoietic cell transplantation based on recipient absolute lymphocyte count. Biol Blood Marrow Transpl. 2018;24:150–5.

    Article  CAS  Google Scholar 

  25. Kekre N, Antin JH. ATG in allogeneic stem cell transplantation: standard of care in 2017? Counterpoint. Blood Adv. 2017;1:573–6.

    Article  Google Scholar 

  26. Shah MV, Jorgensen JL, Saliba RM, Wang SA, Alousi AM, Andersson BS, et al. Early post-transplant minimal residual disease assessment improves risk stratification in acute myeloid leukemia. Biol Blood Marrow Transplant. 2018;24:1514–20.

    Article  Google Scholar 

  27. Liu J, Ma R, Liu YR, Xu LP, Zhang XH, Chen H, et al. The significance of peri-transplantation minimal residual disease assessed by multiparameter flow cytometry on outcomes for adult AML patients receiving haploidentical allografts. Bone Marrow Transplant. 2019;54:567–77.

    Article  Google Scholar 

  28. Schuurhuis GJ, Heuser M, Freeman S, Bene MC, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD working party. Blood. 2018;131:1275–91.

    Article  CAS  Google Scholar 

  29. Oran B, Jorgensen JL, Marin D, Wang S, Ahmed S, Alousi AM, et al. Pre-transplantation minimal residual disease with cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid leukemia. Haematologica. 2017;102:110–7.

    Article  CAS  Google Scholar 

  30. Anthias C, Dignan FL, Morilla R, Morilla A, Ethell ME, Potter MN, et al. Pre-transplant MRD predicts outcome following reduced-intensity and myeloablative allogeneic hemopoietic SCT in AML. Bone Marrow Transplant. 2014;49:679–83.

    Article  CAS  Google Scholar 

  31. Walter RB, Gyurkocza B, Storer BE, Godwin CD, Pagel JM, Buckley SA, et al. Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia. 2015;29:137–44.

    Article  CAS  Google Scholar 

  32. Chen X, Xie H, Wood BL, Walter RB, Pagel JM, Becker PS, et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol. 2015;33:1258–64.

    Article  Google Scholar 

  33. Ustun C, Courville E, DeFor T, Dolan M, Randall N, Yohe S, et al. Myeloablative, but not reduced-intensity, conditioning overcomes the negative effect of flow-cytometric evidence of leukemia in AML. Biol Blood Marrow Transplant. 2016;22:669–75.

    Article  Google Scholar 

Download references

Acknowledgements

We sincerely thank the centers of the EBMT and national registries for contributing patient information and data collection. Supporting Information is available at the EBMT website. Reporting institutions included in this study are available in the Online Supporting Information Appendix.

Authors contributions

AN, MM, and ML—contributed to the conception and design of the study; BD, AN, BNS, ML, MM, LL, SOC—contributed to the writing of the manuscript; AR, MAM, PK, EF, XH, FA, LC, AB, MM, DB, PBS, YA, RH, DCR, PO, AB, SS, RR, PL, JG, MM, HML, KB, SG, FB, FC, JE, NCG, AS, and CS—critically reviewed the manuscript and all authors approved the final version of manuscript.

Author information

Author notes

  1. These authors contributed equally: Arnon Nagler, Bhagirathbhai Dholaria, Myriam Labopin

Authors and Affiliations

  1. Hematology Department, Chaim Sheba Medical Center, Tel Hashomer, Israel

    Arnon Nagler

  2. Service d’Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorobonne University, and INSERM UMRs 938, Paris, France

    Arnon Nagler, Myriam Labopin & Mohamad Mohty

  3. Department of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    Bhagirathbhai Dholaria & Bipin Savani

  4. Bone Marrow Transplantation Department, CHU Saint-Louis, Paris, France

    Gerard Socie

  5. Oncopole, Institut Universitaire du Cancer Toulouse, Toulouse, France

    Anne Huynh

  6. Stem Cell Transplantation Unit, HUCH Comprehensive Cancer Center, Helsinki, Finland

    Maija Itälä-Remes

  7. Service d’Hématologie, CHU Besançon, Besançon, France

    Eric Deconinck

  8. Inserm UMR 1098, Besançon, France

    Eric Deconinck

  9. CHU de Lille, LIRIC, INSERM U995, Université de Lille, Lille, France

    Ibrahim Yakoub-Agha

  10. Service d’Hématologie, CHU Grenoble Alpes—Université Grenoble Alpes, Grenoble, France

    Jean-Yves Cahn

  11. Division of Hematology, Department of Medical Oncology, Gustave Roussy, institut de cancérologie, BMT Service, Villejuif, France

    Jean-Henri Bourhis

  12. Service Hématologie, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, Lyon, France

    Hélène Labussière-Wallet

  13. Institut d’hématologie de Basse-Normandie, CHU CAEN, Caen, France

    Sylvain Chantepie

  14. Hematology department, Hospital Clínic de Barcelona, Barcelona, Spain

    Jordi Esteve

Authors
  1. Arnon Nagler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bhagirathbhai Dholaria
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Myriam Labopin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gerard Socie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Huynh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maija Itälä-Remes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eric Deconinck
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ibrahim Yakoub-Agha
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jean-Yves Cahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean-Henri Bourhis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hélène Labussière-Wallet
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sylvain Chantepie
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jordi Esteve
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Bipin Savani
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Mohamad Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bhagirathbhai Dholaria.

Ethics declarations

Conflict of interest

MM and IY-A have received research support and honoraria from Sanofi. The other authors declare that they have no conflict of interest.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagler, A., Dholaria, B., Labopin, M. et al. The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation. Leukemia 34, 1144–1153 (2020). https://doi.org/10.1038/s41375-019-0631-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0631-5

This article is cited by

Search

Advanced search

Quick links