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Antithymocyte globulin for acute-graft-versus-host-disease prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation: a systematic review

Leukemia volume 26, pages 582–588 (2012)Cite this article

Abstract

Graft-versus-host-disease (GVHD) is a major complication associated with allogeneic hematopoietic cell transplantation (allo-HCT). Antithymocyte globulin (ATG) is recommended for GVHD prophylaxis following allo-HCT, however, evidence on efficacy of ATG is conflicting. Accordingly, we undertook a systematic review. All phase III randomized controlled trials (RCTs) comparing ATG versus control for prevention of GVHD in patients undergoing allo-HCT were eligible. Medline and Cochrane databases were searched. Data on methodological quality, benefits and harms were extracted for each trial and pooled under a random effects model. Seven RCTs enrolling 733 patients met inclusion criteria. Pooled results showed no difference for overall survival with use of ATG (hazard ratio was 0.91; 95% confidence intervals (CI), 0.75–1.10; P=0.32). There was a significant benefit for prevention of grade III/IV acute GVHD (risk ratio (RR)=0.51; 95% CI, 0.27–0.94; P=0.03). There was no benefit associated with ATG use for prevention of either grade II (RR=0.79; 95% CI, 0.48–1.30; P=0.35) or grade I acute GVHD (RR=1.42; 95% CI, 0.75–2.69; P=0.28). Use of ATG was not associated with significant reduction in non-relapse mortality (RR=0.74; 95% CI, 0.53–1.03; P=0.08). Future trials with adequate sample size are required to provide more definitive answers.

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References

  1. Reddy P, Arora M, Guimond M, Mackall CL . GVHD: a continuing barrier to the safety of allogeneic transplantation. Biol Blood Marrow Transplant 2008; 15 (1 Suppl): 162–168.

    PubMed Central  Google Scholar 

  2. Ferrara JL, Levine JE, Reddy P, Holler E . Graft-versus-host disease. Lancet 2009; 373: 1550–1561.

    Article  CAS  Google Scholar 

  3. Mohty M . Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 2007; 21: 1387–1394.

    Article  CAS  Google Scholar 

  4. Genestier L, Fournel S, Flacher M, Assossou O, Revillard JP, Bonnefoy-Berard N . Induction of Fas (Apo-1, CD95)-mediated apoptosis of activated lymphocytes by polyclonal antithymocyte globulins. Blood 1998; 91: 2360–2368.

    CAS  PubMed  Google Scholar 

  5. Michallet MC, Preville X, Flacher M, Fournel S, Genestier L, Revillard JP . Functional antibodies to leukocyte adhesion molecules in antithymocyte globulins. Transplantation 2003; 75: 657–662.

    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: 855–864.

    Article  CAS  Google Scholar 

  7. Champlin RE, Perez WS, Passweg JR, Klein JP, Camitta BM, Gluckman E et al. Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens. Blood 2007; 109: 4582–4585.

    Article  CAS  Google Scholar 

  8. Haynes RB, McKibbon KA, Wilczynski NL, Walter SD, Werre SR, for the Hedges T . Optimal search strategies for retrieving scientifically strong studies of treatment from Medline: analytical survey. BMJ 2005; 330: 1179–117.

    Article  Google Scholar 

  9. Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001; 134: 663–694.

    Article  CAS  Google Scholar 

  10. Juni P, Altman DG, Egger M . Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001; 323: 42–46.

    Article  CAS  Google Scholar 

  11. Egger MSD, Altman D . Systematic reviews in health care. Meta-analysis in context, 2nd edn. BMJ, London 2001.

  12. DerSimonian R, Laird N . Meta-analysis in clinical trials. Controlled clinical trials 1986; 7: 177–188.

    Article  CAS  Google Scholar 

  13. Tierney J, Stewart L, Ghersi D, Burdett S, Sydes M . Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007; 8: 16.

    Article  Google Scholar 

  14. Higgins JPT, Thompson SG, Deeks JJ, Altman DG . Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560.

    Article  Google Scholar 

  15. Begg CB, Mazumdar M . Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088–1101.

    Article  CAS  Google Scholar 

  16. Egger M, Smith DG, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

    Article  CAS  Google Scholar 

  17. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009; 62: e1–e34.

    Article  Google Scholar 

  18. Bacigalupo A, Lamparelli T, Milone G, Sormani MP, Ciceri F, Peccatori J et al. Pre-emptive treatment of acute GVHD: a randomized multicenter trial of rabbit anti-thymocyte globulin, given on day+7 after alternative donor transplants. Bone Marrow Transplant 2010; 45: 385–391.

    Article  CAS  Google Scholar 

  19. Bacigalupo A, Oneto R, Lamparelli T, Gualandi F, Bregante S, Raiola AM et al. Pre-emptive therapy of acute graft-versus-host disease: a pilot study with antithymocyte globulin (ATG). Bone Marrow Transplant 2001; 28: 1093–1096.

    Article  CAS  Google Scholar 

  20. Ramsay NK, Kersey JH, Robison LL, McGlave PB, Woods WG, Krivit W et al. A randomized study of the prevention of acute graft-versus-host disease. N Engl J Med 1982; 306: 392–397.

    Article  CAS  Google Scholar 

  21. Weiden PL, Doney K, Storb R, Thomas ED . Antihuman thymocyte globulin for prophylaxis of graft-versus-host disease. A randomized trial in patients with leukemia treated with HLA-identical sibling marrow grafts. Transplantation 1979; 27: 227–230.

    Article  CAS  Google Scholar 

  22. Ferrara JL, Reddy P . Pathophysiology of graft-versus-host disease. Semin Hematol 2006; 43: 3–10.

    Article  CAS  Google Scholar 

  23. Marks DI, Cullis JO, Ward KN, Lacey S, Syzdlo R, Hughes TP et al. Allogeneic bone marrow transplantation for chronic myeloid leukemia using sibling and volunteer unrelated donors. A comparison of complications in the first 2 years. Ann Intern Med 1993; 119: 207–214.

    Article  CAS  Google Scholar 

  24. Weisdorf DJ, Anasetti C, Antin JH, Kernan NA, Kollman C, Snyder D et al. Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood 2002; 99: 1971–1977.

    Article  CAS  Google Scholar 

  25. Bertz H, Potthoff K, Finke J . Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia. J Clin Oncol 2003; 21: 1480–1484.

    Article  Google Scholar 

  26. 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: 1867–1874.

    Article  CAS  Google Scholar 

  27. 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 

  28. Soiffer RJ, Lerademacher J, Ho V, Kan F, Artz A, Champlin RE et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood 2011; 117: 6963–6970.

    Article  CAS  Google Scholar 

  29. Wetterslev J, Thorlund K, Brok J, Gluud C . Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 2008; 61: 64–75.

    Article  Google Scholar 

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Acknowledgements

This study was performed with internal support from Center for Evidence Based Medicine at the University of South Florida, College of Medicine. No external support was received for the work in form of grants and/or equipment and drugs.

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Authors and Affiliations

  1. Center and Division for Evidence Based Medicine and Health Outcomes Research, Department of Internal Medicine, College of Medicine, University of South Florida, Tampa, FL, USA

    A Kumar, A R Mhaskar, T Reljic, R S Mhaskar & B Djulbegovic

  2. Division of Hematology-Oncology and Bone Marrow Transplantation, Tampa, FL, USA

    A Kumar, C Anasetti & B Djulbegovic

  3. Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, FL, USA

    A Kumar, M A Kharfan-Dabaja & B Djulbegovic

  4. Department of Internal Medicine, Division of Hematology-Oncology and Bone Marrow Transplantation, American University of Beirut, Beirut, Lebanon

    M A Kharfan-Dabaja

  5. Centre Hospitalier et Universitaire (CHU) de Nantes, Service d’Hématologie Clinique en Nantes, Nantes, France

    M Mohty

  6. Université de Nantes, Faculté de Médicine, Nantes, France

    M Mohty

  7. Centre d’Investigation Clinique en Cancérologie (CI2C), CHU de Nantes, Nantes, France

    M Mohty

  8. INSERM CRNCA UMR 892, Nantes, France

    M Mohty

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  1. A Kumar
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Correspondence to A Kumar.

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Competing interests

Mohamad Mohty acted as a consultant and received honoraria from Genzyme and Fresenius whose products are discussed in this report. The other authors declare no conflict of interest.

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Kumar, A., Mhaskar, A., Reljic, T. et al. Antithymocyte globulin for acute-graft-versus-host-disease prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation: a systematic review. Leukemia 26, 582–588 (2012). https://doi.org/10.1038/leu.2011.349

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  • DOI: https://doi.org/10.1038/leu.2011.349

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