Biology of Blood and Marrow Transplantation
Volume 15, Issue 11 , Pages 1422-1430 , November 2009

Improved Nonrelapse Mortality and Infection Rate with Lower Dose of Antithymocyte Globulin in Patients Undergoing Reduced-Intensity Conditioning Allogeneic Transplantation for Hematologic Malignancies

  • Mehdi Hamadani

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
    • Corresponding Author InformationCorrespondence and reprint requests: Mehdi Hamadani, MD, Division of Hematology and Oncology, and Comprehensive Cancer Center, The Ohio State University, M365 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210.
  • ,
  • William Blum

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Gary Phillips

      Affiliations

    • The Ohio State University, Center for Biostatistics, Columbus, Ohio
  • ,
  • Patrick Elder

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Leslie Andritsos

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Craig Hofmeister

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Lynn O'Donnell

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Rebecca Klisovic

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Sam Penza

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Ramiro Garzon

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • David Krugh

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Thomas Lin

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Thomas Bechtel

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Don M. Benson

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • John C. Byrd

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Guido Marcucci

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • ,
  • Steven M. Devine

      Affiliations

    • Division of Hematology/Oncology, Blood and Marrow Transplantation Section, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio

Received 13 June 2009 ,Accepted 7 July 2009.

References 

  1. Bacigalupo A, Lamparelli T, Gualandi F, et al. Prophylactic antithymocyte globulin reduces the risk of chronic graft-versus-host disease in alternative-donor bone marrow transplants. Biol Blood Marrow Transplant. 2002;8:656–661
  2. Ferrara JL, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant. 1999;5:347–356
  3. Hamadani M, Awan FT, Devine SM. The impact of HMG-CoA reductase inhibition on the incidence and severity of graft-versus-host disease in patients with acute leukemia undergoing allogeneic transplantation. Blood. 2008;111:3901–3902
  4. Lee KH, Lee JHs, Lee JH, et al. Hematopoietic cell transplantation from an HLA-mismatched familial donor is feasible without ex vivo-T cell depletion after reduced-intensity conditioning with busulfan, fludarabine, and antithymocyte globulin. Biol Blood Marrow Transplant. 2009;15:61–72
  5. Marmont AM, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood. 1991;78:2120–2130
  6. Bacigalupo A, Lamparelli T, Bruzzi 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
  7. Basara N, Baurmann H, Kolbe K, et al. Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group. Bone Marrow Transplant. 2005;35:1011–1018
  8. Bredeson CN, Zhang MJ, Agovi MA, et al. Outcomes following HSCT using fludarabine, busulfan, and thymoglobulin: a matched comparison to allogeneic transplants conditioned with busulfan and cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:993–1003
  9. Duggan P, Booth K, Chaudhry A, et al. Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis. Bone Marrow Transplant. 2002;30:681–686
  10. Kroger N, Zabelina T, Kruger W, 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
  11. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000;96:2062–2068
  12. Juckett M, Rowlings P, Hessner M, et al. T cell-depleted allogeneic bone marrow transplantation for high-risk non-Hodgkin's lymphoma: clinical and molecular follow-up. Bone Marrow Transplant. 1998;21:893–899
  13. Levine JE, Paczesny S, Mineishi S, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111:2470–2475
  14. Hamadani M, Hofmeister CC, Jansak B, et al. Addition of infliximab to standard acute graft-versus-host disease prophylaxis following allogeneic peripheral blood cell transplantation. Biol Blood Marrow Transplant. 2008;14:783–789
  15. Peggs KS, Sureda A, Qian W, et al. Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes. Br J Haematol. 2007;139:70–80
  16. Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008;111:5530–5536
  17. Ayuk F, Diyachenko G, Zabelina T, et al. Comparison of two doses of antithymocyte globulin in patients undergoing matched unrelated donor allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2008;14:913–919
  18. Meijer E, Cornelissen JJ, Lowenberg B, Verdonck LF. Antithymocyte globulin as prophylaxis of graft failure and graft-versus-host disease in recipients of partially T-cell-depleted grafts from matched unrelated donors: a dose-finding study. Exp Hematol. 2003;31:1026–1030
  19. Remberger M, Svahn BM, Mattsson J, Ringden O. Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation. 2004;78:122–127
  20. Mohty M, Bay JO, Faucher C, et al. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Blood. 2003;102:470–476
  21. Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91:756–763
  22. Przepiorka D, Ippoliti C, Khouri I, et al. Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation. Blood. 1996;88:4383–4389
  23. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828
  24. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204–217
  25. Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol. 1991;28:250–259
  26. Farmer ER. The histopathology of graft-versus-host disease. Adv Dermatol. 1986;1:173–188
  27. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695–706
  28. Khoury HJ, Loberiza FR, Ringden O, et al. Impact of posttransplantation G-CSF on outcomes of allogeneic hematopoietic stem cell transplantation. Blood. 2006;107:1712–1716
  29. Byrne JL, Stainer C, Cull G, et al. The effect of the serotherapy regimen used and the marrow cell dose received on rejection, graft-versus-host disease and outcome following unrelated donor bone marrow transplantation for leukaemia. Bone Marrow Transplant. 2000;25:411–417
  30. Finke J, Bertz H, Schmoor C, et al. Allogeneic bone marrow transplantation from unrelated donors using in vivo anti-T-cell globulin. Br J Haematol. 2000;111:303–313
  31. Russell JA, Turner AR, Larratt L, 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
  32. Sierra J, Storer B, Hansen JA, et al. Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience. Bone Marrow Transplant. 2000;26:397–404
  33. Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Eng J Med. 1998;338:962–968
  34. A Randomized Prospective Multicenter Phase III Trial comparing standard GvHD prophylaxis with cyclosporine and methotrexate with additional pretransplant ATG fresenius (ATG-F) in allogeneic stem cell transplantation from matched unrelated donors—Finke et al. 112:57. ASH Annu Meet Abstr 2009.
  35. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21:1387–1394
  36. Feng X, Kajigaya S, Solomou EE, et al. Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro. Blood. 2008;111:3675–3683
  37. Fang L, Fehse B, Engel M, Zander A, Kroger N. Antithymocyte globulin induces ex vivo and in vivo depletion of myeloid and plasmacytoid dendritic cells. Transplantation. 2005;79:369–371
  38. Grullich C, Ziegler C, Finke J. Rabbit anti T-lymphocyte globulin induces apoptosis in peripheral blood mononuclear cell compartments and leukemia cells, while hematopoetic stem cells are apoptosis resistant. Biol Blood Marrow Transplant. 2009;15:173–182
  39. Beiras-Fernandez A, Walther S, Kaczmarek I, et al. In vitro influence of polyclonal anti-thymocyte globulins on leukocyte expression of adhesion molecules. Exp Clin Transplant. 2005;3:370–374
  40. Haidinger M, Geyeregger R, Poglitsch M, et al. Antithymocyte globulin impairs T-cell/antigen-presenting cell interaction: disruption of immunological synapse and conjugate formation. Transplantation. 2007;84:117–121
  41. Dominietto A, Van Lint MT, Gualandi F. Is timing of anti-thymocyte globulin (ATG)—pre and post hemopoietic stem cell transplants (HSCT)—relevant for graft vs host disease (GvHD)?. Blood. 2003;102:242a
  42. Crawley C, Szydlo R, Lalancette M, et al. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood. 2005;106:2969–2976
  43. Mohty M, Jacot W, Faucher C, et al. Infectious complications following allogeneic HLA-identical sibling transplantation with antithymocyte globulin-based reduced intensity preparative regimen. Leukemia. 2003;17:2168–2177
  44. Ringden O, Labopin M, Gorin NC, et al. Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2004;22:416–423
  45. Ho VT, Mirza NQ, Junco Dd D, Okamura T, Przepiorka D. The effect of hematopoietic growth factors on the risk of graft-vs-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis. Bone Marrow Transplant. 2003;32:771–775

 Financial disclosure: See Acknowledgments on page 1429.

PII: S1083-8791(09)00325-5

doi: 10.1016/j.bbmt.2009.07.006

Biology of Blood and Marrow Transplantation
Volume 15, Issue 11 , Pages 1422-1430 , November 2009