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Impact of low-dose rabbit anti-thymocyte globulin in unrelated hematopoietic stem cell transplantation

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Abstract

We retrospectively evaluated the outcome of administering low-dose rabbit anti-thymocyte globulin (thymoglobulin: ATG-T) to 219 patients (ATG-T group, n = 30; no-ATG-T group, n = 189) who received an initial unrelated hematopoietic stem cell transplantation (uHSCT). The median total dose of ATG-T was 1.5 mg/kg. There was no significant difference in the cumulative incidences of grade II–IV (42 vs. 38 %, P = 0.87) and grade III–IV (5 vs. 7 %, P = 0.52) acute GVHD. In patients who received uHSCT from a donor with at least one HLA allele mismatch, the cumulative incidence of extensive chronic GVHD was significantly lower in the ATG-T group than that in the no-ATG-T group (13 vs. 44 %, P = 0.02). No patient in the ATG-T group developed chronic lung dysfunction. The probabilities of 1-year, GVHD-free/relapse-free survival (GRFS) were 61 % in the ATG-T group and 35 % in the no-ATG-T group (P = 0.02). Patients in the ATG-T group discontinued immunosuppressive drugs significantly earlier than those in the no-ATG-T group (P < 0.01). The use of low-dose ATG-T did not increase the incidence of severe infectious disease. The use of low-dose ATG-T in patients who received uHSCT was associated with a superior GRFS, reflecting the reduced incidence of severe/persistent GVHD without compromising overall survival.

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References

  1. Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, et al. Bone-marrow transplantation (first of two parts). N Engl J Med. 1975;292:832–43.

    Article  CAS  PubMed  Google Scholar 

  2. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Horan JT, Logan BR, Agovi-Johnson MA, Lazarus HM, Bacigalupo AA, Ballen KK, et al. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol. 2011;29:805–13.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Socie G, Stone JV, Wingard JR, Weisdorf D, Henslee-Downey PJ, Bredeson C, et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med. 1999;341:14–21.

    Article  CAS  PubMed  Google Scholar 

  5. Socie G, Ritz J. Current issues in chronic graft-versus-host disease. Blood. 2014;124:374–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jamil MO, Mineishi S. State-of-the-art acute and chronic GVHD treatment. Int J Hematol. 2015;101:452–66.

    Article  CAS  PubMed  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;10:855–64.

    Article  CAS  PubMed  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;117:6375–82.

    Article  CAS  PubMed  Google Scholar 

  9. Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE, et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant. 2006;12:560–5.

    Article  PubMed  Google Scholar 

  10. Oh H, Loberiza FR Jr, Zhang MJ, Ringden O, Akiyama H, Asai T, et al. Comparison of graft-versus-host-disease and survival after HLA-identical sibling bone marrow transplantation in ethnic populations. Blood. 2005;105:1408–16.

    Article  CAS  PubMed  Google Scholar 

  11. Hahn T, McCarthy PL Jr, Zhang MJ, Wang D, Arora M, Frangoul H, et al. Risk factors for acute graft-versus-host disease after human leukocyte antigen-identical sibling transplants for adults with leukemia. J Clin Oncol. 2008;26:5728–34.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Murata M. Prophylactic and therapeutic treatment of graft-versus-host disease in Japan. Int J Hematol. 2015;101:467–86.

    Article  CAS  PubMed  Google Scholar 

  13. Remberger M, Svahn BM, Mattsson J, Ringden O. Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation. 2004;78:122–7.

    CAS  PubMed  Google Scholar 

  14. Kim HJ, Min WS, Cho BS, Eom KS, Kim YJ, Min CK, et al. Successful prevention of acute graft-versus-host disease using low-dose antithymocyte globulin after mismatched, unrelated, hematopoietic stem cell transplantation for acute myelogenous leukemia. Biol Blood Marrow Transplant. 2009;15:704–17.

    Article  CAS  PubMed  Google Scholar 

  15. Fuji S, Ueno N, Hiramoto N, Asakura Y, Yakushijin K, Kamiyama Y, et al. Reduced-intensity conditioning regimen with low-dose ATG-F for unrelated bone marrow transplant is associated with lower non-relapse mortality than a regimen with low-dose TBI: a single-center retrospective analysis of 103 cases. Int J Hematol. 2013;98:608–14.

    Article  CAS  PubMed  Google Scholar 

  16. Hatanaka K, Fuji S, Ikegame K, Kato R, Wake A, Hidaka M, et al. Low incidences of acute and chronic graft-versus-host disease after unrelated bone marrow transplantation with low-dose anti-T lymphocyte globulin. Int J Hematol. 2012;96:773–80.

    Article  CAS  PubMed  Google Scholar 

  17. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.

    Article  CAS  PubMed  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  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood. 2004;104:3501–6.

    Article  CAS  PubMed  Google Scholar 

  21. Fuji S, Kim SW, Yano S, Hagiwara S, Nakamae H, Hidaka M et al. A prospective multicenter study of unrelated bone marrow transplants using a reduced-intensity conditioning regimen with low-dose ATG-F. Bone Marrow Transplant. 2015. doi:10.1038/bmt.2015.268 [Epub ahead of print].

  22. 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;125:1333–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Walker I, Schultz KR, Toze CL, Kerr HM, Moore J, Szwajcer D et al. Thymoglobulin decreases the need for immunosuppression at 12 months after myeloablative unrelated donor transplantation: CBMTG0801, a controlled trial. American Society of Hematology Annual Meeting. Blood. 2014;124. Abstract 38.

  26. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21:1387–94.

    Article  CAS  PubMed  Google Scholar 

  27. Devillier R, Furst S, El-Cheikh J, Castagna L, Harbi S, Granata A, et al. Antithymocyte globulin in reduced-intensity conditioning regimen allows a high disease-free survival exempt of long-term chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:370–4.

    Article  CAS  PubMed  Google Scholar 

  28. Remberger M, Ringden O, Hagglund H, Svahn BM, Ljungman P, Uhlin M, et al. A high antithymocyte globulin dose increases the risk of relapse after reduced intensity conditioning HSCT with unrelated donors. Clin Transplant. 2013;27:E368–74.

    Article  CAS  PubMed  Google Scholar 

  29. Bonifazi F, Solano C, Wolschke C, et al. Prevention of chronic GvHD after HLA-indentical 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). American Society of Hematology Annual Meeting. Blood. 2014;124. Abstract 37.

  30. Dirou S, Malard F, Chambellan A, Chevallier P, Germaud P, Guillaume T, et al. Stable long-term pulmonary function after fludarabine, antithymocyte globulin and i.v. BU for reduced-intensity conditioning allogeneic SCT. Bone Marrow Transplant. 2014;49:622–7.

    Article  CAS  PubMed  Google Scholar 

  31. Milano F, Au MA, Boeckh MJ, Deeg HJ, Chien JW. Evaluating the impact of antithymocyte globulin on lung function at 1 year after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2011;17:703–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zander AR, Kroger N, Schleuning M, Finke J, Zabelina T, Beelen D, et al. ATG as part of the conditioning regimen reduces transplant-related mortality (TRM) and improves overall survival after unrelated stem cell transplantation in patients with chronic myelogenous leukemia (CML). Bone Marrow Transplant. 2003;32:355–61.

    Article  CAS  PubMed  Google Scholar 

  33. Schattenberg A, van der Meer A, Preijers F, Schaap N, Rinkes M, van der Maazen R, et al. Addition of ATG to the conditioning regimen is a major determinant for outcome after transplantation with partially lymphocyte-depleted grafts from voluntary unrelated donors. Bone Marrow Transplant. 2004;33:1115–21.

    Article  CAS  PubMed  Google Scholar 

  34. Crocchiolo R, Esterni B, Castagna L, Furst S, El-Cheikh J, Devillier R, et al. Two days of antithymocyte globulin are associated with a reduced incidence of acute and chronic graft-versus-host disease in reduced-intensity conditioning transplantation for hematologic diseases. Cancer. 2013;119:986–92.

    Article  CAS  PubMed  Google Scholar 

  35. 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;117:6963–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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;98:2942–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the Japanese Ministry of Health, Labour and Welfare and the National Cancer Research and Development Fund. We thank the medical, nursing, data-processing, laboratory, and clinical staffs at the participating centers for their important contributions to this study and their dedicated patient care.

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Authors and Affiliations

  1. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan

    Kodai Kuriyama, Shigeo Fuji, Yoshihiro Inamoto, Kinuko Tajima, Takashi Tanaka, Yoshitaka Inoue, Reiko Ito, Yoshiki Hayashi, Ayumu Ito, Saiko Kurosawa, Sung-Won Kim, Takuya Yamashita & Takahiro Fukuda

  2. Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

    Kodai Kuriyama

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  1. Kodai Kuriyama
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Correspondence to Shigeo Fuji.

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Kuriyama, K., Fuji, S., Inamoto, Y. et al. Impact of low-dose rabbit anti-thymocyte globulin in unrelated hematopoietic stem cell transplantation. Int J Hematol 103, 453–460 (2016). https://doi.org/10.1007/s12185-016-1947-9

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  • DOI: https://doi.org/10.1007/s12185-016-1947-9

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