Allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of severe acute and chronic graft-versus-host disease (GVHD) compared to bone marrow transplantation. Anti-thymocyte globulin (ATG) can reduce severe acute and chronic GVHD in PBSCT; however, an optimal dose of ATG remains undefined. We conducted a multicenter phase II study to investigate safety and efficacy of low-dose ATG (a total of 2 mg/kg Thymoglobulin) in patients undergoing HLA-matched PBSCT after myeloablative conditioning. The primary endpoint was grades III–IV GVHD at 100 days. Seventy-seven patients were enrolled and 72 patients with a median age of 46.5 years were eligible for analysis. The primary endpoint, cumulative incidence of grades III–IV acute GVHD at 100 days was 1.4% (95% CI, 0.1–6.7%), which was greatly less than our pre-defined statistical threshold value (18.0%). The incidence of chronic GVHD at 1 year was also low (all-grade; 15.3%, moderate to severe; 5.6%). Non-relapse mortality, relapse, overall survival, disease-free survival, and GVHD-free, relapse-free survival at 1 year were 4.2%, 20.8%, 84.7%, 75.0%, and 69.4%, respectively. Low dose thymoglobulin is promising to reduce severe acute and chronic GVHD in HLA-matched PBSCT following myeloablative conditioning.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Impact of anti-thymocyte globulin on survival outcomes in female-to-male allogeneic hematopoietic stem cell transplantation
Scientific Reports Open Access 03 May 2023
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Friedrichs B, Tichelli A, Bacigalupo A, Russell NH, Ruutu T, Shapira MY, et al. Long-term outcome and late effects in patients transplantedwith mobilised blood or bone marrow: a randomised trial. Lancet Oncol. 2010;11:331–8.
Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367:1487–96.
Nagafuji K, Matsuo K, Teshima T, Mori S, Sakamaki H, Hidaka M, et al. Peripheral blood stem cell versus bone marrow transplantation from HLA-identical sibling donors in patients with leukemia: a propensity score-based comparison from the Japan Society for Hematopoietic Stem Cell Transplantation registry. Int J Hematol. 2010;91:855–64.
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.
Solh M, Zhang X, Connor K, Brown S, Solomon SR, Morris LE, et al. Factors predicting graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation: multivariable analysis from a single center. Biol Blood Marrow Transpl. 2016;22:1403–9.
Zheng CC, Zhu XY, Tang BL, Zhang XH, Zhang L, Geng LQ, et al. Clinical separation of cGvHD and GvL and better GvHD-free/relapse-free survival (GRFS) after unrelated cord blood transplantation for AML. Bone Marrow Transpl. 2016;52:88–94 [Epub ahead of print].
Inamoto Y, Kimura F, Kanda J, Sugita J, Ikegame K, Nakasone H, et al. Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups. Haematologica. 2016;101:1592–602.
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.
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 Transpl. 2006;12:560–5.
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.
Socié 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.
Kröger 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.
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.
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.
Yu ZP, Ding JH, Wu F, Liu J, Wang J, Cheng J, et al. Quality of life of patients after allogeneic hematopoietic stem cell transplantation with antihuman thymocyte globulin. Biol Blood Marrow Transpl. 2012;18:593–9.
Wang Y, Fu HX, Liu DH, Xu LP, Zhang XH, Chang YJ, et al. Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial. Bone Marrow Transpl. 2014;49:426–33.
Basara N, Baurmann H, Kolbe K, Yaman A, Labopin M, Burchardt A, 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 Transpl. 2005;35:1011–8.
Deeg HJ, Storer BE, Boeckh M, Martin PJ, McCune JS, Myerson D, et al. Reduced incidence of acute and chronic graft-versus-host disease with the addition of thymoglobulin to a targeted busulfan/cyclophosphamide regimen. Biol Blood Marrow Transpl. 2006;12:573–84.
Bredeson CN, Zhang MJ, Agovi MA, Bacigalupo A, Bahlis NJ, Ballen K, et al. Outcomes following HSCT using fludarabine, busulfan, and thymoglobulin: a matched comparison to allogeneic transplants conditioned with busulfan and cyclophosphamide. Biol Blood Marrow Transpl. 2008;14:993–1003.
Call SK, Kasow KA, Barfield R, Madden R, Leung W, Horwitz E, et al. Total and active rabbit antithymocyte globulin (rATG;Thymoglobulin) pharmacokinetics in pediatric patients undergoing unrelated donor bone marrow transplantation. Biol Blood Marrow Transpl. 2009;15:274–8.
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 Transpl. 2009;15:704–17.
Busca A, Locatelli F, Flonta SE, Ciccone G, Baldi I, D’Ardia S, et al. In vivo T-cell depletion with pretransplant low-dose antithymocyte globulin is associated with reduced transplant-related mortality and improved clinical outcome in patients receiving allogeneic hematopoietic stem cell transplantation from unrelated and partially matched related donors. Am J Hematol. 2011;86:214–7.
Bashir Q, Munsell MF, Giralt S, de Padua Silva L, Sharma M, Couriel D, et al. Randomized phase II trial comparing two dose levels of thymoglobulin in patients undergoing unrelated donor hematopoietic cell transplant. Leuk Lymphoma. 2012;53:915–9.
Al-Kadhimi Z, Gul Z, Rodriguez R, Chen W, Smith D, Mitchell A, et al. Anti-thymocyte globulin (thymoglobulin), tacrolimus, and sirolimus as acute graft-versus-host disease prophylaxis for unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2012;18:1734–44.
Baron F, Mohty M, Blaise D, Socié G, Labopin M, Esteve J, et al. Anti-thymocyte globulin as graft-versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation: a review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2017;102:224–34.
Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, et al. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest. 2015;125:2677–89.
Chawla S, Dharmani-Khan P, Liu Y, Prokopishyn N, Amlish Munir M, Griffiths C, et al. High serum level of antithymocyte globulin immediately before graft infusion is associated with a low likelihood of chronic, but not acute, graft-versus-host disease. Biol Blood Marrow Transpl. 2014;20:1156–62.
Shiratori S, Kosugi-Kanaya M, Hayase E, Okada K, Goto H, Sugita J, et al. T-cell depletion effects of low-dose antithymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation. Transpl Immunol. 2018;46:21–2.
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.
Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25:3503–10.
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.
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.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transpl. 2005;11:945–56.
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.
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–54.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clin Res ed). 2003;327:557–60.
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.
Konuma T, Tsukada N, Kanda J, Uchida N, Ohno Y, Miyakoshi S, et al. Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older. Am J Hematol. 2016;91:E284–92.
Kanda J, Brazauskas R, Hu ZH, Kuwatsuka Y, Nagafuji K, Kanamori H, et al. Graft-versus-host disease after HLA-matched sibling bone marrow or peripheral blood stem cell transplantation: comparison of North American Caucasian and Japanese populations. Biol Blood Marrow Transpl. 2016;22:744–51.
Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P, et al. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoiet ic cell transplantation. Cytotherapy. 2012;14:1258–75.
Servais S, Menten-Dedoyart C, Beguin Y, Seidel L, Gothot A, Daulne C, et al. Impact of pre-transplant anti-t cell globulin (ATG) on immune recovery after myeloablative allogeneic peripheral blood stem cell transplantation. PLoS ONE. 2015;10:e0130026.
Admiraal R, Nierkens S, de Witte MA, Petersen EJ, Fleurke GJ, Verrest L, et al. Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis. Lancet Haematol. 2017;4:e183–91.
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.
Ito A, Kitano S, Tajima K, Kim Y, Tanaka T, Inamoto Y, et al. Impact of low-dose anti-thymocyte globulin on immune reconstitution after allogeneic hematopoietic cell transplantation. Int J Hematol. 2020;111:120–30.
Kuriyama K, Fuji S, Inamoto Y, Tajima K, Tanaka T, Inoue Y, et al. Impact of low-dose rabbit anti-thymocyte globulin in unrelated hematopoietic stem cell transplantation. Int J Hematol. 2016;103:453–60.
Imataki O, Matsumoto K, Uemura M. Low-dose anti-thymocyte globulin reduce severe acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. J Cancer Res Clin Oncol. 2017;143:709–15.
Shichijo T, Fuji S, Tajima K, Kubo H, Nozaki K, Honda T, et al. Beneficial impact of low-dose rabbit anti-thymocyte globulin in unrelated hematopoietic stem cell transplantation: focusing on difference between stem cell sources. Bone Marrow Transpl. 2018;53:634–9.
Bryant A, Mallick R, Huebsch L, Allan D, Atkins H, Anstee G, et al. Low-dose antithymocyte globulin for graft-versus-host-disease prophylaxis in matched unrelated allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2017;23:2096–101.
Tandra A, Covut F, Cooper B, Creger R, Brister L, McQuigg B, et al. Low dose anti-thymocyte globulin reduces chronic graft-versus-host disease incidence rates after matched unrelated donor transplantation. Leuk Lymphoma. 2018;59:1644–51.
Mountjoy L, Jain T, Kunze KL, Khera N, Sproat LZ, Jennifer W, et al. Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation. Leuk Lymphoma. 2020;1–7. https://doi.org/10.1080/10428194.2020.1747067.
This work was in supported by grants from North Japan Hematology Study Group, and the Japan Agency for Medical Research and Development (AMED, 19ek0510025h0002).
Japan Study Group for Cell Therapy and Transplantation (JSCT)
Masahiro Imamura14, Shuichi Taniguchi15, Chihiro Shimazaki16, Shinji Nakao17, Mitsune Tanimoto18, Kenji Imajo19, Koichi Akashi20, Takanori Teshima21, Takashi Okamura22, Koji Nagafuji23, Toshihiro Miyamoto20, Yuju Ohno24, Takahiro Fukuda25, Tetsuya Eto26, Morio Matsumoto27, Hirokazu Okumura28, Tohru Murayama29, Kazutaka Sunami30, Naoki Kobayashi14, Naoyuki Uchida15, Yoshinobu Kanda31, Hideki Tsujimura32, Koji Kato20, Yasushi Takamatsu33, Junichi Sugita21, Michihiro Hidaka34, Yuichiro Nawa35, Mine Harada36
Conflict of interest
TT has received research funds from Sanofi.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Members of the Japan Study Group for Cell Therapy and Transplantation (JSCT) are listed below Acknowledgements.
About this article
Cite this article
Shiratori, S., Sugita, J., Ota, S. et al. Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 56, 129–136 (2021). https://doi.org/10.1038/s41409-020-0985-3
This article is cited by
Impact of anti-thymocyte globulin on survival outcomes in female-to-male allogeneic hematopoietic stem cell transplantation
Scientific Reports (2023)
Low-dose antithymocyte globulin inhibits chronic graft-versus-host disease in peripheral blood stem cell transplantation from unrelated donors
Bone Marrow Transplantation (2021)
High lymphocyte counts before antithymocyte globulin administration predict acute graft-versus-host disease
Annals of Hematology (2021)