Role of antithymocyte globulin in matched sibling donor peripheral blood stem cell transplantation for hematologic malignancies

Liping Dou, Lu Wang, Xin Li, Yvchen Liu, Fei Li, Lijun Wang, Xiaoning Gao, Wenrong Huang, Shuhong Wang, Chunji Gao, Li Yu, Daihong Liu, Liping Dou, Lu Wang, Xin Li, Yvchen Liu, Fei Li, Lijun Wang, Xiaoning Gao, Wenrong Huang, Shuhong Wang, Chunji Gao, Li Yu, Daihong Liu

Abstract

Background: High incidence of chronic graft-versus-host disease (GVHD) has been a major drawback of matched sibling donor peripheral blood stem cell transplantation (MSD -PBSCT). This study aimed to investigate the safety and efficacy of antithymocyte globulin (ATG) as a standardized part of GVHD prophylaxis in patients receiving MSD -PBSCT.

Methods: A total of 72 patients with hematological malignancies receiving MSD -PBSCT who displayed similar baseline characteristics were either given rabbit ATG ( n = 42) or no ATG (n = 30), in addition to cyclosporine, methotrexate, and mycophenolate mofetil as a standard GVHD prophylaxis regimen. Either patients or donors aged ≥40 years were included in the study. Thymoglobulin was administered at a daily dose of 1.5 mg/kg on day -5 and 3.5 mg/kg on day -4 prior to transplant (the total dose was 5 mg/kg).

Results: After a median follow-up of 874 days, the 3-year cumulative incidence of chronic GVHD (cGVHD) was 37.3% in the ATG group and 52.1% in the non -ATG group. The 3-year overall and disease-free survival probability were 71.0% and 62.0% (ATG versus non -ATG, P = .262) and 66.7% and 58.4% (ATG versus non -ATG, P = .334). No difference was found in the 2-year cumulative incidence of nonrelapse mortality and relapse between the ATG and non -ATG groups. This significant reduction in the incidence of cGVHD without increased relapse risk and nonrelapse mortality led to a 3-year GVHD-free, relapse-free survival probability of 66.7% and 40.0% in the ATG and non-ATG groups, respectively.

Conclusions: These data suggested that rabbit antithymocyte globulin in the current protocol for GVHD prophylaxis was well tolerable and efficacious.The clinical trial was registered on January 1, 2016 (ClinicalTrials.gov Identifier NCT02677181). https://ichgcp.net/clinical-trials-registry/NCT02677181.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.

Figures

Figure 1
Figure 1
Flow chart illustrating patient selection for analysis. ATG = antithymocyte globulin.
Figure 2
Figure 2
Cumulative incidence of aGVHD and cGVHD after MSD-PBSCT with rATG combined with cyclosporine, mycophenolate, and short-term methotrexate as GVHD prophylaxis compared with the non -ATG group. ATG = antithymocyte globulin, GVHD = graft-versus-host disease.
Figure 3
Figure 3
Cumulative incidence of NRM, relapse, OS, DFS, and GRFS after MSD-PBSCT with rATG combined with cyclosporine, mycophenolate, and short-term methotrexate for GVHD prophylaxis compared with the non -ATG group. ATG = antithymocyte globulin, DFS = disease-free survival, GRFS = severe GVHD-free, relapse-free survival, NRM = non-relapse mortality, OS = overall survival.

References

    1. Bonifazi F, Solano C, Wolschke C, et al. . Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study. Lancet Haematol 2019;6:e89–99.
    1. Nishihori T, Al-Kadhimi Z, Hamadani M, et al. . Antithymocyte globulin in allogeneic hematopoietic cell transplantation: benefits and limitations. Immunotherapy 2016;8:435–47.
    1. Bosch M, Dhadda M, Hoegh-Petersen M, et al. . Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy 2012;14:1258–75.
    1. Bonifazi F, Bandini G, Arpinati M, et al. . Intensification of GVHD prophylaxis with low-dose ATG-F before allogeneic PBSC transplantation from HLA-identical siblings in adult patients with hematological malignancies: results from a retrospective analysis. Bone Marrow Transplant 2012;47:1105–11.
    1. Admiraal R, Lindemans CA, van Kesteren C, et al. . Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation. Blood 2016;128:2734–41.
    1. Sakellari I, Batsis I, Bousiou Z, et al. . The Role of Low-dose Anti-thymocyte Globulin as Standard Prophylaxis in Mismatched and Matched Unrelated Hematopoietic Peripheral Stem Cell Transplantation for Hematologic Malignancies. Clin Lymphoma Myeloma Leuk 2017;17:658–66.
    1. Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. . Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol 2015;2:e194–203.
    1. Locatelli F, Bernardo ME, Bertaina A, et al. . Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:1126–36.
    1. Socie G, Schmoor C, Bethge WA, 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.
    1. Soiffer RJ, Kim HT, McGuirk J, 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.
    1. Kroger N, Solano C, Wolschke C, et al. . Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med 2016;374:43–53.
    1. Li HH, Li F, Gao CJ, et al. . Similar incidence of severe acute GVHD and less severe chronic GVHD in PBSCT from unmanipulated, haploidentical donors compared with that from matched sibling donors for patients with haematological malignancies. Br J Haematol 2017;176:92–100.
    1. Dou L, Hou C, Ma C, et al. . Reduced risk of chronic GVHD by low dose rATG in adult matched sibling donor peripheral blood stem cell transplantation for hematologic malignancies. Ann Hematol 2020;99:167–79.
    1. Zhao XF, Mao XF, Wan DM, et al. . Modified busulfan and cyclophosphamide conditioning regimen for allogeneic hematopoietic stem cell transplantation in the treatment of patients with hematologic malignancies. Transplant Proc 2014;46:1531–5.
    1. Lee SE, Cho BS, Kim JH, et al. . Risk and prognostic factors for acute GVHD based on NIH consensus criteria. Bone Marrow Transplant 2013;48:587–92.
    1. Rihn C, Cilley J, Naik P, et al. . Definition of myeloid engraftment after allogeneic hematopoietic stem cell transplantation. Haematologica 2004;89:763–4.
    1. Vigorito AC, Campregher PV, Storer BE, et al. . Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD. Blood 2009;114:702–8.
    1. Arora M, Klein JP, Weisdorf DJ, et al. . Chronic GVHD risk score: a center for international blood and marrow transplant research analysis. Blood 2011;117:6714–20.
    1. Armand P, Kim HT, Logan BR, et al. . Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 2014;123:3664–71.
    1. Sandmaier BM, Kornblit B, Storer BE, et al. . Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol 2019;6:e409–18.
    1. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 2012;12:443–58.
    1. Giebel S, Labopin M, Czerw T, et al. . Impact of anti-thymocyte globulin on results of allogeneic peripheral blood stem cell transplantation for patients with Philadelphia-positive acute lymphoblastic leukaemia: an analysis by the Acute Leukemia Working Party of the EBMT. Eur J Cancer 2019;106:212–9.
    1. Retiere C, Willem C, Guillaume T, et al. . Impact on early outcomes and immune reconstitution of high-dose post-transplant cyclophosphamide vs anti-thymocyte globulin after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation. Oncotarget 2018;9:11451–64.
    1. Theurich S, Fischmann H, Shimabukuro-Vornhagen A, et al. . Polyclonal anti-thymocyte globulins for the prophylaxis of graft-versus-host disease after allogeneic stem cell or bone marrow transplantation in adults. Cochrane Database Syst Rev 2012;Cd009159.
    1. Gagelmann N, Ayuk F, Wolschke C, et al. . 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.
    1. Storek J, Mohty M, Boelens JJ. Rabbit anti-T cell globulin in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2015;21:959–70.
    1. Tandra A, Covut F, Cooper 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.
    1. Bonifazi F, Olivieri J, Sessa M, et al. . Low-dose anti-T lymphoglobulin as prophylaxis for graft-versus-host disease in unrelated donor transplantations for acute leukemias and myelodysplastic syndromes. Biol Blood Marrow Transplant 2018;24:2450–8.
    1. Lopez M, Clarkson MR, Albin M, et al. . A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. J Am Soc Nephrol 2006;17:2844–53.
    1. Czerw T, Labopin M, Giebel S, et al. . Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT. Cancer 2018;124:2523–33.
    1. Devillier R, Labopin M, Chevallier P, 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.
    1. Salomon RM, Ripley B, Kennedy JS, et al. . Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biol Psychiatry 2003;54:96–104.
    1. Sharf R, Sarhan M, Dileone RJ. Orexin mediates the expression of precipitated morphine withdrawal and concurrent activation of the nucleus accumbens shell. Biol Psychiatry 2008;64:175–83.
    1. Välimäki M, Pelkonen R, Härkönen M, et al. . Hormonal changes in noncirrhotic male alcoholics during ethanol withdrawal. Alcohol Alcohol 1984;19:235–42.

Source: PubMed

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