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Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation.
Biol Blood Marrow Transplant. 2017 Dec; 23(12):2096-2101.BB

Abstract

Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (alloHCT). Prophylactic in vivo T cell depletion with antithymocyte globulin (ATG) has been associated with decreased GVHD rates in many alloHCT settings. Despite decades of clinical study, optimal ATG dosing has not been established. Understanding that higher rates of GVHD are observed with matched unrelated donor (MUD) versus matched related donor (MRD) alloHCT, at our institution MUD alloHCT recipients have historically had low-dose Thymoglobulin (total dose, 2.5 mg/kg; Genzyme-Sanofi, Cambridge, MA) added to our standard MRD GVHD prophylaxis regimen. In this retrospective cohort study we assessed post-HCT the effectiveness of our uniquely low-dose ATG strategy by comparing ATG exposed (MUD) and unexposed (MRD) alloHCT recipients for GVHD and other clinical HCT outcomes. This retrospective single-center study included all HCT patients transplanted for any malignant indication at The Ottawa Hospital from 2009 to 2014. MUD patients received rabbit ATG (Thymoglobulin) at a total dose of 2.5 mg/kg given over 2 days (.5 mg/kg on day -2; 2.0 mg/kg on day -1 before stem cell infusion) in addition to standard GVHD prophylaxis. Primary outcomes assessed were incidence of acute and chronic GVHD, defined as new-onset GVHD requiring systemic immunosuppressive therapy at less or more than 100 days, respectively. Secondary outcomes included disease relapse and survival. There were 110 and 77 patients in the ATG exposed (MUD) and unexposed (MRD) cohorts, respectively. At baseline there were no significant differences in median age at transplant, sex, disease indication or risk index, graft source, conditioning regimen, or intensity between cohorts. A higher proportion of 7/8 mismatched donor transplants (13% versus 3%, P = .02) and a higher median CD34+ dose (7.9 versus 4.9 × 108 cells; P < .01) was observed in the ATG exposed cohort. No differences were noted in platelet engraftment. ATG exposed patients had significantly shorter time to neutrophil engraftment than the unexposed cohort (16 versus 19 days, respectively; P < .01). ATG exposed patients had significantly lower rates of GVHD than ATG unexposed patients (57% versus 79%; P = .01), with differences predominantly in rates of chronic GVHD (18% versus 44%, P < .01). At median follow-up of 28 (range, 3 to 69) and 25 (range, 2 to 73) months for survivors in ATG exposed and unexposed cohorts, respectively, no significant differences in overall survival (median overall survival not met for either cohort), relapse incidence (26% versus 29%, P = .73), or relapse-free survival (RFS) (not met in ATG exposed and 26 months in ATG unexposed, P = .22) were observed between groups. The ATG exposed cohort had significantly higher GVHD-free RFS (GRFS) with a 2-year GRFS of 23% versus 3% (P = .003). There were no significant differences between cohorts in proportion of patientswith post-HCT infectious episodes or intensive care unit admissions. Here we report significantly lower rates of chronic GVHD and significant improvement in GRFS in an ATG exposed MUD alloHCT cohort compared with an ATG unexposed MRD cohort. These findings were observed without differences in relapse, survival, infectious complications, or intensive care unit admissions. Our findings highlight the association of unconventionally low-dose ATG with improved GVHD outcomes and suggest a need for prospective study of ATG use in lower doses.

Authors+Show Affiliations

The Ottawa Hospital Division of Hematology, University of Ottawa, Ottawa, Ontario, Canada.The Ottawa Hospital Department of Biostatistics, University of Ottawa, Ottawa, Ontario, Canada.Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Department of Medicine, Ottawa, Ontario, Canada; The Ottawa Hospital Bone Marrow Transplant Programme, University of Ottawa, Ottawa, Ontario, Canada.Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Department of Medicine, Ottawa, Ontario, Canada; The Ottawa Hospital Bone Marrow Transplant Programme, University of Ottawa, Ottawa, Ontario, Canada.Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Department of Medicine, Ottawa, Ontario, Canada; The Ottawa Hospital Bone Marrow Transplant Programme, University of Ottawa, Ottawa, Ontario, Canada.The Ottawa Hospital Bone Marrow Transplant Programme, University of Ottawa, Ottawa, Ontario, Canada.Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Department of Medicine, Ottawa, Ontario, Canada; The Ottawa Hospital Bone Marrow Transplant Programme, University of Ottawa, Ottawa, Ontario, Canada.Department of Biology, University of Ottawa, Ottawa, Ontario, Canada.Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Department of Medicine, Ottawa, Ontario, Canada; The Ottawa Hospital Bone Marrow Transplant Programme, University of Ottawa, Ottawa, Ontario, Canada.Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Department of Medicine, Ottawa, Ontario, Canada; The Ottawa Hospital Bone Marrow Transplant Programme, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: nkekre@toh.ca.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28821454

Citation

Bryant, Adam, et al. "Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 23, no. 12, 2017, pp. 2096-2101.
Bryant A, Mallick R, Huebsch L, et al. Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2017;23(12):2096-2101.
Bryant, A., Mallick, R., Huebsch, L., Allan, D., Atkins, H., Anstee, G., Sabloff, M., Scrivens, N., Maze, D., Bredeson, C., & Kekre, N. (2017). Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 23(12), 2096-2101. https://doi.org/10.1016/j.bbmt.2017.08.007
Bryant A, et al. Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2017;23(12):2096-2101. PubMed PMID: 28821454.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation. AU - Bryant,Adam, AU - Mallick,Ranjeeta, AU - Huebsch,Lothar, AU - Allan,David, AU - Atkins,Harold, AU - Anstee,Grizel, AU - Sabloff,Mitchell, AU - Scrivens,Nicholas, AU - Maze,Dawn, AU - Bredeson,Chris, AU - Kekre,Natasha, Y1 - 2017/08/15/ PY - 2017/07/04/received PY - 2017/08/08/accepted PY - 2017/8/20/pubmed PY - 2018/8/2/medline PY - 2017/8/20/entrez KW - Antithymocyte globulin KW - Graft-versus-host disease KW - Matched unrelated donor allogeneic hematopoietic stem cell transplantation SP - 2096 EP - 2101 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol. Blood Marrow Transplant. VL - 23 IS - 12 N2 - Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (alloHCT). Prophylactic in vivo T cell depletion with antithymocyte globulin (ATG) has been associated with decreased GVHD rates in many alloHCT settings. Despite decades of clinical study, optimal ATG dosing has not been established. Understanding that higher rates of GVHD are observed with matched unrelated donor (MUD) versus matched related donor (MRD) alloHCT, at our institution MUD alloHCT recipients have historically had low-dose Thymoglobulin (total dose, 2.5 mg/kg; Genzyme-Sanofi, Cambridge, MA) added to our standard MRD GVHD prophylaxis regimen. In this retrospective cohort study we assessed post-HCT the effectiveness of our uniquely low-dose ATG strategy by comparing ATG exposed (MUD) and unexposed (MRD) alloHCT recipients for GVHD and other clinical HCT outcomes. This retrospective single-center study included all HCT patients transplanted for any malignant indication at The Ottawa Hospital from 2009 to 2014. MUD patients received rabbit ATG (Thymoglobulin) at a total dose of 2.5 mg/kg given over 2 days (.5 mg/kg on day -2; 2.0 mg/kg on day -1 before stem cell infusion) in addition to standard GVHD prophylaxis. Primary outcomes assessed were incidence of acute and chronic GVHD, defined as new-onset GVHD requiring systemic immunosuppressive therapy at less or more than 100 days, respectively. Secondary outcomes included disease relapse and survival. There were 110 and 77 patients in the ATG exposed (MUD) and unexposed (MRD) cohorts, respectively. At baseline there were no significant differences in median age at transplant, sex, disease indication or risk index, graft source, conditioning regimen, or intensity between cohorts. A higher proportion of 7/8 mismatched donor transplants (13% versus 3%, P = .02) and a higher median CD34+ dose (7.9 versus 4.9 × 108 cells; P < .01) was observed in the ATG exposed cohort. No differences were noted in platelet engraftment. ATG exposed patients had significantly shorter time to neutrophil engraftment than the unexposed cohort (16 versus 19 days, respectively; P < .01). ATG exposed patients had significantly lower rates of GVHD than ATG unexposed patients (57% versus 79%; P = .01), with differences predominantly in rates of chronic GVHD (18% versus 44%, P < .01). At median follow-up of 28 (range, 3 to 69) and 25 (range, 2 to 73) months for survivors in ATG exposed and unexposed cohorts, respectively, no significant differences in overall survival (median overall survival not met for either cohort), relapse incidence (26% versus 29%, P = .73), or relapse-free survival (RFS) (not met in ATG exposed and 26 months in ATG unexposed, P = .22) were observed between groups. The ATG exposed cohort had significantly higher GVHD-free RFS (GRFS) with a 2-year GRFS of 23% versus 3% (P = .003). There were no significant differences between cohorts in proportion of patientswith post-HCT infectious episodes or intensive care unit admissions. Here we report significantly lower rates of chronic GVHD and significant improvement in GRFS in an ATG exposed MUD alloHCT cohort compared with an ATG unexposed MRD cohort. These findings were observed without differences in relapse, survival, infectious complications, or intensive care unit admissions. Our findings highlight the association of unconventionally low-dose ATG with improved GVHD outcomes and suggest a need for prospective study of ATG use in lower doses. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/28821454/Low_Dose_Antithymocyte_Globulin_for_Graft_versus_Host_Disease_Prophylaxis_in_Matched_Unrelated_Allogeneic_Hematopoietic_Stem_Cell_Transplantation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(17)30629-8 DB - PRIME DP - Unbound Medicine ER -