Abstract
HLA 1-locus-mismatched unrelated donors (1MMUD) have been used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. We retrospectively analyzed 3313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD between 2009 and 2014. We compared the outcomes of MUD (n=2089) and 1MMUD with antithymocyte globulin (ATG) (1MM-ATG(+); n=109) with those of 1MMUD without ATG (1MM-ATG(−); n=1115). The median total dose of ATG (thymoglobulin) was 2.5 mg/kg (range 1.0–11.0 mg/kg) in the 1MM-ATG(+) group. The rates of grade III–IV acute GvHD, non-relapse mortality (NRM) and overall mortality were significantly lower in the MUD group than in the 1MM-ATG(−) group (hazard ratio (HR) 0.77, P=0.016; HR 0.74; P<0.001; and HR 0.87, P=0.020, respectively). Likewise, the rates of grade III–IV acute GVHD, NRM and overall mortality were significantly lower in the 1MM-ATG(+) group than in the 1MM-ATG(−) group (HR 0.42, P=0.035; HR 0.35, P<0.001; and HR 0.71, P=0.042, respectively). The outcome of allo-HCT from 1MM-ATG(−) was inferior to that of allo-HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared with the use of low-dose ATG without increasing the risk of relapse.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N, Milpied N et al. Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol 2006; 24: 5695–5702.
Schetelig J, Bornhauser M, Schmid C, Hertenstein B, Schwerdtfeger R, Martin H et al. Matched unrelated or matched sibling donors result in comparable survival after allogeneic stem-cell transplantation in elderly patients with acute myeloid leukemia: a report from the cooperative German Transplant Study Group. J Clin Oncol 2008; 26: 5183–5191.
Kanda J, Saji H, Fukuda T, Kobayashi T, Miyamura K, Eto T et al. Related transplantation with HLA-1 Ag mismatch in the GVH direction and HLA-8/8 allele-matched unrelated transplantation: a nationwide retrospective study. Blood 2012; 119: 2409–2416.
Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M et al. Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood 2004; 104: 1923–1930.
Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.
Kanda Y, Kanda J, Atsuta Y, Maeda Y, Ichinohe T, Ohashi K et al. Impact of a single human leucocyte antigen (HLA) allele mismatch on the outcome of unrelated bone marrow transplantation over two time periods. A retrospective analysis of 3003 patients from the HLA Working Group of the Japan Society for Blood and Marrow Transplantation. Br J Haematol 2013; 161: 566–577.
Kanda J, Ichinohe T, Fuji S, Maeda Y, Ohashi K, Fukuda T et al. Impact of HLA mismatch direction on the outcome of unrelated bone marrow transplantation: a retrospective analysis from the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2015; 21: 305–311.
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: 560–565.
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: 2942–2947.
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: 855–864.
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: 6375–6382.
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: 704–717.
Mohty M, Labopin M, Balere ML, Socie G, Milpied N, Tabrizi R et al. Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Leukemia 2010; 24: 1867–1874.
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: 453–460.
Hamadani M, Blum W, Phillips G, Elder P, Andritsos L, Hofmeister C et al. Improved nonrelapse mortality and infection rate with lower dose of antithymocyte globulin in patients undergoing reduced-intensity conditioning allogeneic transplantation for hematologic malignancies. Biol Blood Marrow Transplant 2009; 15: 1422–1430.
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: 6963–6970.
Baron F, Labopin M, Blaise D, Lopez-Corral L, Vigouroux S, Craddock C et al. Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2014; 49: 389–396.
Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol 2007; 86: 269–274.
Atsuta Y . Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol 2016; 103: 3–10.
Morishima Y, Sasazuki T, Inoko H, Juji T, Akaza T, Yamamoto K et al. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood 2002; 99: 4200–4206.
Kawase T, Morishima Y, Matsuo K, Kashiwase K, Inoko H, Saji H et al. High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism. Blood 2007; 110: 2235–2241.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.
Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.
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: 1333–1338.
Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009; 15: 367–369.
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: 1141–1154.
Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.
Kanda Y . Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013; 48: 452–458.
Kanda J . Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. Int J Hematol 2016; 103: 11–19.
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: 164–173.
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: 1408–1416.
Morishima Y, Kawase T, Malkki M, Morishima S, Spellman S, Kashiwase K et al. Significance of ethnicity in the risk of acute graft-versus-host disease and leukemia relapse after unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1197–1203.
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 Transplant 2016; 22: 744–751.
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 2016; 51: 451–453.
Acknowledgements
We thank all of the physicians and staff members of the collaborating institutes of the Japan Society for Hematopoietic Stem Cell Transplantation.
Author contributions
KK, JK and YK designed the study and performed the statistical analysis; KK, JK, SF, MM, K Ikegame and YK interpreted the data and wrote the manuscript; KY, TF, TH, YO, NU, YK, K Iwato, TS, MH and HH provided the patient data; TF, TI and YA collected the patient data; and all of the authors interpreted the data, and reviewed and approved the final manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
Rights and permissions
About this article
Cite this article
Kawamura, K., Kanda, J., Fuji, S. et al. Impact of the presence of HLA 1-locus mismatch and the use of low-dose antithymocyte globulin in unrelated bone marrow transplantation. Bone Marrow Transplant 52, 1390–1398 (2017). https://doi.org/10.1038/bmt.2017.153
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2017.153
This article is cited by
-
Human leukocyte antigen 7/8-matched unrelated bone marrow transplantation using anti-thymocyte globulin in children
International Journal of Hematology (2023)
-
Outcomes of patients with hematological malignancies who undergo unrelated donor hematopoietic stem cell transplantation with ATG-Fresenius versus ATG-Genzyme
Annals of Hematology (2023)
-
Personalizing rabbit anti-thymocyte globulin therapy for prevention of graft-versus-host disease after allogeneic hematopoietic cell transplantation: is there an optimal dose?
Bone Marrow Transplantation (2020)
-
Influence of HLA 1–3-locus mismatch and antithymocyte globulin administration in unrelated bone marrow transplantation
Annals of Hematology (2020)
-
Feasibility of salvage cord blood transplantation using a fludarabine, melphalan, and low-dose anti-thymocyte globulin conditioning regimen
International Journal of Hematology (2019)