{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:09:40Z","timestamp":1787224180884,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2017,3,28]],"date-time":"2017-03-28T00:00:00Z","timestamp":1490659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Rabbit anti-thymocyte globulins (ATGs) are widely used for the prevention of acute and chronic graft versus host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, most prospective and retrospective studies did not reveal an overall survival (OS) benefit associated with ATG. Homozygosity for human leukocyte antigen (HLA)-C group 1 killer-cell immunoglobulin-like receptor ligands (KIR-L), i.e. C1\/1 KIR-L status, was recently shown to be a risk factor for severe aGVHD. Congruously, we have previously reported favorable outcomes in C1\/1 recipients after ATG-based transplants in a monocentric analysis. Here, within an extended cohort, we test the hypothesis that incorporation of ATG for GVHD prophylaxis may improve survival particularly in HSCT recipients with at least one C1 KIR-ligand. Retrospectively, 775 consecutive allogeneic (excluding haploidentical) HSCTs were analyzed, including peripheral blood and bone marrow grafts for adults with hematological diseases at two Austrian HSCT centers. ATG-Fresenius\/Grafalon, Thymoglobuline, and alemtuzumab were applied in 256, 87, and 7 transplants, respectively (subsequently summarized as \u201cATG\u201d), while 425 HSCT were performed without ATG. Median follow-up of surviving patients is 48 months. Adjusted for age, disease-risk, HLA-match, donor and graft type, sex match, cytomegalovirus serostatus, conditioning intensity, and type of post-grafting GVHD prophylaxis, Cox regression analysis of the entire cohort (n = 775) revealed a significant association of ATG with decreased non-relapse mortality (NRM) (risk ratio (RR), 0.57; p = 0.001), and overall mortality (RR, 0.71; p = 0.014). Upon stratification for HLA-C KIR-L, the greatest benefit for ATG emerged in C1\/1 recipients (n = 291), by reduction of non-relapse (RR, 0.34; p = 0.0002) and overall mortality (RR, 0.50; p = 0.003). Less pronounced, ATG decreased NRM (RR, 0.60; p = 0.036) in HLA-C group 1\/2 recipients (n = 364), without significantly influencing overall mortality (RR, 0.70; p = 0.065). After exclusion of higher-dose ATG-based transplants, serotherapy significantly improved both NRM (RR, 0.54; p = 0.019; n = 322) and overall mortality (RR, 0.60; p = 0.018) in C1\/2 recipients as well. In both, C1\/1 (RR, 1.70; p = 0.10) and particularly in C1\/2 recipients (RR, 0.94; p = 0.81), there was no statistically significant impact of ATG on relapse incidence. By contrast, in C2\/2 recipients (n = 121), ATG neither reduced NRM (RR, 1.10; p = 0.82) nor overall mortality (RR, 1.50; p = 0.17), but increased the risk for relapse (RR, 4.38; p = 0.02). These retrospective findings suggest ATG may provide a survival benefit in recipients with at least one C1 group KIR-L, by reducing NRM without significantly increasing the relapse risk.<\/jats:p>","DOI":"10.3390\/biomedicines5020013","type":"journal-article","created":{"date-parts":[[2017,3,28]],"date-time":"2017-03-28T10:24:33Z","timestamp":1490696673000},"page":"13","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation"],"prefix":"10.3390","volume":"5","author":[{"given":"Johannes","family":"Clausen","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Stra\u00dfl","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Stiefel","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Buxhofer-Ausch","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrid","family":"Machherndl-Spandl","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical University, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansj\u00f6rg","family":"Steitzer","sequence":"additional","affiliation":[{"name":"Austrian Red Cross, Transfusion Service for Upper Austria, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Danzer","sequence":"additional","affiliation":[{"name":"Austrian Red Cross, Transfusion Service for Upper Austria, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hedwig","family":"Kasparu","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ansgar","family":"Weltermann","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Nachbaur","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical University, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.bbmt.2014.11.676","article-title":"Rabbit anti-T cell globulin in allogeneic hematopoietic cell transplantation","volume":"21","author":"Storek","year":"2015","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.bbmt.2006.10.017","article-title":"Adult recipients of matched related donor blood cell transplants given myeloablative regimens including pretransplant antithymocyte globulin have lower mortality related to graft-versus-host disease: A matched pair analysis","volume":"13","author":"Russell","year":"2007","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.bbmt.2005.12.034","article-title":"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","volume":"12","author":"Bacigalupo","year":"2006","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1158\/1078-0432.CCR-14-0586","article-title":"Impact of chronic graft-versus-host disease on late relapse and survival on 7,489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia","volume":"21","author":"Boyiadzis","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6375","DOI":"10.1182\/blood-2011-01-329821","article-title":"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","volume":"117","author":"Socie","year":"2011","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E368","DOI":"10.1111\/ctr.12131","article-title":"A high antithymocyte globulin dose increases the risk of relapse after reduced intensity conditioning hsct with unrelated donors","volume":"27","author":"Remberger","year":"2013","journal-title":"Clin. Transpl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1182\/blood.V124.21.729.729","article-title":"Higher doses of antithymocyte globulin (ATG) increase the risk of relapse in acute myeloid leukemia (AML) patients undergoing matched related donor allogeneic transplantation in first complete remission (CR1): An analysis from the acute leukemia working party of ebmt","volume":"124","author":"Devillier","year":"2014","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.bbmt.2015.01.016","article-title":"Risk factors for steroid-refractory acute graft-versus-host disease after allogeneic stem cell transplantation from matched related or unrelated donors","volume":"21","author":"Calmettes","year":"2015","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1097\/MOH.0b013e32833f10f1","article-title":"Natural killer cells and tumor control","volume":"17","author":"Cooley","year":"2010","journal-title":"Curr. Opin. Hematol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3109\/07853890.2011.554430","article-title":"The role of natural killer cells in hematopoietic stem cell transplantation","volume":"44","author":"Tsirigotis","year":"2012","journal-title":"Ann. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3389\/fimmu.2013.00027","article-title":"The role of KIR genes and ligands in leukemia surveillance","volume":"4","author":"Babor","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/j.1365-2249.2007.03360.x","article-title":"Impact of natural killer cell dose and donor killer-cell immunoglobulin-like receptor (KIR) genotype on outcome following human leucocyte antigen-identical haematopoietic stem cell transplantation","volume":"148","author":"Clausen","year":"2007","journal-title":"Clin. Exp. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1182\/blood-2009-07-229740","article-title":"NK cells expressing inhibitory KIR for non-self-ligands remain tolerant in HLA-matched sibling stem cell transplantation","volume":"115","author":"Bjorklund","year":"2010","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/bmt.2008.432","article-title":"Kir genes and kir ligands affect occurrence of acute gvhd after unrelated, 12\/12 HLA matched, hematopoietic stem cell transplantation","volume":"44","author":"Ludajic","year":"2009","journal-title":"Bone Marrow Transpl."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.humimm.2007.01.019","article-title":"Donor-recipient combinations of group A and B KIR haplotypes and HLA class I ligand affect the outcome of HLA-matched, sibling donor hematopoietic cell transplantation","volume":"68","author":"McQueen","year":"2007","journal-title":"Hum. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5058","DOI":"10.1182\/blood-2007-01-065383","article-title":"Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic hct","volume":"109","author":"Miller","year":"2007","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.bbmt.2015.05.002","article-title":"Impact of KIR and HLA genotypes on outcomes after reduced-intensity conditioning hematopoietic cell transplantation","volume":"21","author":"Sobecks","year":"2015","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1038\/sj.leu.2403839","article-title":"A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related hla-identical hematopoietic stem cell transplantation","volume":"19","author":"Verheyden","year":"2005","journal-title":"Leukemia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.bbmt.2009.10.021","article-title":"The role of missing killer cell immunoglobulin-like receptor ligands in T cell replete peripheral blood stem cell transplantation from hla-identical siblings","volume":"16","author":"Clausen","year":"2010","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/bmt.2011.187","article-title":"Bone marrow may be the preferable graft source in recipients homozygous for HLA-C group 2 ligands for inhibitory killer IG-like receptors","volume":"47","author":"Clausen","year":"2012","journal-title":"Bone Marrow Transpl."},{"key":"ref_21","unstructured":"Robinson, J., Halliwell, J.A., McWilliam, H., Lopez, R., and Marsh, S.G. (2015, May 01). IPD\u2014The immuno polymorphism database. Available online: https:\/\/www.ebi.ac.uk\/ipd\/kir\/ligand.html."},{"key":"ref_22","first-page":"825","article-title":"1994 consensus conference on acute gvhd grading","volume":"15","author":"Przepiorka","year":"1995","journal-title":"Bone Marrow Transpl."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.bbmt.2005.09.004","article-title":"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","volume":"11","author":"Filipovich","year":"2005","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.bbmt.2008.12.497","article-title":"Reduced-intensity conditioning regimen workshop: Defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research","volume":"15","author":"Giralt","year":"2009","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/bmt.2013.204","article-title":"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","volume":"49","author":"Baron","year":"2014","journal-title":"Bone Marrow Transpl."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6963","DOI":"10.1182\/blood-2011-01-332007","article-title":"Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies","volume":"117","author":"Soiffer","year":"2011","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.bbmt.2014.01.016","article-title":"Antithymocyte globulin before allogeneic stem cell transplantation for progressive myelodysplastic syndrome: A study from the french society of bone marrow transplantation and cellular therapy","volume":"20","author":"Dulery","year":"2014","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1016\/j.bbmt.2009.07.006","article-title":"Improved nonrelapse mortality and infection rate with lower dose of antithymocyte globulin in patients undergoing reduced-intensity conditioning allogeneic transplantation for hematologic malignancies","volume":"15","author":"Hamadani","year":"2009","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1038\/bmt.2015.148","article-title":"Lower dose anti-thymocyte globulin for gvhd prophylaxis results in improved survival after allogeneic stem cell transplantation","volume":"50","author":"Binkert","year":"2015","journal-title":"Bone Marrow Transpl."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/bmt.2013.107","article-title":"Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice","volume":"49","author":"Ruutu","year":"2014","journal-title":"Bone Marrow Transpl."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1056\/NEJMoa1200503","article-title":"HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1","volume":"367","author":"Venstrom","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1182\/blood-2003-02-0438","article-title":"The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia","volume":"103","author":"Cook","year":"2004","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1182\/blood-2008-06-164103","article-title":"Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: Evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity","volume":"113","author":"Pende","year":"2009","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.bbmt.2016.09.028","article-title":"Recipient HLA-C haplotypes and microrna 148a\/b binding sites have no impact on allogeneic hematopoietic cell transplantation outcomes","volume":"23","author":"Hoff","year":"2017","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1056\/NEJMoa1506002","article-title":"Antilymphocyte globulin for prevention of chronic graft-versus-host disease","volume":"374","author":"Kroger","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2942","DOI":"10.1182\/blood.V98.10.2942","article-title":"Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from gruppo italiano trapianti midollo osseo (GITMO)","volume":"98","author":"Bacigalupo","year":"2001","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/S1470-2045(09)70225-6","article-title":"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","volume":"10","author":"Finke","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S1470-2045(15)00462-3","article-title":"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","volume":"17","author":"Walker","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/sj.bmt.1704157","article-title":"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)","volume":"32","author":"Zander","year":"2003","journal-title":"Bone Marrow Transpl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1097\/01.TP.0000133513.29923.44","article-title":"Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation","volume":"78","author":"Remberger","year":"2004","journal-title":"Transplantation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1038\/sj.bmt.1704957","article-title":"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","volume":"35","author":"Basara","year":"2005","journal-title":"Bone Marrow Transpl."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.bbmt.2010.12.702","article-title":"Use of matched unrelated donors compared with matched related donors is associated with lower relapse and superior progression-free survival after reduced-intensity conditioning hematopoietic stem cell transplantation","volume":"17","author":"Ho","year":"2011","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1016\/j.bbmt.2007.09.004","article-title":"Comparable outcomes after nonmyeloablative hematopoietic cell transplantation with unrelated and related donors","volume":"13","author":"Mielcarek","year":"2007","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1097\/TP.0000000000000976","article-title":"Impact of thymoglobulin by stem cell source (peripheral blood stem cell or bone marrow) after myeloablative stem cell transplantation from HLA 10\/10-matched unrelated donors. A report from the societe francaise de greffe de moelle et de therapie cellulaire","volume":"100","author":"Ravinet","year":"2016","journal-title":"Transplantation"}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/5\/2\/13\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:31:23Z","timestamp":1760207483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/5\/2\/13"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,28]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,6]]}},"alternative-id":["biomedicines5020013"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines5020013","relation":{},"ISSN":["2227-9059"],"issn-type":[{"value":"2227-9059","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,28]]}}}