PMID- 28536356 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 2227-9059 (Print) IS - 2227-9059 (Electronic) IS - 2227-9059 (Linking) VI - 5 IP - 2 DP - 2017 Mar 28 TI - 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. LID - 10.3390/biomedicines5020013 [doi] LID - 13 AB - 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 "ATG"), 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. FAU - Clausen, Johannes AU - Clausen J AD - Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria. johannes.clausen@ordensklinikum.at. FAU - Bohm, Alexandra AU - Bohm A AD - Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria. alexaboehm@yahoo.de. FAU - Strassl, Irene AU - Strassl I AD - Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria. irene.strassl@ordensklinikum.at. FAU - Stiefel, Olga AU - Stiefel O AD - Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria. olga.stiefel@ordensklinikum.at. FAU - Buxhofer-Ausch, Veronika AU - Buxhofer-Ausch V AD - Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria. veronika.buxhofer-ausch@ordensklinikum.at. FAU - Machherndl-Spandl, Sigrid AU - Machherndl-Spandl S AD - Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria. sigrid.machherndl-spandl@ordensklinikum.at. FAU - Konig, Josef AU - Konig J AD - Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria. josef.koenig@ordensklinikum.at. FAU - Schmidt, Stefan AU - Schmidt S AD - Department of Hematology and Oncology, Medical University, 6020 Innsbruck, Austria. stefan.schmidt@i-med.ac.at. FAU - Steitzer, Hansjorg AU - Steitzer H AD - Austrian Red Cross, Transfusion Service for Upper Austria, 4020 Linz, Austria. hansjoerg.steitzer@o.roteskreuz.at. FAU - Danzer, Martin AU - Danzer M AD - Austrian Red Cross, Transfusion Service for Upper Austria, 4020 Linz, Austria. martin.danzer@o.roteskreuz.at. FAU - Kasparu, Hedwig AU - Kasparu H AD - Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria. hedwig.kasparu@ordensklinikum.at. FAU - Weltermann, Ansgar AU - Weltermann A AD - Department of Hematology and Oncology, Elisabethinen Hospital, 4020 Linz, Austria. ansgar.weltermann@ordensklinikum.at. FAU - Nachbaur, David AU - Nachbaur D AD - Department of Hematology and Oncology, Medical University, 6020 Innsbruck, Austria. david.nachbaur@i-med.ac.at. LA - eng PT - Journal Article DEP - 20170328 PL - Switzerland TA - Biomedicines JT - Biomedicines JID - 101691304 PMC - PMC5489799 OTO - NOTNLM OT - HLA-C OT - KIR ligand OT - antithymocyte globulin OT - graft-versus-host disease OT - hematopoietic stem cell transplantation OT - killer cell immunoglobulin-like receptor OT - serotherapy COIS- Johannes Clausen received consultation honoraria from Neovii Biotec, the manufacturer of Grafalon (formerly ATG-Fresenius). All other authors declare no conflict of interest. EDAT- 2017/05/26 06:00 MHDA- 2017/05/26 06:01 PMCR- 2017/03/28 CRDT- 2017/05/25 06:00 PHST- 2017/02/27 00:00 [received] PHST- 2017/03/15 00:00 [revised] PHST- 2017/03/23 00:00 [accepted] PHST- 2017/05/25 06:00 [entrez] PHST- 2017/05/26 06:00 [pubmed] PHST- 2017/05/26 06:01 [medline] PHST- 2017/03/28 00:00 [pmc-release] AID - biomedicines5020013 [pii] AID - biomedicines-05-00013 [pii] AID - 10.3390/biomedicines5020013 [doi] PST - epublish SO - Biomedicines. 2017 Mar 28;5(2):13. doi: 10.3390/biomedicines5020013.