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

Abstract

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.

Homozygous HLA-C1 is Associated with Reduced Risk of Relapse after HLA-Matched Transplantation in Patients with Myeloid Leukemia

“…However, T cell-depleted HLA-C1/C2 recipients relapsed much more frequently even if they had received a myeloablative regimen, indicating that T cell depletion affected the GVL effect, and that other KIRs on NK cells might not trigger sufficient GVL reactivity. These results agree with a report from Austrian European Society for Blood and Marrow Transplantation centers, in which HLA-C1/C1 recipients experienced the greatest benefits of ATG for survival compared with HLA-C1/C2 or HLA-C2/C2 recipients [38]; however, survival and relapse of their HLA-C1/C2 recipients using ATG were not as negative as those in our present series.…”

The impact of donor and recipient KIR genes and KIR ligands on the occurrence of acute graft-versus-host disease and graft survival after HLA-identical sibling hematopoietic stem cell transplantation

“…Multivariate analysis using a Cox proportional hazard model from the findings of Yabe and Clausen suggested that ATG preadministration was a critical factor in grade III-IV aGVHD under consideration of the HLA-C KIR-L status (33,34).…”

“…In the present study, using Cox proportional hazard modeling, we showed that grade of GVHD after the time of transplantation and ATG conditioning regimen were prognostic factors affecting transplant survival. Multivariate analysis using a Cox proportional hazard model from the findings of Yabe and Clausen suggested that ATG preadministration was a critical factor in grade III-IV aGVHD under consideration of the HLA-C KIR-L status (33,34).…”

Major Histocompatibility Complex and Hematopoietic Stem Cell Transplantation: Beyond the Classical HLA Polymorphism

“…Interestingly, Clausen et al observed an opposite effect of missing KIR ligands in patients transplanted with bone marrow when compared to peripheral blood stem cells as graft source, in recipients homozygous for HLA-C group 2 ligands for inhibitory killer Ig-like receptors [ 44 ]. Recently, the same authors suggested that the use of anti-thymocyte globulin (ATG) may provide a survival benefit in recipients with at least one C1 group KIR-L, by reducing transplant-related mortality (TRM) without significantly increasing the relapse risk [ 45 ]. Given the central role of NK cell alloreactivity in preventing leukemia relapse, in the setting of haplo-HSCT it is crucial to determine in different potential donors if alloreactive NK cells are present and the size of such alloreactive populations.…”