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.
Highlights
Serotherapy using one of the two commercially available rabbit anti-thymocyte globulin (ATG)preparations is commonly applied for in vivo T cell depletion in allogeneic hematopoietic cell transplantation (HSCT), with the aim to augment standard prophylaxis against graft versus host disease (GVHD)
As recently summarized [9,10,11], we have previously suggested a role for the human leukocyte antigen (HLA) class I ligands to inhibitory killer cell immunoglobulin-like receptors (KIR) in transplant outcomes [12]
The study reveals three major findings which will be discussed below: (a) It confirms the previously reported significance of an HLA-C1 homozygous (C1/1) killer-cell immunoglobulin-like receptor ligands (KIR-L) status as risk factor for severe aGVHD and non-relapse mortality (NRM); (b) Findings further suggest that serotherapy with ATG is appropriate to overcome the aGVHD risk factor, C1 homozygosity, and even more, to limit aGVHD-associated NRM
Summary
Preparations is commonly applied for in vivo T cell depletion in allogeneic hematopoietic cell transplantation (HSCT), with the aim to augment standard prophylaxis against graft versus host disease (GVHD). Prospective and retrospective studies have demonstrated a significant potential of ATG to reduce the incidence and severity of acute and chronic graft versus host disease (GVHD). As recently reviewed [1], most of these studies failed to show a survival benefit resulting from the improved control of GVHD. This may in part be due to the studies’ population size and follow-up period, since prevention of late-onset non-relapse mortality (NRM) due to steroid-refractory or -dependent cGVHD and resulting infections, may show its benefit as late as several years after.
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