Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation

Abstract

BackgroundAllogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCTMethods and FindingsThe study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into ‘discovery’ (135 pairs) and ‘validation’ (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50–5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33–5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42–4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11–2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10–0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17–0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants.ConclusionsThe present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without ...

Killer‐cell immunoglobulin‐like receptor assessment algorithms in haemopoietic progenitor cell transplantation: current perspectives and future opportunities

“…The Receptor‐Ligand Model (RLM) is a competing model that aims to mismatch donor iKIR and recipient iKIR ligand to reduce donor NK cell inhibition, and consequently increase NK cell cytotoxic activity . This model describes a KIR mismatch as the absence of a KIR ligand in the patient that is recognised by the donor's KIR repertoire, taking advantage of the “missing self” model to drive NK cell activation.…”

“…In conflict with the majority of studies assessing the influence of KIR mismatching, some groups have investigated matching KIR diplotypes between donor and recipient, either as a complete diplotype or by assessing iKIR and aKIR genes separately . KIR matching has been found to reduce risk of chronic graft vs host disease (cGvHD), with iKIR matching presenting a stronger influence in outcomes over aKIR .…”

“…In conflict with the majority of studies assessing the influence of KIR mismatching, some groups have investigated matching KIR diplotypes between donor and recipient, either as a complete diplotype or by assessing iKIR and aKIR genes separately . KIR matching has been found to reduce risk of chronic graft vs host disease (cGvHD), with iKIR matching presenting a stronger influence in outcomes over aKIR . No correlation were found with relapse rates, acute graft vs host disease (aGvHD) or survival, but reduced relapse and improved relapse‐free survival was observed when the RLM model was applied to the KIR‐matched group .…”

“…KIR matching has been found to reduce risk of chronic graft vs host disease (cGvHD), with iKIR matching presenting a stronger influence in outcomes over aKIR . No correlation were found with relapse rates, acute graft vs host disease (aGvHD) or survival, but reduced relapse and improved relapse‐free survival was observed when the RLM model was applied to the KIR‐matched group . Unfortunately, applying HLA matching, KIR matching and the RLM model in parallel is only applicable to patients who present a KIR/Ligand mismatch within their own genotype, and greatly reduces the optimal potential pool of donors who fit these criteria when assessed in parallel with other established criteria (such as CMV serostatus and age of donor).…”

“…KIR2DS2 positive donors may also be beneficial for C2/C2 patients receiving a 9/10 HLA matched graft, reducing TRM without affecting relapse rates . Unfortunately, established donor selection algorithms, such as the B content scoring model, may offer no benefit for C2/C2 patients …”