The Effect of KIR Ligand Incompatibility on the Outcome of Unrelated Donor Transplantation: A Report from the Center for International Blood and Marrow Transplant Research, the European Blood and Marrow Transplant Registry, and the Dutch Registry

Abstract

Matching for HLA class I alleles, including HLA-C, is an important criterion for outcome of unrelated donor transplantation. However, haplotype-mismatched transplantations for myeloid malignancies, mismatched for killer immunoglobulin-like receptor (KIR) ligands in the graft-versus-host (GVH) direction, is associated with lower rates of graft-versus-host disease (GVHD), relapse, and mortality. This study investigated the effect of KIR ligand mismatching on the outcome of unrelated donor transplantation. The outcomes after 1571 unrelated donor transplantations for myeloid malignancies where donor-recipient pairs were HLA-A, -B, -C, and -DRB1 matched (n = 1004), GVH KIR ligand-mismatched (n = 137), host-versus-graft (HVG) KIR ligand-mismatched (n = 170), and HLA-B and/or -C-mismatched but KIR ligand-matched (n = 260) were compared using Cox regression models. Treatment-related mortality (TRM), treatment failure, and overall mortality were lowest after matched transplantations. Patients who received grafts from donors mismatched at the KIR ligand in the GVH or HVG direction and mismatched at HLA-B and/or C but matched at the KIR ligand had similar rates of TRM, treatment failure, and overall mortality. There were no differences in leukemia recurrence between the 4 groups. These results do not support the choice of an unrelated donor on the basis of KIR ligand mismatch determined from HLA typing.

Deleterious effects of KIR ligand incompatibility on clinical outcomes in haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion

“…The association of the KIR ligand mismatch with a higher incidence of aGVHD might be the result of the alloreactivity of T cells. Likewise, the results in the reports of Farag et al 2 also suggest any effect of KIR ligand incompatibility may have been marked by the effect of alloreactivity T cells and/ or of posttransplantation immunosuppression.…”

“…1 The effect of this incompatibility on outcomes of haploidentical or mismatched unrelated hematopoitic stem cell transplantation (HSCT) remains controversial, [1][2][3] possibly because of assessments using different transplant protocols with varying levels of T-cell depletion in vitro or in vivo. In recent years, we have successfully established a novel conditioning protocol that includes anti-thymocyte globulin followed by haploidentical HSCT without in vitro T-cell depletion, and we have found that this protocol can achieve outcomes comparable to those obtained with HLA-matched transplantation.…”

NK cell receptors and their ligands in leukemia

“…However several other retrospective HSCT studies could not confirm these beneficial effects of KIR ligand incompatibility despite the use of ATG. 34,35,37,38 In contrast, some reports found that KIR ligand incompatibility was even associated with an increased rate of treatment-related mortality (TRM) caused by infection. 35,37,38 A possible mechanism underlying the increased infection-related mortality in these patients is that donor alloreactive NK cells may kill the patient's dendritic cells and in this way interfere with immunity against opportunistic infections.…”

“…The first study that demonstrated that KIR ligand incompatibility could reduce the risk of relapse, promote engraftment and protect against GvHD in AML patients transplanted with a graft from related haploidentical donors was published by Ruggeri et al, 2 which is confirmed in their later study. 30 After this initial study, additional studies retrospectively analyzed cohorts of related 31 and unrelated [32][33][34][35][36][37][38][39] HLA-mismatched HSCT to address the impact of NK alloreactivity on different transplant outcome variables (an overview is given in Table 1). A second study of related haploidentical transplants published by Bishara et al 31 failed to confirm any beneficial effect of KIR ligand incompatibility.…”

Natural killer cell immune escape in acute myeloid leukemia

“…30,31 Although these findings were confirmed by some groups, others failed to show any benefit. [32][33][34][35][36][37][38] Results of those studies are discussed in more detail elsewhere by Verheyden and Demanet. 39 Another NK cell escape mechanism demonstrated in the HSCT setting is the overexpression of the inhibitory receptor CD94/ NKG2A on reconstituted NK cells that recognizes human leukocyte antigen-E on AML blasts, which is associated with a low cytotoxic capacity.…”