External validation of models for KIR2DS1/KIR3DL1-informed selection of hematopoietic cell donors fails

Abstract

Several studies suggest that harnessing natural killer (NK) cell reactivity mediated through killer cell immunoglobulin-like receptors (KIRs) could reduce the risk of relapse after allogeneic hematopoietic cell transplantation. Based on one promising model, information on KIR2DS1 and KIR3DL1 and their cognate ligands can be used to classify donors as KIR-advantageous or KIR-disadvantageous. This study was aimed at externally validating this model in unrelated donor hematopoietic cell transplantation. The impact of the predictor on overall survival (OS) and relapse incidence was tested in a Cox regression model adjusted for patient age, a modified disease risk index, Karnofsky performance status, donor age, HLA match, sex match, cytomegalovirus match, conditioning intensity, type of T-cell depletion, and graft type. Data from 2222 patients with acute myeloid leukemia or myelodysplastic syndrome were analyzed. KIR genes were typed by using high-resolution amplicon-based next-generation sequencing. In univariable analyses and subgroup analyses, OS and the cumulative incidence of relapse of patients with a KIR-advantageous donor were comparable to patients with a KIR-disadvantageous donor. The adjusted hazard ratio from the multivariable Cox regression model was 0.99 (Wald test, P = .93) for OS and 1.04 (Wald test, P = .78) for relapse incidence. We also tested the impact of activating donor KIR2DS1 and inhibition by KIR3DL1 separately but found no significant impact on OS and the risk of relapse. Thus, our study shows that the proposed model does not universally predict NK-mediated disease control. Deeper knowledge of NK-mediated alloreactivity is necessary to predict its contribution to graft-versus-leukemia reactions and to eventually use KIR genotype information for donor selection.

Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia

“…Against this background we set out to validate an HLA-matched unrelated donor selection algorithm for patients with AML and MDS which was essentially aimed at reducing the inhibitory potential of donor NK cells and increasing the activating potential by donor selection based on information on KIR2DS1 and KIR3DL1 ( 12 , 13 ). We recently reported results of a study in AML patients where we failed to replicate the findings of the original report ( 23 ). Here, we present the data on patients with MDS or secondary AML.…”

Estimation of German KIR Allele Group Haplotype Frequencies

“…Since NK cells are the first lymphocytes to reconstitute in patients after HSCT (26), efforts have been made to exploit their potential to elicit a rapid and targeted immune response against remaining leukemic cells (27)(28)(29)(30)(31)(32). Recent research indicates an impact of donor KIR genotype on the outcome of HSCT, but results remain controversial (33)(34)(35)(36)(37).…”

Umbilical Cord Blood and iPSC-Derived Natural Killer Cells Demonstrate Key Differences in Cytotoxic Activity and KIR Profiles

“…These findings have been adopted in practice, as when otherwise similarly HLA-matched allogeneic or haploidentical HSCT donors are available, HSCT donor selection algorithms consider KIR profiles as a donor selection criteria ( 35 , 37 – 39 ). However, selection of KIR ligand mismatches in HSCT remains an active area of investigation, as a recent study found that optimization of donors based on KIR2DS1 and KIR3DL1 expression did not provide a survival benefit ( 40 ).…”