External Validation of Models for KIR2DS1/KIR3DL1-informed Selection of Hematopoietic Cell Donors fails

TY - JOUR

T1 - External Validation of Models for KIR2DS1/KIR3DL1-informed Selection of Hematopoietic Cell Donors fails

AU - Schetelig, Johannes

AU - Baldauf, Henning

AU - Heidenreich, Falk

AU - Massalski, Carolin

AU - Frank, Sandra

AU - Sauter, Jürgen

AU - Stelljes, Matthias

AU - Ayuk, Francis

AU - Bethge, Wolfgang Andreas

AU - Bug, Gesine

AU - Klein, Stefan

AU - Wendler, Sarah

AU - Lange, Vinzenz

AU - de Wreede, Liesbeth C

AU - Fuerst, Daniel

AU - Kobbe, Guido

AU - Ottinger, Hellmut D

AU - Beelen, Dietrich W

AU - Mytilineos, Joannis

AU - Fleischhauer, Katharina

AU - Schmidt, Alexander H

AU - Bornhauser, Martin

AU - German Cooperative Transp ; Deutsch Register Stammzelltransp

N1 - © 2020 by The American Society of Hematology.

PY - 2020/4/16

Y1 - 2020/4/16

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Donor Selection

KW - Female

KW - Genotype

KW - Graft vs Host Disease/etiology

KW - Hematopoietic Stem Cell Transplantation/adverse effects

KW - Humans

KW - Leukemia, Myeloid, Acute/genetics

KW - Male

KW - Middle Aged

KW - Myelodysplastic Syndromes/genetics

KW - Proportional Hazards Models

KW - Receptors, KIR/genetics

KW - Receptors, KIR3DL1/genetics

KW - Retrospective Studies

KW - Transplantation, Homologous/adverse effects

KW - Unrelated Donors

KW - Young Adult

U2 - 10.1182/blood.2019002887

DO - 10.1182/blood.2019002887

M3 - SCORING: Journal article

C2 - 31932846

VL - 135

SP - 1386

EP - 1395

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 16

ER -