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

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 the...

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Main Authors: Schetelig, Johannes (Author) , Baldauf, Henning (Author) , Heidenreich, Falk (Author) , Massalski, Carolin (Author) , Frank, Sandra (Author) , Sauter, Jürgen (Author) , Stelljes, Matthias (Author) , Ayuk, Francis Ayuketang (Author) , Bethge, Wolfgang A. (Author) , Bug, Gesine (Author) , Klein, Stefan (Author) , Wendler, Sarah (Author) , Lange, Vinzenz (Author) , de Wreede, Liesbeth C. (Author) , Fürst, Daniel (Author) , Kobbe, Guido (Author) , Ottinger, Hellmut D. (Author) , Beelen, Dietrich W. (Author) , Mytilineos, Joannis (Author) , Fleischhauer, Katharina (Author) , Schmidt, Alexander H. (Author) , Bornhäuser, Martin (Author)
Format: Article (Journal)
Language:English
Published: 13 January 2020
In: Blood
Year: 2020, Volume: 135, Issue: 16, Pages: 1386-1395
ISSN:1528-0020
DOI:10.1182/blood.2019002887
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2019002887
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Author Notes:Johannes Schetelig, Henning Baldauf, Falk Heidenreich, Carolin Massalski, Sandra Frank, Jürgen Sauter, Matthias Stelljes, Francis Ayuketang Ayuk, Wolfgang A. Bethge, Gesine Bug, Stefan Klein, Sarah Wendler, Vinzenz Lange, Liesbeth C. de Wreede, Daniel Fürst, Guido Kobbe, Hellmut D. Ottinger, Dietrich W. Beelen, Joannis Mytilineos, Katharina Fleischhauer, Alexander H. Schmidt, and Martin Bornhäuser, on behalf of the German Cooperative Transplant Study Group and the Deutsches Register für Stammzelltransplantationen
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Summary: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.
Item Description:Gesehen am 15.07.2020
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2019002887

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