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
Frontiers in Immunology, vol. 11, pp. 584520
Abstract
Results from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Several competing models have been developed to classify donors as KIR-advantageous or disadvantageous. Basically, these models differ by grouping donors based on distinct KIR–KIR–ligand combinations or by haplotype motif assignment. This study aimed to validate different models for unrelated donor selection for patients with Myelodysplatic Syndromes (MDS) or secondary Acute Myeloid Leukemia (sAML). In a joint retrospective study of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) registry data from 1704 patients with secondary AML or MDS were analysed. The cohort consisted mainly of older patients (median age 61 years) with high risk disease who had received chemotherapy-based reduced intensity conditioning and anti-thymocyte globulin prior to allogeneic HCT from well-matched unrelated stem cell donors. The impact of the predictors on Overall Survival (OS) and relapse incidence was tested in Cox regression models adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type. KIR genes were typed using high-resolution amplicon-based next generation sequencing. In univariable and multivariable analyses none of the models predicted OS and the risk of relapse consistently. Our results do not support the hypothesis that optimizing NK-mediated alloreactivity is possible by KIR-genotype informed selection of HLA-matched unrelated donors. However, in the context of allogeneic transplantation, NK-cell biology is complex and only partly understood. KIR-genes are highly diverse and current assignment of haplotype motifs based on the presence or absence of selected KIR genes is over-simplistic. As a consequence, further research is highly warranted and should integrate cutting edge knowledge on KIR genetics, and NK-cell biology into future studies focused on homogeneous groups of patients and treatment modalities.
Authors 22
-
Johannes Schetelig corresponding
Deutsche Knochenmarkspenderdatei
Affiliation as printed
DKMS Clinical Trials Unit, Dresden, Germany
Medizinische Klinik und Poliklinik I, University Hospital Dresden, Dresden, Germany
-
Deutsche Knochenmarkspenderdatei
Affiliation as printed
DKMS Clinical Trials Unit, Dresden, Germany
-
European Society for Blood and Marrow Transplantation
Affiliation as printed
EBMT Data Office Leiden, Leiden, Netherlands
-
Affiliation as printed
Center for International Blood and Marrow Transplant Research, Minneapolis, MN, United States
-
Deutsche Knochenmarkspenderdatei
Affiliation as printed
DKMS Clinical Trials Unit, Dresden, Germany
Medizinische Klinik und Poliklinik I, University Hospital Dresden, Dresden, Germany
-
Leiden University Medical Center · Deutsche Knochenmarkspenderdatei
Affiliation as printed
DKMS Clinical Trials Unit, Dresden, Germany
Leiden University Medical Center, Department of Biomedical Data Sciences, Leiden, Netherlands
-
Affiliation as printed
Center for International Blood and Marrow Transplant Research, Minneapolis, MN, United States
-
Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Maastricht University Medical Center, Department of Internal Medicine, Maastricht, Netherlands
-
Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
Affiliation as printed
A.O.U. Citta della Salute e della Scienza di Torino, Turin, Italy
-
University of Milan · Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Affiliation as printed
Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
-
Affiliation as printed
DKMS Life Science Lab, Dresden, Germany
-
Affiliation as printed
DKMS Life Science Lab, Dresden, Germany
-
Affiliation as printed
GKT School of Medicine, London, United Kingdom
-
Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
-
Radboud University Medical Center
Affiliation as printed
Radboud University Medical Centre, Nijmegen, Netherlands
-
Affiliation as printed
St. James's Hospital, Dublin, Ireland
-
Affiliation as printed
Fred Hutchinson Cancer Research Center, Seattle, WA, United States
-
Universität Hamburg · University Medical Center Hamburg-Eppendorf
Affiliation as printed
University Hospital Eppendorf, Hamburg, Germany
-
Memorial Sloan Kettering Cancer Center
Affiliation as printed
Memorial Sloan Kettering Cancer Center, New York & Scientific Director, CIBMTR Immunobiology Working Committee, New York City, NY, United States
-
Deutsche Knochenmarkspenderdatei
Affiliation as printed
DKMS Clinical Trials Unit, Dresden, Germany
DKMS Life Science Lab, Dresden, Germany
-
Inserm · Université de Lille · Centre Hospitalier Universitaire de Lille · Lille Inflammation Research International Center
Affiliation as printed
CHU de Lille, LIRIC, INSERM U995, Université de Lille, Lille, France
-
Université Paris Cité · Assistance Publique – Hôpitaux de Paris · Hôpital Saint-Louis
Affiliation as printed
Hopital Saint-Louis, APHP, Université de Paris, Paris, France
Cited by 24 stored of 25
No patents citing this paper on Lens.org (checked 2026-10-11).