Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor's Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor KIR genotype was determined by high resolution amplicon-based next generation sequencing. We analyzed data from 5,017 transplants. The median patient age at alloHCT was 56 years. Patients were transplanted for AML between 2013 and 2018. Donor-recipient pairs were matched for HLA-A, -B, -C, -DRB1, and -DQB1 (79%) or had single HLA mismatches. Myeloablative conditioning was given to 56% of patients. Fifty-two percent of patients received anti-thymocyte-globulin-based graft-versus-host disease prophylaxis, 32% calcineurin-inhibitor-based prophylaxis, and 7% post-transplant cyclophosphamide-based prophylaxis. We tested several previously reported classifications in multivariable regression analyses but could not confirm outcome associations. Exploratory analyses in 1,939 patients (39%) who were transplanted from donors with homozygous centromeric (cen) or telomeric (tel) A or B motifs, showed that the donor cen B/B-tel A/A diplotype was associated with a trend to better event-free survival (HR 0.84, p=.08) and reduced risk of non-relapse mortality (NRM) (HR 0.65, p=.01). When we further dissected the contribution of B subtypes, we found that only the cen B01/B01-telA/A diplotype was associated with a reduced risk of relapse (HR 0.40, p=.04) while all subtype combinations contributed to a reduced risk of NRM. This exploratory finding has to be validated in an independent data set. In summary, the existing body of evidence is not (yet) consistent enough to recommend use of donor KIR genotype information for donor selection in routine clinical practice.

Anthony Nolan Research Institute Royal Free Hospital London and Cancer Institute University College London London United Kingdom

Biomedical Data Sciences Leiden University Medical Center Leiden Netherlands

Bone Marrow Transplant Unit Department of Hematology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Center for Cellular Immunotherapy and Stem Cell Transplantation 3rd Medical Department Hematology and Oncology University Cancer Center Mainz Mainz Germany

Center for International Blood and Marrow Transplant Research National Marrow Donor Program Minneapolis MN United States

Clinical Trials Unit DKMS Group Dresden Germany

Department of Haematology and Stem Cell Transplantation Birmingham Heartlands Hospital Birmingham United Kingdom

Department of Hematology and Medical Oncology Weill Cornell Medicine New York Presbyterian Hospital New York NY United States

Department of Hematology Instituto Português de Oncologia de Lisboa Lisboa Portugal

Department of Internal Medicine 1 University Hospital TU Dresden Dresden Germany

Department of Medicine 5 University of Heidelberg Heidelberg Germany

Department of Microbiology and Immunology Medical University of South Carolina Charleston SC United States

Department of Stem Cell Transplantation Fundeni Clinical Institute Bucharest Romania

DKMS Group Tübingen Germany

DKMS Life Science Lab Dresden Germany

EBMT Leiden Study Unit Leiden Netherlands

Haematology and BMT Ospedale San Raffaele s r l Milan Italy

Institut Paoli Calmettes Centre de Lutte Contre le Cancer Marseille France

Institute for Experimental Cellular Therapy University Hospital Essen Germany

Klinik für Hämatologie und Stammzelltransplantation Universitätsklinikum Essen Essen Germany

National Cancer Institute Division of Cancer Epidemiology and Genetics Bethesda MD United States

RM Gorbacheva Research Institute Pavlov University St Petersburg Russia

Service Hématologie clinique de Thérapie cellulaire Centre Hospitalier Universitaire Bordeaux Université de Bordeaus Bordeaux France

Transplant Unit and Intensive Care Unit Institute of Hematology and Bood Transfusion Prague Czechia

University Medical Center Groningen University of Groningen Groningen Netherlands

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