title: Impact of Donor Activating KIR Genes on HSCT Outcome in C1-Ligand Negative Myeloid Disease Patients Transplanted with Unrelated Donors-A Retrospective Study.
abstract: Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14-1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05-1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01-1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01-1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15-1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91-1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08-0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11-0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13-0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26-5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance.
authors.affiliation: Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttenberg-Hessen and University Hospital of Ulm, Ulm, Germany.|Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Neuchel
authors.affiliation: Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttenberg-Hessen and University Hospital of Ulm, Ulm, Germany.|Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fürst
authors.affiliation: Department of Hematology/Oncology, University of Leipzig, Leipzig, Germany.
authors.forename: Dietger
authors.initials: D
authors.lastname: Niederwieser
authors.affiliation: Department of Hematology/Oncology, University Clinic Ulm, Ulm, Germany.
authors.forename: Donald
authors.identifier: http://orcid.org/0000-0002-1952-5443
authors.initials: D
authors.lastname: Bunjes
authors.affiliation: Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttenberg-Hessen and University Hospital of Ulm, Ulm, Germany.|Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.
authors.forename: Chrysanthi
authors.initials: C
authors.lastname: Tsamadou
authors.affiliation: Department of Hematology/Oncology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wulf
authors.affiliation: Department of Internal Medicine I, Universitätsklinikum des Saarlandes, Homburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.affiliation: Department of Medicine III, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Centre for Bone Marrow and Blood Stem Cell Transplantation, Deutsche Klinik für Diagnostik, Wiesbaden, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Stuhler
authors.affiliation: Department of Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttenberg-Hessen and University Hospital of Ulm, Ulm, Germany.|Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
authors.affiliation: Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttenberg-Hessen and University Hospital of Ulm, Ulm, Germany.|Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.|DRST-German Registry for Stem Cell Transplantation, Essen, Germany.
authors.forename: Joannis
authors.initials: J
authors.lastname: Mytilineos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003172:Complement C1 / Q000378:metabolism; D005260:Female; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D008297:Male; D008875:Middle Aged; D054340:Receptors, KIR / Q000235:genetics*; D012189:Retrospective Studies; D016896:Treatment Outcome; D061349:Unrelated Donors; D055815:Young Adult
chemical_list: D003172:Complement C1; D008024:Ligands; D054340:Receptors, KIR