title: Impact of natural killer cell dose and donor killer-cell immunoglobulin-like receptor (KIR) genotype on outcome following human leucocyte antigen-identical haematopoietic stem cell transplantation.
abstract: To define the role of quantitative graft composition and donor killer-cell immunoglobulin-like receptor (KIR) genotype in clinical outcome following unmanipulated peripheral blood stem cell transplantation (PBSCT) from human leucocyte antigen (HLA)-identical siblings, 43 consecutive transplants for haematological malignancies were analysed retrospectively. Twenty-four patients underwent myeloablative conditioning and 19 received busulphan/fludarabine-based reduced intensity conditioning (RIC). In patients with acute myelogenous leukaemia or myelodysplastic syndrome (AML/MDS; n = 18), no relapse occurred following transplants meeting both a high (above median) natural killer (NK) cell count and missing HLA-ligand(s) to donor's KIR(s), compared to all other AML/MDS patients (0% versus 44%; P = 0.049). Missing HLA-B and/or HLA-C ligand combined with missing HLA-A3/11 (KIR3DL2 unblocked) predicted for reduced relapse incidence regardless of diagnosis or conditioning type (P = 0.028). Moreover, in AML/MDS patients, this constellation predicted superior overall survival (OS) (P = 0.046). Transplants with more than two different activating donor KIRs were associated with an increased risk for non-relapse mortality (NRM), both by univariate and multivariate analysis. Quantitative graft composition had a significant impact exclusively in RIC transplants. Here, a trend towards reduced relapse incidence was found in patients receiving high numbers of NK cells (16% versus 54%; P = 0.09). In patients receiving high versus low T cell numbers, OS was superior (83% versus 37%; P = 0.01), due mainly to reduced NRM (0% versus 33%; P = 0.046). By multivariate analysis, relapse risk was decreased significantly in patients receiving high NK cell numbers (P = 0.039). These data suggest that both the number of transplanted NK cells and the donor KIR genotype play a role in graft-versus-malignancy mechanisms in HLA-identical PBSCT.
authors.affiliation: Division of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria. johannes.clausen@uibk.ac.at
authors.forename: J
authors.initials: J
authors.lastname: Clausen
authors.forename: D
authors.initials: D
authors.lastname: Wolf
authors.forename: A L
authors.initials: AL
authors.lastname: Petzer
authors.forename: E
authors.initials: E
authors.lastname: Gunsilius
authors.forename: P
authors.initials: P
authors.lastname: Schumacher
authors.forename: B
authors.initials: B
authors.lastname: Kircher
authors.forename: G
authors.initials: G
authors.lastname: Gastl
authors.forename: D
authors.initials: D
authors.lastname: Nachbaur
mesh_terms: D000208:Acute Disease; D002908:Chronic Disease; D003586:Cytomegalovirus Infections / Q000276:immunology; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy; D020350:Graft vs Tumor Effect / Q000235:genetics; D019337:Hematologic Neoplasms / Q000276:immunology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006650:Histocompatibility Testing; D006801:Humans; D007694:Killer Cells, Natural / Q000637:transplantation*; D008024:Ligands; D018655:Lymphocyte Count; D008297:Male; D009894:Opportunistic Infections / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics*; D054340:Receptors, KIR; D054347:Receptors, KIR3DL2; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods; D016896:Treatment Outcome
chemical_list: C515084:KIR3DL2 protein, human; D008024:Ligands; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054347:Receptors, KIR3DL2