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.

Fig. 1

Cumulative incidence of relapse (a) in patients undergoing reduced intensity conditioning (RIC) transplants (n = 19) and (b) in patients with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) (n = 18), stratified according to a high natural killer (NK) cell count and the presence of donor killer-cell immunoglobulin-like receptor (KIR) missing the respective human leucocyte antigen (HLA)-B or HLA-C ligand. Patients fulfilling both criteria were compared to all other patients.

Fig. 2

Cumulative relapse incidence following transplants with a missing ligand to both killer-cell immunoglobulin-like receptor (KIR)3DL2 and at least one other inhibitory KIR (n = 11), compared to all other patients (n = 24).

Fig. 3

Kaplan–Meier estimate of overall survival in patients with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS), stratified by the presence (n = 6) or absence (n = 12) of missing ligand to both killer-cell immunoglobulin-like receptor (KIR)3DL2 and at least one other inhibitory KIR.

Fig. 4

Kaplan–Meier estimate of disease-free survival following transplants for acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS), stratified by fulfilling (n = 5) or not (n = 13) the constellation of at least two killer-cell immunoglobulin-like receptor (KIR) ligands missing (including those to KIR3DL2) and a high natural killer cell dose.