Contrasting relapse rate associated with the absence of HLA-A3/A11 in T cell-replete haploidentical transplantation

Natural killer cell alloreactivity contributes to the graft-versus-leukemia (GVL) effect of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). However, its importance remains controversial across studies.

In this retrospective analysis, we studied NK cell alloreactivity and its association with clinical outcomes using the education model in patients with hematologic malignancies undergoing transplantation. Patients were stratified by the presence or absence of alloreactivity assessment, which was defined by the coexistence (in the donor) of four germline-encoded inhibitory killer cell immunoglobulin-like receptors (iKIRs) and their corresponding self-human leukocyte antigen (HLA)-I ligands.

In a cohort of 1,209 patients,793 individuals (65.6%) had no loss of iKIR ligands, while 416 cases showed alloreactivity characterized by the absence of at least one ligand. Among the missing single ligand, the absence of HLA-A3/A11 epitope was the most prevalent (28.4%), followed by Bw4 (25.2%), C2 (23.6%), and C1 (10.6%). Only patients with KIR3DL2-A3/A11-mediated alloreactivity exhibited a substantially reduced 3-year cumulative incidence of relapse (CIR) compared to those without this predicted alloreactivity (16.2%; 95% confidence interval [CI], 10.1-23.5%; and 30.1%; 95% CI, 27.1-33.3%; P = 0.0006). Multivariate analysis confirmed A3/A11 deficiency as an independent protective factor against relapse (adjusted hazard ratio 0.487; 95% CI, 0.300-0.790; P = 0.0035). Moreover, alternative predictive models failed to reliably forecast relapse risk.

Our result suggest that NK cell alloreactivity driven by the absence of HLA-A3/A11 may enhance NK cell-mediated surveillance against leukemia cells; therefore, incorporating KIR3DL2-A3/A11 compatibility assessment can refine donor selection strategies aimed at reducing relapse incidence in patients undergoing haplo-HSCT.