Missing KIR-Ligands in Single Mismatched Unrelated Hematopoietic Stem Cell Transplantation

Occurrences of relapse and transplantation related mortality (TRM) are major complications after allogeneic hematopoietic stem cell transplantation (HSCT). In haploidentical transplantation, mismatches for inhibitory killer cell immunoglobulin-like receptor (KIR)-ligand in GvHD direction have been shown to be associated with lower rates of relapse.

To investigate a potential effect of NK alloreactivity as predicted by the missing ligand model in the setting of unrelated transplantation, we investigated 496 patients transplanted for malignant disorders with single HLA-B or HLA-C mismatched donors and T-cell-replete grafts. “Missing ligand” was defined as absence of a donor KIR ligand HLA-C group 1,2 or HLA-Bw4 allele in the patient in GvH-direction only or in combined HvG/GvH direction. Overall survival (OS), disease free survival (DFS), relapse, and treatment related mortality (TRM) were assessed using Kaplan-Meier analysis, competing risks regression and extended Cox regression models.

Out of the 496 transplantation pairs, 109 (22.0%) were identified as belonging to the “missing ligand“-group, the remaining 387 (78.0%) were used as a control group. Univariate and multivariate analysis did not show any differences regarding OS or DFS between the two groups. Univariate analysis showed no significant difference regarding TRM (31.6% vs. 21.1%, p=0.13) and a significant higher risk for relapse (29.0% vs. 38.7%, p=0.048) in the “missing ligand” group. Multivariate competing risks regression showed no significant difference for TRM (HR 0.76, CI 0.49-1.23, p=0.28) and a trend towards increased rates of relapse (HR 1.49, CI 1.00 – 2.20, p=0.05) for the patients within the “missing ligand” group.

The results of this study do not confirm previous results seen in haploidentical HSCT. T-cell alloreactivity dominates over NK cell alloreactivity and leads to a diminished reconstitution of KIR expression in T-cell-replete grafts and potentially impaired "licensing" compared to T-cell depleted transplantations. This effect could explain differences between the haploidentical related and single mismatched unrelated transplantation.