KIR Gene Haplotype: An Independent Predictor of Clinical Outcome in MDS Patients

Myelodysplastic syndromes (MDS) are a group of hematopoietic disorders affecting the myeloid lineage, characterized by cytopenias and clonal evolution to AML. Immune responses against MDS, partly mediated by NK cells, have the potential to affect disease progression. However, immune evasion remains an important barrier. NK cells express both activating and inhibitory killer immunoglobulin-like receptors (KIRs) that interact to regulate NK effector function. Based on the number and distribution of inherited KIR genes, individuals can be classified in two broad haplotypes. Haplotype A comprises a single activating KIR (aKIR) gene (KIR2DS4), while haplotype B incorporates various combinations of aKIR genes (up to 6). We hypothesized that the aKIR gene repertoire may be useful in refining predictions of clinical outcomes in MDS. Thus, we studied the variations in aKIR gene content and haplotype in MDS and their relationship to the risk of AML transformation and patient outcomes.

We first compared the number of aKIR genes in 108 MDS patients treated at MDACC with that in 139 HSC donors. The median number of aKIR genes was significantly lower in MDS than controls: 2 (range 0-6) vs 3 (range 0-6), p=0.001. Functional studies revealed that compared to healthy controls, NK cells from MDS patients demonstrate less Interferon gamma production (p<0.0001) and less degranulation (p=0.0028) in response to K562 cell line, and have lower killing ability evidenced by chromium release assay (p=0.04).

We next examined the influence of KIR haplotype on the risk of AML transformation and outcomes in the cohort of 108 MDS patients (28 KIR haplotype A and 80 KIR haplotype B patients). On multivariate analysis, cytogenetic risk group and KIR haplotype were identified as independent predictors of MDS progression to AML. The relative risk of MDS-AML transformation in patients with haplotype A vs. haplotype B was 2.67 (1.13-6.31) (p=0.02). Similarly, cytogenetic risk group, IPSS and KIR haplotype independently predicted survival. MDS patients with KIR haplotype A had worse adjusted PFS (RR with 95%CI 2.96 [1.59-5.52], p=0.001) and OS (2.25 [1.17-4.31], p=0.02), compared to patients with haplotype B.

These novel findings may help identify a subgroup of MDS patients with a high risk of disease progression and poor outcomes, who would likely benefit from adoptive NK cell therapy.