Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML

Response to tyrosine kinase inhibitors (TKIs) is variable in chronic myeloid leukemia (CML), and elevated natural killer (NK) cells during TKI therapy are positively correlated with superior outcomes. NK cell function involves interactions of their killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I on target cells, and the avidity of KIR-HLA interactions depends on the combination of KIR and HLA alleles. We hypothesized that KIR and HLA polymorphisms may influence response to TKIs. KIR and HLA allele genotyping was performed by next generation sequencing for 76 CML cases, and association with clinical outcome was analyzed. Second generation TKIs as first-line therapy and patients' sex (female) were strongly associated with achievement of complete molecular response (MR) after 2 years (p<0.001 and p=0.002, respectively). After adjustment for these two characteristics, several KIR alleles remained associated with achievement of MR: KIR2DL4*005/011 or *008 (HR=1.797, p=0.032); KIR2DS4*003 or *007/010 (HR=3.348, p<0.001); KIR3DL1*005 (HR=2.746, p=0.003); and KIR3DL2*009 or *010 (HR=1.980 (1.109-3.524), p=0.021). Strong linkage among these alleles exists, implying that they comprise favorable KIR allele haplotypes. Allelic polymorphisms of KIR3DL1 and HLA-B determine their differential avidity into strong/weak or no interaction. Patients carrying non-interacting KIR3DL1 and HLA-B allele pairs achieved better outcomes than those with strongly interacting pairs, and KIR3DL1*005 associated with a positive outcome among patients with weak-interacting pairs. Thus, KIR3DL1*005 and its associated haplotypes associated with superior TKI therapeutic effects. The combinations of these KIR and HLA alleles may correlate with potent NK cell immunity against CML.