Allelic Polymorphisms of <i>KIR</i> s and <i>HLA</i> s Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML

Abstract

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 <i>KIR</i> and <i>HLA</i> alleles. We hypothesized that <i>KIR</i> and <i>HLA</i> polymorphisms may influence response to TKIs. <i>KIR</i> and <i>HLA</i> 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 (CMR: MR^4.0) after 2 years (<i>P</i> < 0.001 and <i>P</i> = 0.002, respectively). After adjustment for these two characteristics, several <i>KIR</i> alleles remained associated with achievement of MR^4.0: <i>KIR2DL4*005/011</i> or <i>*008</i> (HR = 1.797, <i>P</i> = 0.032); <i>KIR2DS4*003</i> or <i>*007/010</i> (HR = 3.348, <i>P</i> < 0.001); <i>KIR3DL1*005</i> (HR = 2.746, <i>P</i> = 0.003); and <i>KIR3DL2*009</i> or <i>*010</i> [HR = 1.980 (1.109-3.524), <i>P</i> = 0.021]. Strong linkage among these alleles exists, implying that they comprise favorable KIR allele haplotypes. Allelic polymorphisms of <i>KIR3DL1</i> and HLA-B determine their differential avidity into strong/weak or no interaction. Patients carrying noninteracting <i>KIR3DL1</i> and <i>HLA-B</i> allele pairs achieved better outcomes than those with strongly interacting pairs, and <i>KIR3DL1*005</i> associated with a positive outcome among patients with weak-interacting pairs. Thus, <i>KIR3DL1*005</i> and its associated haplotypes associated with superior TKI therapeutic effects. The combinations of these <i>KIR</i> and <i>HLA</i> alleles may correlate with potent NK cell immunity against CML. <i>Cancer Immunol Res; 6(6); 745-54. ©2018 AACR</i>.