HLA diversity is associated with TKI response and treatment‐free remission in chronic myeloid leukemia

Immune surveillance is increasingly recognized as a key determinant of cancer treatment outcomes. However, the impact of Human Leukocyte Antigen (HLA) diversity in chronic myeloid leukemia (CML) remains poorly understood and has been scarcely investigated. We retrospectively analyzed 367 CML patients with high-resolution HLA typing to investigate the impact of HLA allele distribution and HLA evolutionary divergence (HED) on disease susceptibility, molecular response, and treatment-free remission (TFR). Compared to 2832 healthy donors, CML patients exhibited significantly lower HED scores for all class I loci (A, B, C) and HLA-DQB1 (FDR < 0.001), suggesting a narrower immunopeptidome repertoire at diagnosis. Specific alleles, such as HLA-A*30:01 (OR [95% CI] = 2.08 [1.26-3.25]) and B*14:02 (OR = 1.90 [1.26-2.79]), were associated with increased CML risk (FDR < 0.01). Among 289 patients with clinical follow-up, HLA-DQB1*06:04 (aHR [95% CI] = 3.71 [1.57-8.77]) and DRB1*13:02 (aHR = 3.95 [1.77-8.81]) were associated with faster MR4 achievement in imatinib-treated patients (FDR < 0.01), while B*44:02 (aHR = 4.83 [1.62-14.41]) predicted favorable response to dasatinib (FDR < 0.05). In the TFR cohort (<i>n</i> = 105), alleles A*26:01 (aHR = 3.47 [1.44-8.38]), A32:01 (aHR = 3.28 [1.52-7.09], FDR < 0.05), and B18:01 (aHR = 12.96 [3.59-46.77], FDR < 0.001) were significantly associated with increased relapse risk. Conversely, a higher HED score for HLA-C was associated with improved TFR in dasatinib-treated patients (<i>P</i> = 0.0067). These findings suggest that HLA genotype and class-specific HED may influence CML susceptibility and outcomes and could inform TKI selection and discontinuation strategies.