Inhibitory killer immunoglobulin-like receptors (KIR3DL1) bind the HLA-Bw4 (an HLA-B allele) epitope, and the amino acid at position 80 of the Bw4 epitope determines the binding affinity. New research indicates that KIR3DL1-HLA-Bw status reflects natural killer (NK)-cell responses and is associated with treatment-free remission (TFR) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).
Hiroshi Ureshino, MD, PhD, of Hiroshima University in Japan, and colleagues published their results from the Polymorphisms of Killer immunoglobulin- like receptor, which affect Stop Tyrosine kinase Inhibitor in patients with Chronic myeloid leukemia (POKSTIC) trial in Blood Neoplasia. The retrospective observational study enrolled 76 patients between October 2020 and September 2022 who agreed to participate during enrollment in larger tyrosine kinase inhibitors (TKIs) discontinuation clinical trials (DOMEST, DADI, and first-line DADI).
Researchers have previously identified several predictors of a successful TFR in patients with CML-CP. These include longer TKI treatment duration, deep molecular remission (DMR) status at TKI discontinuation, and male sex. Although previous studies have characterized inhibitory killer immunoglobulin-like receptors (KIR), less is known about activating KIRs.
“We have previously reported that KIR/HLA polymorphisms are involved in achieving deep molecular remission and were surprised to find the same result for TFR,” Dr. Ureshino said. “Thus, patients with CML with a favorable genetic background for the KIR/HLA polymorphism have a high rate of achieving DMR and subsequently TFR.”
The authors noted in their paper that their study includes a smaller number of patients than previously published TKI stop studies. That said, they explained that the previous studies that investigated the interaction between KIR3DL1-HLA-Bw and clinical outcome have primarily been performed in European and American populations. HLA-A*24:02, which harbors the HLA-Bw4 epitope (Bw4-80IIe), is relatively predominant in East Asian individuals but uncommon in Europeans and Americans.
In the current study, univariate analysis revealed that long-term TKI treatment of 55 months was associated with a lower risk of molecular relapse than shorter treatment of 28 months (hazard ratio [HR] = 0.476; p=0.034), but KIR genotype, KIR allele type, the combination of KIR and its cognate ligand HLA-Bw, C genotype, and differences in T-cell and NK-cell fractions were not associated with the risk of molecular relapse. However, univariate and multivariate analysis, which included KIR3DL1-HLA-Bw4, age, type of TKI and treatment duration, gender, and previous interferon exposure, revealed KIR3DL1-HLA-Bw4 to be an independent risk factor for a higher risk of molecular relapse (HR=2.206; p=0.024). Thus, for patients with CML-CP, KIR3DL and its cognate ligand HLA-Bw were associated with successful achievement of TFR after TKI discontinuation.
The investigators then evaluated the T-cell or NK-cell counts before TKI discontinuation according to KIR3DL1-HLA-Bw status to see whether KIR/HLA genotyping reflected immune cell fractions. The researchers found that patients at a higher risk of relapse had a significantly lower number of NK cells at TKI discontinuation than the other patients (CD16+/CD56+ NK cells: median 499.63 cells/µL versus 629.17 cells/µL, respectively; p=0.049). They concluded that the KIR/HLA combination may be important for regulation of NK-cell immune responses.
“The genetic polymorphisms of KIR and HLA can be predictive of TFR in CML,” Dr. Ureshino said. “As for KIRs/HLAs, they do not change throughout life, so it is sufficient that we test the KIRs/HLAs once.” Unfortunately, KIR/HLA genetic polymorphisms are not typically tested in a clinical setting, he said. Because the KIR3DL1/HLA-Bw combination depends on mainly HLA-Bw polymorphism, he proposed that clinicians consider assessing HLA-Bw polymorphism as a means to predict TFR.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Ureshino H, Ueda Y, Fujisawa S, et al. KIR3DL1-HLA-Bw status in CML is associated with achievement of TFR: the POKSTIC trial, a multicenter observational study. Blood Neoplasia. 2024;1(1):100001.
