Genetic landscape of patients at diagnosis of chronic myeloid leukemia in the chronic phase: association with targeted therapy efficacy

Background. Despite advances in the treatment of chronic myeloid leukemia (CML), the problem of resistance to tyrosine kinase inhibitors (TKIs) remains unresolved. The role of additional gene mutations (besides BCR::ABL1) in resistance development is widely discussed. These mutations may influence the development of the disease, its course, progression, and the effectiveness of targeted therapy.

Aim – to determine the spectrum and frequency of genetic abnormalities in patients with chronic phase CML at the onset of the disease and to identify genetic factors that predict the poor prognosis for the effectiveness of targeted therapy with ATP-competing TKIs.

Materials and methods. The study included 61 patients with CML diagnosed in chronic phase: 37 with a long-term stable optimal response to first-line imatinib therapy – favorable CML course (median age 61 (23–83) years, median follow-up 47 (27–78) months), and 24 with resistance to three or more 1^st- to 3^rd-generation TKIs (median age 53 (15–81) years, median follow-up 43 (13–90) months). All patients underwent standard examination and high-throughput DNA sequencing using a custom panel of 123 genes.

Results. Additional mutations in the overall cohort of patients were identified in 59 % of cases in 24 genes: in the group with a favorable CML course – in 40 % of patients, with a resistant course – in 88 %. Mutations of unfavorable significance were determined in 13 and 38 %, of uncertain significance – in 3 and 21 %, benign – in 32 and 67 %, respectively. The most common pathogenic mutations were ASXL1 (10 % of cases in the overall cohort, 5 % in the group with favorable CML, and 17 % in those with resistant CML) and KMT2C (13, 3, and 29 % in the above cohorts, respectively). The presence of additional pathogenic mutations, the number of such mutations (>1), and the presence of pathogenic mutations in the ASXL1 or KMT2C gene are statistically significantly correlated with a decrease in progression-free and overall survival. All five patients who died due to CML progression were resistant to therapy with three or more TKIs and harbored additional pathogenic mutations; three of them had two pathogenic gene mutations, one of which – in all three cases – was an ASXL1 mutation. A comparison of genetic, cytogenetic and clinical data was carried out.

Conclusion. The obtained results demonstrate the need to incorporate next-generation sequencing of patients’ genetic landscapes at diagnosis into the risk assessment of CML progression, the effectiveness of targeted therapy, and the selection of TKIs for each individual case. However, further studies in larger patient cohorts are currently needed to identify definitive prognostic markers.