Frequency, distribution, and impact on prognosis of BCR-ABL1 kinase domain mutations in tyrosine kinase inhibitor resistant chronic myelogenous leukemia patients

Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease characterized by the BCR::ABL1 fusion gene. Despite the improved outcomes with the introduction of tyrosine kinase inhibitors (TKIs), primary and acquired resistance has become a big challenge. Through the various mechanisms, ABL1 tyrosine kinase domain (TKD) mutations play a major role in the resistance. Of the 287 patients in our study, 261 patients’ resistance status were available, and 110 of 261 (42.2%) were resistant to imatinib. At a median follow-up of 114 months, the 3-year, 5-year, and 7-year OS was 86.8%, 82.6%, and 77.2% for our cohort. ABL1 TKD mutations were detected in 13 of 93 (14.4%) imatinib-resistant patients. 8 of them had the T315I mutation, 2 had the Y253H mutation, and the remaining patients had one E255K, V299L, and F317L mutation each. In the IM-resistant patients, the mean size of the spleen was larger (181.8 mm vs 153 mm), peripheral white blood cell count (153.2x109/L vs 104.3x109/L), and plasma β2-microglobulin levels (3,040.1 ng/mL vs 2,581.5 ng/mL) were higher, hemoglobin (10.7 g/dL vs 11.5 g/dL), and hematocrit levels (32.3% vs 35.4%) were lower (p<0.05). Also, could not detect any significant correlation between fusion signal patterns and the rate of IM resistance. In conclusion, ABL1 TKD mutations are important causes of TKI resistance in CML patients and must be used for choosing the appropriate subsequent TKI. Also, methods used for the detection of these mutations are important and each methods have advantages and disadvantages.

Keywords

• Chronic Myeloid Leukemia
• ABL1 tyrosine kinase domain mutations
• TKI resistance
• T315I

References

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