ABL1 TKI Resistance mutations
Chronic myeloid leukemia (Cml) is characterized by the presence of the t(9:22) BCR/ABL1 fusion protein. Recent advances have resulted in a number of therapeutic drugs that inhibit the ABL1 tyrosine kinase. Imatinib mesylate (Gleevec) is the prototype of these tyrosine kinase inhibitors (TKI), and patients on TKIs live with what is more and more viewed as a chronic ailment rather than a potentially lethal disease. Unfortunately, a significant subset of patients can develop functional resistance to TKI, due in a large number of cases (approximately 50%) to the acquisition of point mutations in the kinase domain (KD) of the chimeric ABL1 gene. To date, over 50 distinct mutations have been described, although a smaller subset of these (<20) account for the majority of patients with clinical resistance to TKI.
Recognition of TKI resistance is important in Cml, as the effect of some mutations can be overcome by increasing imatinib dosage, whereas others require switching to either a different (second-generation) TKI, or alternative therapy. It is estimated that over 25% of Cml patients will switch TKIs at least once during their lifetime due to TKI intolerance or resistance. The common T315I KD mutation is particularly important, given that this alteration confers pan-resistance to all currently employed TKI except ponatinib.
Similar considerations are also present in patients with Philadelphia chromosome positive B-cell acute lymphoblastic leukemia, who can also be treated using TKI therapy.
This panel tests for mutations in the ABL1 gene that are associated with resistance to Tyrosine kinase inhibitor treatment in chronic myeloid leukemia (Cml) and BCR-ABL1 positive ALL.
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