BCR-ABL Point Mutations and TKI Treatment in CML Patients

Most newly diagnosed CML patients in the Chronic Phase (CP), when treated with imatinib, achieve durable responses. However, a small percentage of these patients as well as most advanced-phase patients relapse on imatinib therapy. Among several resistant mechanisms, “point mutation within the BCR-ABL kinase domain” that interferes with imatinib binding is most important. To overcome imatinib-resistance, four second generation ABL Tyrosine Kinase Inhibitors (TKIs) such as dasatinib, nilotinib, bosutinib and bafetinib were developed. Since there are slight differences in the strong and weak points for each mutation among each TKI, it is very important to identify the type of bcr-abl mutationpresent in ABL TKI-resistant patients. Unfortunately, none of second generation BCR-ABL TKIs can inhibit T315I clone. Thus, a third-generation BCR-ABL TKI, ponatinib was developed and had been already used in clinic. Furthermore, a lot of novel agents which can override BCR-ABL KD mutations including T315I are being developed.