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Ponatinib for the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia

ABSTRACT Introduction Patients with chronic myeloid leukemia in chronic phase (CP-CML) who are resistant or intolerant to second-generation tyrosine kinase inhibitors (TKIs) may benefit from treatment with a third-generation TKI, like ponatinib. Areas covered In this review, the authors discuss the role of ponatinib, an oral pan-inhibitor of BCR-ABL1, with potent activity in heavily pretreated patients, including T315I mutation. In the long-term follow-up of the PACE trial, 60% of patients with prior TKIs exposure achieved a major cytogenetic response with ponatinib and 40% a major molecular response; 5-year overall survival was 73%. Cardiovascular adverse events represent the major toxicity associated with ponatinib. Adopting a dose-reduction approach appeared to be safe: starting with 45 or 30 mg and decreasing to 15 mg once BCR-ABL1/ABL1≤1% is achieved. In patients who are not candidates for ponatinib therapy, asciminib or other novel TKIs like HQP1351, represent alternative options. Expert opinion In patients with CP-CML resistant or intolerant to second-generation TKIs, we favor using a third-generation TKI such as ponatinib. Although we initiate a donor search as soon as a patient fails a second-generation TKI, we still prefer treating patients with ponatinib and will only consider transplantation in the event of no response or disease progression.