Chronic myeloid leukemia (CML) is a hematological condition with a large range of treatment options developed over the last decade. Drug development programs predominantly target the BCR-ABL fusion gene resulting from the Philadelphia chromosome translocation. As a tyrosine kinase, the BCR-ABL product is susceptible to tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, and dasatinib.
Each TKI has its own unique properties, indications, and side effects, though the most common adverse events in the TKI family include gastrointestinal side effects, myelosuppression, rash, headache, and peripheral edema. Most patients tolerate TKIs well, with only about 5% to 10% of patients discontinuing the medication due to side effects.1
Some patients, however, will discontinue TKIs due to resistance. Primary resistance is when a TKI does not attain clinical response; secondary resistance is when a patient initially responds but then relapses. Primary resistance and secondary resistance can occur in up to 25% and 8% to 10% of patients with CML, respectively.2,3
Because of the potential for TKI intolerance and resistance, ponatinib was developed as an oral agent against the mutated BCR-ABL protein, specifically the T315I mutation. Soon after its initial release, ponatinib was removed from the market based on concerns over arterial and venous thromboses, as well as liver toxicity. Ponatinib was eventually re-released, though multiple black box warnings were updated in the prescribing information (PI).
The current PI for ponatinib states that there were arterial occlusions in “at least 35%” of treated patients compared to 6% of patients having venous thromboembolisms.4 These vascular adverse events led to myocardial infarctions, strokes, and peripheral vascular disease.