Understanding How Ponatinib Works in Ph+ ALL

Dr. Ibrahim Aldoss, a hematologist-oncologist and associate professor at City of Hope, recently discussed the mechanism of action of ponatinib (Iclusig) and highlighted the phase 3 PhALLCON trial (NCT03589326) in patients with newly diagnosed, Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL).

According to Aldoss, ponatinib effectively inhibits BCR:ABL1 and all single-mutation variants, including BCR:ABL1 T315I mutations. He suggests that using ponatinib as a frontline therapy may lead to enhanced long-term outcomes by increasing early and deep rates of minimal residual disease (MRD) negativity or preventing the emergence of the BCR:ABL1 resistance mutation.

The PhALLCON trial, a global, registrational, open-label study, included adults ages 18 years or older with newly diagnosed Ph-positive ALL who were randomly assigned to receive either ponatinib or imatinib (Gleevec) in combination with reduced-intensity chemotherapy. Patients then received single-agent ponatinib or imatinib after cycle 20.

Ponatinib was administered at a daily dose of 30 mg initially, which could be reduced to 15 mg daily once complete molecular remission was achieved. If a patient experienced loss of MRD negativity, the dose could be re-escalated to 30 mg. Imatinib was given at the standard dose of 600 mg daily for Ph-positive ALL.

The primary end point of the PhALLCON trial was achieving a sustained molecular remission for 4 weeks at the end of cycle 3. Aldoss highlights that achieving complete molecular remission within the first 3 months of TKI treatment has been linked to superior long-term survival outcomes. Secondary end points included event-free survival and overall survival, providing further insights into treatment efficacy and patient outcomes.