Dr Aldoss on the Mechanism of Action of Ponatinib in Ph+ ALL

Ibrahim Aldoss, MD, hematologist-oncologist, associate professor, Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; member, the Gehr Family Center for Leukemia Research, codirector, the Hematology Tissue Bank, City of Hope and the Leukemia Registry, discusses the mechanism of action of ponatinib (Iclusig) and highlights the phase 3 PhALLCON trial (NCT03589326) in patients with newly diagnosed, Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL).

Ponatinib effectively inhibits BCR:ABL1 and all single-mutation variants, including BCR:ABL1 T315I mutations, Aldoss begins. Comparative analyses indicate 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:ABL1resistance mutation, he states.

The PhALLCON trial, a global, registrational, open-label study, was conducted in adults ages 18 years or older with newly diagnosed Ph-positive ALL and examined the use of ponatinib, he explains. Patients were randomly assigned in a 2:1 ratio to receive either ponatinib or imatinib (Gleevec) in combination with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20, Aldoss says.

Randomization was stratified based on patient age at enrollment, he expands. Ponatinib was administered at a daily dose of 30 mg initially, which was reduced to 15 mg daily once complete molecular remission was achieved at the end of induction or afterward to manage toxicity. The study allowed for dose re-escalation to 30 mg if the patient experienced loss of MRD negativity. Imatinib was administered at the standard dose of 600 mg daily for Ph-positive ALL, he reports.

The primary end point of the study was achieving a molecular remission that was sustained for 4 weeks at the end of cycle 3, Aldoss continues. This end point was chosen because achieving complete molecular remission within the first 3 months of TKI treatment has been associated with superior long-term survival outcomes, according to Aldoss. Secondary end points included event-free survival and overall survival, providing additional insights into treatment efficacy and patient outcomes, he concludes.