U.S. FDA approves ponatinib plus chemotherapy for adult patients with newly diagnosed Ph+ ALL

On March 19, 2024, it was announced that the U.S. Food and Drug Administration (FDA) had granted accelerated approval to ponatinib, a BCR::ABL1 tyrosine kinase inhibitor, plus chemotherapy for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).^1,2 This approval is based on promising efficacy and safety outcomes from the III PhALLCON study (NCT03589326), which met its primary endpoint of minimal residual disease (MRD)-negative complete remission (CR) at the end of induction.²

PhALLCON study

PhALLCON is a randomized, multicenter, open-label trial of ponatinib versus imatinib combined with low-intensity chemotherapy in adult patients with newly diagnosed Ph+ ALL. A total of 245 adult patients were randomized 2:1 to either ponatinib (n = 1,640) or imatinib (n = 81) arm. The key results were as follows^1,2:

• A significantly higher improvement in MRD-negative CR rate at the end of induction for the ponatinib versus imatinib arm, at 30% and 12%, respectively (p = 0.0004).
• Similar safety profiles between the two arms, with no new safety signals reported.
• The most common adverse events were hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.

The U.S. FDA has recommended a dose of 30 mg ponatinib orally once daily, reduced to a dose of 15 mg orally once daily when an MRD-negative CR is achieved at the end of induction. Ponatinib should be continued with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity.

Conclusion

This approval marks an important clinical development, providing adult patients in the US with the first and only targeted frontline treatment for Ph+ ALL.