FDA Approves Ponatinib Plus Chemo for Newly Diagnosed Ph+ ALL

FDA Approves Ponatinib Plus Chemo for Newly Diagnosed Ph+ ALL

The FDA granted accelerated approval to ponatinib (Iclusig) in addition to chemotherapy for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).¹

The approval was based on findings from the PhALLCON trial (NCT03589326), which enrolled 245 adult patients with newly diagnosed Ph+ ALL. In this randomized, active-controlled, multicenter, open-label trial, patients were randomly assigned in a 2:1 fashion to receive either 30 mg of ponatinib orally once per day or 600 mg of imatinib (Gleevec) once per day. Both treatment assignments were given with chemotherapy. Of note, imatinib with chemotherapy is a regimen that has not been approved by the FDA, according to the agency’s notice of the approval.

The chemotherapy regimen consisted of 3 induction cycles with vincristine and dexamethasone, 6 consolidation cycles alternating between methotrexate and cytarabine, and 11 maintenance cycles with vincristine and prednisone. The dose of ponatinib was decreased to 15 mg once per day after the induction phase was completed and when patients achieved minimal residual disease (MRD)-negative complete remission (CR).

The efficacy of treatment was based on MRD-negative CR rate at the end of the induction cycle. The researchers of this trial observed an MRD-negative CR rate of 30% in patients assigned ponatinib and 12% in those assigned imatinib (risk difference, 0.18; 95% CI, 0.08-0.28; P = .0004).

The most common adverse reactions that occurred in this trial include arthralgia, hepatic dysfunction, headache, rash and related conditions, abdominal pain, pyrexia, fatigue, constipation, oral mucositis, nausea, pancreatitis/elevated lipase, hypertension, hemorrhage, peripheral neuropathy, fluid retention and edema, febrile neutropenia, paresthesia, vomiting, and cardiac arrhythmias, according to the FDA’s alert.

The recommended dose for ponatinib is 30 mg orally once per day, which is reduced to 15 mg orally once per day once MRD-negative CR is achieved at the end of the induction cycle. Treatment with ponatinib with chemotherapy can be continued for up to 20 cycles until loss of response or unacceptable toxicity.

According to prescribing information for ponatinib, there is a boxed warning about the risk for arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.² Arterial occlusive events included stroke, myocardial infarction, severe peripheral vascular disease, stenosis of larger arterial vessels of the brain, and the need for urgent revascularization procedures. The warning noted that patients with and without cardiovascular risk factors experienced these events, including those aged 50 years or younger. Cancer teams are asked to monitor for evidence of arterial occlusive events and to interrupt or discontinue ponatinib based on severity.

Reference

1. FDA grants accelerated approval to ponatinib with chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. News release. FDA. March 19, 2024. Accessed March 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ponatinib-chemotherapy-newly-diagnosed-philadelphia-chromosome
2. Iclusig. Prescribing information. Takeda; 2024. Accessed March 19, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/203469s037lbl.pdf