A New First-line Therapy for Certain Leukemias
The BCR-ABL inhibitor ponatinib was approved for some patients with acute lymphoblastic leukemia.
The U.S. Food and Drug Administration (FDA) has granted accelerated approval to ponatinib (Iclusig) in combination with chemotherapy for adult patients with untreated acute lymphoblastic leukemia (ALL) that harbors a mutation known as the Philadelphia chromosome (Ph).
Ph is an aberrant DNA fragment that forms when a portion of the BCR gene fuses to a portion of the ABL gene. The resulting fusion product, BCR-ABL, causes white blood cells to grow uncontrollably, which can lead to many types of blood cancer, including ALL. Ponatinib kills cancer cells by blocking the activity of BCR-ABL.
Ponatinib was previously approved as monotherapy for patients with Ph-positive ALL who have a particular Ph mutation or who are not eligible to receive other kinase inhibitors. The latest approval makes ponatinib in combination with chemotherapy available to patients with newly diagnosed ALL that has any Ph mutation regardless of the patient’s eligibility for other kinase inhibitors.
The accelerated approval is based on results from the randomized, active-controlled, multicenter, open-label PhALLCON phase III clinical trial, which enrolled 245 adult patients with newly diagnosed Ph-positive ALL. Patients were randomly assigned (2:1) to receive either ponatinib with chemotherapy or imatinib (Gleevec) with chemotherapy.
At the time of data collection, 30% of patients in the ponatinib arm had a complete response with no signs of residual cancer, compared with 12% of patients in the imatinib arm.
The recommended dose for ponatinib is 30 mg once per day; if the patient experiences a complete response with no minimal residual disease after the first phase of treatment, the dose may be decreased to 15 mg once per day. Ponatinib combined with chemotherapy should be continued for up to 20 cycles, or until the cancer stops responding or the patient experiences unacceptable toxicity.
The prescribing information for ponatinib includes a boxed warning for life-threatening cardiovascular events and liver toxicities.
ALL is a blood cancer characterized by the overgrowth of immune cells known as lymphocytes. The Ph mutation is present in approximately 25% of adult ALL cases. According to federal statistics, it was estimated that 6,550 individuals would be diagnosed with ALL and 1,330 patients would die of the disease in the United States in 2024.
The FDA rendered its decision on March 19, 2024. Accelerated approval means that continued approval may be contingent upon a confirmatory trial.
