Ponatinib Shows Promise in CML Even After Early Trial Termination


Despite the early trial termination due to safety concerns, an analysis suggests that ponatinib offers improved efficacy over imatinib in newly diagnosed CML.

Ponatinib; source: Ariad Pharmaceuticals

Despite the early termination of a phase III trial due to safety concerns, an analysis suggests that ponatinib offers improved efficacy over imatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). That improvement comes at the expense of higher rates of adverse events, according to the EPIC trial.

EPIC was a multinational, multicenter, randomized, open-label trial. It included 307 patients, with a median follow-up of only 5.1 months. The trial was terminated in October 2013 after a signal for increased risk of arterial thrombotic events was observed in the ponatinib treatment arm. Because of that early termination, none of the predefined endpoints could be thoroughly analyzed, but researchers presented other relevant data based on a cutoff of April 1, 2014. The analysis, led by Jeffrey H. Lipton, MD, PhD, of Princess Margaret Cancer Centre at the University of Toronto in Canada, was presented at the American Society of Hematology Annual Meeting in San Francisco in December 2014.

Data were available for 306 of the 307 patients (154 ponatinib, 152 imatinib); 14 ponatinib patients and 2 imatinib patients discontinued the study due to adverse events.

“Molecular response rates for ponatinib were uniformly higher compared with imatinib for all response measures and at all time points,” the authors wrote in an abstract. The major molecular response (MMR) at any time point was 41% with ponatinib, compared with only 18% with imatinib. Furthermore, 94% of ponatinib patients achieved < 10% BCR-ABL transcript levels at 3 months, compared with 68% of imatinib patients. A full 98% of those patients deemed “low-risk” achieved that milestone with ponatinib, compared with 76% of low-risk imatinib patients. Similarly, 96% of intermediate-risk and 85% of high-risk patients achieved < 10% BCR-ABL levels with ponatinib, compared with 69% and 42% of intermediate- and high-risk imatinib patients.

The most common all-grade treatment-emergent adverse events with ponatinib were rash (38%), abdominal pain (36%), and headache (33%). In imatinib patients, the most common such events were nausea (34%), muscle spasms (34%), and diarrhea (27%). Grade 3/4 adverse events occurred slightly more in ponatinib patients (12%) than imatinib patients (7%). Among the most frequent serious treatment-emergent adverse events in ponatinib patients were pancreatitis (5 patients), atrial fibrillation (3 patients), and thrombocytopenia (3 patients); no such events occurred in 3 or more imatinib patients.

The adverse event that led to trial termination, serious arterial thrombotic events, occurred in 7% of ponatinib patients and only 0.7% of imatinib patients. The authors noted, however, that though the groups were generally well balanced at baseline, there was a higher proportion of ponatinib patients with one or more cardiovascular risk factors (63% vs 52%).

“Despite early termination, at a median follow-up of 5 months, preliminary evidence suggests that ponatinib has improved efficacy over imatinib in newly diagnosed CP-CML patients,” the authors wrote in the abstract. “Future investigations of ponatinib in the frontline setting will likely use lower doses and account for relevant risk factors.”

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