Ponatinib Shows Strong Activity in CML and ALL, Carries Thrombotic Risk

Ponatinib; source: Ariad Pharmaceuticals

Ponatinib showed significant antileukemic activity in patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), according to a phase II study. The study included a wide range of disease stages and mutation status; patients in the trial had a relatively high rate of adverse thrombotic events, an issue which has led to recent regulatory controversy surrounding the drug.

In general, newly diagnosed CML patients receive the tyrosine kinase inhibitor (TKI) imatinib. “Although initial response rates are high, imatinib fails in up to 40% of patients because of disease resistance, frequently because of BCR-ABL kinase domain mutations or unacceptable side effects,” wrote study authors led by Jorge E. Cortes, MD, of MD Anderson Cancer Center in Houston. Patients who require a second-generation TKI and still do not respond have a very poor prognosis, they continued, and unless a patient is among the few who are eligible for an allogeneic stem cell transplantation, the disease is likely to be fatal.

Ponatinib is a TKI that has activity against unmutated and mutated BCR-ABL, including the common T315I mutation present in 20% of TKI-resistant patients. The new study was a phase II trial of 449 patients with CML or Philadelphia chromosome-positive ALL. These were heavily pretreated patients: 37% had received two TKIs previously (imatinib, dasatinib, nilotinib, or bosutinib), and 55% had received at least three. Other patients had been treated with chemotherapy agents; all patients received an initial dose of 45 mg ponatinib daily.

There was a mean follow-up of 15 months; 56% of the 267 patients with chronic phase CML had a major cytogenetic response at 12 months, which was the study’s primary endpoint. A total of 46% had a complete cytogenetic response, and 34% had a major molecular response. “Patients who received fewer previous tyrosine kinase inhibitors, were younger, and had a shorter interval between diagnosis and enrollment in the study tended to have higher response rates,” the authors wrote.

Among the 83 patients with accelerated phase CML the response rates were similar, at 55% for a major hematologic response by 6 months, and 39%, 24%, and 16% for major cytogenetic responses, complete cytogenetic responses, and major molecular responses, respectively. Again, those who received fewer TKIs before the study fared better on ponatinib.

Among patients with blast phase CML, 31% had a major hematologic response by 6 months, while 23% achieved a major cytogenetic response, and 18% had a complete cytogenetic response. Forty-one percent of those with Ph-positive ALL had a major hematologic response, 47% had a major cytogenetic response, and 38% had a complete cytogenetic response.

While the most common nonhematologic adverse events in the study included rash, dry skin, and abdominal pain, the researchers did observe a substantial number of arterial thrombotic events. Regardless of whether the event was considered related to treatment, 7.1% of all patients had a cardiovascular event, 3.6% had a cerebrovascular event, and 4.9% had a peripheral vascular event. These data are contributing to recent US Food and Drug Administration decisions to first issue a safety alert for ponatinib, and to then request a discontinuation of marketing by the manufacturer, Ariad Pharmaceuticals. Most recently, the European Medicines Association allowed ponatinib to stay on the market but listed recommendations for reducing the risk of thrombotic events.

The study authors noted that the accumulating evidence on arterial thrombosis with ponatinib has also led to the termination of the frontline therapy study known as EPIC. “Awareness of these ponatinib-associated events is critical in the treatment of patients who are receiving ponatinib,” they wrote. “In this study, arterial thrombotic events were observed predominantly in patients with either a documented ischemic condition or one or more risk factors at baseline. Patients with these clinical features should be carefully monitored.”