FDA Approves Ponatinib for Rare Leukemias

Zosia Chustecka

December 14, 2012

Ponatinib (Iclusig, Araid) was approved today by the US Food and Drug Administration (FDA) for use in patients with 2 leukemias that have stopped responding to other therapies, and offers new hope for these subgroups of patients.

The approval comes 2 months earlier than expected.

Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) and also Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (Ph+ ALL) who have relapsed or are refractory to other therapies. Many of these patients, but not all, have developed a T315I mutation, which makes the disease resistant to the standard treatment with tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec).

"The approval of ponatinib is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have few therapeutic options," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.

A Major Advance

Ponatanib was described as a "major advance" last week at the annual meeting of the American Society of Hematology by ASH President Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto in Ontario, Canada.

Over the past decade, CML has changed from a fatal disease to a chronic condition that is held in check by targeted therapies such as imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), and, more recently, bosutinib (Bosulif).

These TKIs have transformed the lives of patients with CML, he explained. However, some patients develop resistance to these drugs, and around 5% to 20% develop the T315I mutation, which makes them resistant to all the TKIs. "These patients would eventually develop a blast crisis and then die," but ponatinib offers hope of a rescue medication for these patients, Dr. Keating explained.

The approval is based on results from the phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, which were presented at the meeting. The results show that ponatinib works in patients who are resistant to or who cannot tolerate other therapies and confirms the efficacy seen in the recently published phase 1 clinical trial (N Engl J Med. 2012;367:2075-2088), as reported by Medscape Medical News.

"We have simply never had any treatment produce such high rates of durable response in a heavily pretreated group of patients," said lead author Jorges Cortes, MD, professor of medicine and deputy chair of the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston.

Durable Advances

The PACE trial was conducted in Europe and the United States in 449 patients with CML or with Ph+ ALL. All patients had been heavily pretreated, with a median of 3 TKIs. Most of the patients (96%) had received imatinib, 84% had received dasatinib, 65% had received nilotinib, and some patients had received the newest agent, bosutinib, Dr. Cortes said.

The median time from diagnosis to enrollment in this study was 6 years (range, 0.3 - 28 years). Almost one third of patients (29%) had the T315I mutation; a few other mutations were found, but 44% of patients had no mutation.

Patients were categorized according to disease stage.

For patients with chronic-phase CML (270 of 449 participants), the primary end point was a major cytogenetic response within 12 months of treatment (where more than 65% of cells are normal). This was achieved in 55% of patients with chronic-phase CML (50% who had been resistant/intolerant to TKIs and 70% with the T315I mutation).

These responses are durable, Dr. Cortes reported. It is estimated that the major cytogenetic response will be sustained at 12 months in 91% of patients with chronic-phase CML.

Remarkably, a complete cytogenetic response (no Ph+ cells measured in the body) was achieved in 46% of patients with chronic-phase CML, and even higher response rates were observed in patients who had been exposed to fewer TKIs and had a shorter duration of disease, Dr. Cortes noted.

For patients with accelerated-phase CML (n = 85) or blast-phase CML/Ph+ ALL (n = 94), the primary end point was a major hematologic response (normal white blood cell counts) within 6 months of treatment. This was achieved in 58% of patients with accelerated-phase CML (57% who had been resistant/intolerant and 50% with the T315I mutation) and in 34% of those with blast-phase CML/Ph+ ALL (35% who had been resistant/intolerant and 33% with the T315I mutation).

Dr. Cortes reported that the responses were similar in patients with and without the T315I mutation, which confirms previous observations. It shows that ponatinib works across a wide range of TKI resistance, whether or not a mutation is present, he explained.

Ponatinib is generally well tolerated. The most common adverse events reported were rash, abdominal pain, headache, dry skin, constipation, fatigue, pyrexia, nausea, arthralgia, and hypertension. There were also some cases of pancreatitis (6% of all patients), some elevation of pancreatic enzymes (lipase in 19%, amylase 7%), and some myelosuppression (thrombocytopenia in 42%, neutropenia in 34%, and anemia in 20%).

Ponatinib was approved with a boxed warning alerting patients and healthcare professionals that the drug can cause blood clots and liver toxicity.

"Ponatinib may be an important new treatment for CML and Ph+ ALL resistant or intolerant to previous TKIs," Dr. Cortes concluded.

"This therapy may be able to transform highly fatal forms of leukemia into a curable disease," he said in a statement.