Ponatinib Works in CML When Nothing Else Is Effective

Zosia Chustecka

December 11, 2012

The investigational drug ponatinib (Ariad Pharmaceuticals) offers hope to patients with chronic myeloid leukemia (CML) who have stopped responding to all other therapies. It is currently awaiting approval in the United States.

Dr. Jorges Cortes

"We have simply never had any treatment produce such high rates of durable response in a heavily pretreated group of patients," said 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.

Dr. Cortes presented preliminary results from the phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial here at the American Society of Hematology 54th Annual Meeting. It has shown 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.

The PACE trial was highlighted as "a major advance" by ASH president Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto in Ontario, Canada, at a premeeting press briefing.

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 tyrosine kinase inhibitors (TKIs) have transformed the lives of CML patients. However, some patients develop resistance to these drugs, and around 5% to 20% develop the T3151 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.

Durable Advances

The PACE trial was conducted in Europe and the United States in 449 patients with CML or with Philadelphia-chromosome-positive acute lymphocytic leukemia (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 T3151 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 chronic-phase CML patients (50% who had been resistant/intolerant to TKIs and 70% with the T3151 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 T3151 mutation) and in 34% of those with blast-phase CML/Ph+ ALL (35% who had been resistant/intolerant and 33% with the T3151 mutation).

Dr. Cortes reported that the responses were similar in patients with and without the T3151 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 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. Dr. Jorges Cortes

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

"Our next step is to test ponatinib's potential as an initial therapy in an attempt to prevent the occurrence of relapse, which may decrease the prospect of a normal lifespan," he added. Ariad's phase 3 trial, known as EPIC, is already underway. EPIC is comparing ponatinib with imatinib in newly diagnosed chronic-phase CML patients.

The study was funded by Ariad, the manufacturer of ponatinib. Dr. Cortes reports receiving research funding from Novartis, Bristol-Myers Squibb, Ariad, Pfizer, and ChemGenex; and doing consultancy work for Ariad, Pfizer, and Teva. Several of his coauthors are employees of Ariad. Dr. Keating has served on the data safety monitoring board for Clavis, Novartis, and Pfizer.

American Society of Hematology (ASH) 54th Annual Meeting: Abstract 163. Presented December 10, 2012.