Ponatinib for Patients with Rare Types of Leukemia

Atlanta—After a median >12 months of treatment, patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who took ponatinib responded well to the drug, according to a phase 2, multicenter, multinational study. The response occurred regardless of the disease stage or presence or type of mutation.

Ponatinib, an oral tyrosine kinase inhibitor, was also well tolerated with most adverse events being grade 1 or 2 and manageable. Dry skin or rash was the most common adverse event, found in approximately 40% of patients.

Jorge E. Cortes, MD, the study’s lead author and professor at the University of Texas MD Anderson Cancer Center in Houston, presented the results in an oral abstract session at the ASH meeting. A few days following the presentation, the FDA approved ponatinib for use in patients with CML and Ph+ ALL, ahead of the agency’s approval goal date of March 27, 2013.

Dr. Cortes said there have been recent advancements in the treatment of CML, including the introduction of new drugs such as imatinib, dasatinib, and erlotinib. However, he added that some patients who have received multiple tyrosine kinase inhibitors did not have a good response, while others have mutations that are not sensitive to available drugs.

The PACE (Ponatinib Ph+ ALL and CML Evaluation) trial included 449 patients who were resistant or intolerant to dasatinib or nilotinib or had the T315I mutation: 270 had chronic phase CML, 85 had acute phase CML, and 94 had Ph+ ALL or blast phase CML. Each took 45 mg of ponatinib once daily.

Median age was 60 years in the chronic phase and acute phase CML groups and 54 years in the Ph+ ALL/blast phase CML group. Approximately 90% of patients were resistant to dasatinib or nilotinib, and 93% had taken at least 2 tyrosine kinase inhibitors before enrolling in the study.

The authors collected data through November 9, 2012, and 49% of patients remained on the study drug by that date. Of the patients, 19% discontinued due to disease progression, 12% due to an adverse event, 4% due to lack of efficacy, 4% due to death, and 11% due to other reasons, including investigator decision, non-compliance, and withdrawal. Median follow-up was 15.3 months in patients with chronic phase CML, 15.8 months in patients with acute phase CML, and 6.2 months in patients with Ph+ ALL or blast phase CML.

Of patients with chronic phase CML, 56% had a major cytogenetic response; 57% of patients with acute phase CML and 34% of patients with Ph+ ALL or blast phase CML had a major hematologic response.

In the chronic phase CML group, 67% had a cytogenetic response, including 56% with a major cytogenetic response and 46% with a complete cytogenetic response. Median time to response was 2.8 months for a major cytogenetic response and 5.5 months for a major molecular response.

Dr. Cortes noted that the major cytogenetic responses were durable, with 91% of patients with chronic phase CML who achieved a major cytogenetic response remaining in response for up to 12 months.

At 12 months, 84% of patients with chronic phase CML had progression-free survival; overall survival was 94%. The most common serious adverse event was pancreatitis, found in 5% of patients, including 6% who had chronic phase CML.