February 2013 Vol 6, No 1, Special Issue - Leukemia
Wayne Kuznar

Atlanta, GA—The new oral tyrosine kinase inhibitor (TKI) ponatinib (Iclusig) has significant activity and is well tolerated in patients with highly pretreated chronic myeloid leukemia (CML) or with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) who otherwise lack therapeutic options. Twelve-month follow-up data from a pivotal phase 2 trial of ponatinib in this population were reported by Jorge E. Cortes, MD, Professor of Medicine and Deputy Chair, Department of Leukemia, at M.D. Anderson Cancer Center, Houston, at the 2012 ASH meeting.

“This therapy may be able to transform highly fatal forms of leukemia into a curable disease in these patients—we have simply never had any treatment produce such high rates of durable response in such a heavily treated group of patients,” he said.

As a result of these data, the US Food and Drug Administration (FDA) approved ponatinib for the treatment of CML and Ph+ ALL in adults under its accelerated approval program.

Approximately 5% to 20% of pa­tients with CML and Ph+ ALL have the “gatekeeper” T315I BCR-ABL mutation, which confers resistance to dasatinib or nilotinib.

Ponatinib binds to the BCR-ABL active site and had shown potent activity against native BCR-ABL and BCR-ABL mutants, including T315I, in earlier clinical trials. In addition, high levels of response to ponatinib had been observed in patients with no mutations who have experienced resistance or intolerance to the other TKIs.

The international, open-label clinical trial Ponatinib Ph+ ALL and CML Evaluation (PACE) measured the safety and efficacy of ponatinib, 45 mg daily, in 449 patients with Ph+ leukemia (CML or Ph+ ALL) who were in various stages of disease. Among this heavily treated cohort, more than 90% of patients had been administered at least 2 TKIs, and approximately 60% of the patients in the chronic phase had received 3 TKIs.

A significant predictor of response to a new drug for CML is how well a patient responds to previous drugs, said Dr Cortes. Only 25% of patients with CML in the trial had any response at all to previous TKIs.

The primary end point for chronic phase was a major cytogenetic re­sponse at any time within 12 months for CML, and a major hematologic response within 6 months after treatment for patients with advanced-phase CML or Ph+ ALL. “For patients in more advanced stages of disease, who can be difficult to treat or are more likely to be resistant to all therapies, the goal is to generate a major hematologic response,” said Dr Cortes.

In the chronic phase, which included 267 patients, the rate of response to ponatinib was 56%. In the 83 patients in the accelerated phase, almost 60% of patients achieved a major hematologic response.

In addition, Dr Cortes pointed out, “We’re already getting deep molecular responses—one third are getting major molecular responses.” A significant 91% of these patients are predicted to maintain their responses.

“These are very encouraging, sustained responses,” he acknowledged. “Of note, responses are happening regardless of mutations. Patients with mutations other than T315I respond very well.” A total of 57% have achieved a major cytogenetic response. Among the patients with no mutations, the response rate was 49%.

Of note, “the drug is very well tolerated,” Dr Cortes said.

Common side effects, which are usually mild and manageable, in­cluded skin rash and dry skin. Only 1 patient had to leave the study because of pancreatitis.

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Last modified: March 4, 2013
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