A previously invincible mutation in chronic myeloid leukemia (CML) has been thwarted by an investigational drug, ponatinib, in a phase I clinical trial. All 12 patients in the trial with chronic phase CML and the T315I mutation had a complete hematologic response, meaning an absence of CML cells in the blood, after treatment with ponatinib. Eleven had a major reduction in CML cells in the bone marrow and nine achieved a complete cytogenetic response, meaning no cells in the marrow.

CML is caused by the abnormal gene BCR-ABL, which occurs when two chromosomes swap portions of their DNA from the BCR and ABL genes during cell division. This abnormality is called the Philadelphia chromosome and the resultant BCR-ABL fusion protein drives the overproduction of white blood cells that characterizes CML. BCR-ABL is a tyrosine kinase, a type of protein that acts as an on-off switch by attaching a phosphate group to other proteins.

Imatinib revolutionized the treatment of CML, but 30% to 40% of patients become resistant to it. The more potent, second-generation drugs nilotinib and dasatinib work for 40% to 50% of these patients. Preclinical experiments indicated ponatinib acts against BCR-ABL and all known mutant forms of the protein, including T315I. The mutation T315I is present in up to 20% of patients, and it blocks the docking station where the three other successful CML drugs normally connect to the mutant protein.

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This phase I trial enrolled 81 patients with blood cancers, which included 60 with CML and five with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). The patients had relapsed or resistant disease and 91% had been treated with at least two of the approved drugs. Median follow-up was 56 weeks.

Ponatinib also induced high response rates among the broader group of patients who had mutations other than T315I or no detectable mutations. Among 65 patients with relapsed or resistant CML at varying stages of the disease or with Philadelphia-chromosome positive ALL, 67% with other mutations and 46% with no mutations achieved a complete cytogenetic response.

“Ponatinib is a promising new treatment for patients who have run out of options and its activity against a variety of mutations and in patients with no known mutations suggests a broad range of efficacy for this drug,” said trial principal investigator Jorge Cortes, MD, professor in The University of Texas M.D. Anderson Department of Leukemia. Cortes will present the results of a pivotal phase II clinical trial of ponatinib at the 54th ASH Annual Meeting and Exposition in December.

In October, the US Food and Drug Administration accepted a new drug application by ARIAD Pharmaceuticals for accelerated review of ponatinib for patients with resistant or intolerant CML or Philadelphia chromosome-positive ALL.

This study was reported in the New England Journal of Medicine (2012; doi:10.1056/NEJMoa1205127).