A previously invincible mutation in chronic myeloid leukemia (CML)has been thwarted by ponatinib (AP24534; Iclusig®, Ariad Pharmaceuticals, Inc) an investigational drug in a phase I clinical trial. The results of the trial were reported in the New England Journal of Medicine. The results of a pivotal phase II clinical trial of ponatinib were presented at the 54th Annual Meeting and Exposition of the American Society of Hematology (ASH), December 8 – 11, 2012 in Atlanta, GA.

In the trial, all 12 patients with chronic phase CML and the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors, had no traces of CML cells in the blood after treatment with ponatinib. Eleven patients had a major reduction in CML cells in the bone marrow and nine achieved a complete response, with no CML cells in the marrow.

Gatekeeper mutant
T315I is present in up to 20% of patients and blocks the docking station where three other successful CML drugs normally connect to the mutant protein to stop the cancer. “The fight with cancer is an ongoing battle. It can constantly ‘outsmart’ us by developing mutations and other changes. In this study, we were able to come up with a treatment that is capable of overcoming the most resistant mutation in CML, and thus represents a new evolution in targeted therapy,? says senior study author Moshe Talpaz, M.D., Alexander J. Trotman Professor of Leukemia Research at the University of Michigan Comprehensive Cancer Center. “This shows we can ‘fingerprint’ the tumor and develop treatment which not only fits a certain cancer, but a very specific molecular subset within the cancer,” Talpaz adds.

A broader group of patients
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 acute lymphoblastic leukemia (ALL), 67% with other mutations and 46% with no mutations achieved a complete response.

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A promising new treatment
“Ponatinib is a promising new treatment for patients who have run out of options and its activity against a wide variety of mutations and in patients with no known mutations suggests a broad range of efficacy for this drug,” said trial principal investigator Jorge E.Cortes, M.D., Professor in The University of Texas MD Anderson Department of Leukemia.

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Regulatory process
On October, the U.S. Food and Drug Administration accepted a new drug application for accelerated review of ponatinib for patients with resistant or intolerant CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

Success of targeted therapies
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.

Discovery of other drugs, including imatinib (Gleevec) revolutionized treatment of CML. Now approximately 90% of patients survive for at least five years, up from about 50% before imatinib. Two second-generation drugs, nilotinib (Tasigna) and dasatinib (Sprycel) are more potent than imatinib. Each can be used in frontline therapy. “Imatinib is a terrific drug, however 30% to 40% of CML patients become resistant to it,” Cortes said. “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. The most common non-hematologic side effects were skin disorders, fatigue and nausea. Pancreatitis occurred in 11 patients and was a serious adverse event in eight. Nine of the 11 experienced one episode of pancreatitis, only two discontinued treatment.

Twelve patients with acute myeloid leukemia also participated in the trial. A separate paper will address those results.

For more information:
– Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O’Hare T, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012Nov 29;367(22):2075-88. doi: 10.1056/NEJMoa1205127. [PubMed]
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Full Prescribing Information Ponatinib (AP24534; Iclusig?, Ariad Pharmaceuticals, Inc

Clinical trial
NCT00660920 – Safety Study of AP24534 to Treat Chronic Myelogenous Leukemia (CML) and Other Hematological Malignancies.

Photo: Moshe Talpaz, M.D.,Professor , Department of Internal Medicine, University of Michigan. Courtesty: University of Michigan.

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