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Ponatinib acts against the most resistant types of chronic myeloid leukemia
Date:11/28/2012

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 the drug imatinib (Gleevec) revolutionized treatment of CML. Now approximately 90 percent of patients survive for at least five years, up from about 50 percent 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 30-40 percent of CML patients become resistant to it," Cortes said. "Nilotinib and dasatinib work for 40-50 percent of these patients."

Preclinical experiments indicated ponatinib acts against BCR-ABL and all known mutant forms of the protein.

Ponatinib active against known mutations and no mutations

The phase I trial enrolled 81 patients with blood cancers at five centers, 60 with CML and five with Philadelphia Chromosome-positive ALL. The patients had relapsed or resistant disease and 91 percent had been treated with at least two of the approved drugs. Median follow-up was 56 weeks.

  • Among 43 chronic phase CML patients, 42 had complete hematological response, 31 (72 percent) had a major cytogenetic response, 27 (63 percent) had a complete cytogenetic response (no CML cells in the bone marrow) and 19 (44 percent) achieved major molecular responses.
  • Duration of response for chronic phase patients with major cytogenetic response ranged from 8 to 117 weeks, with median duration yet to be reached.
  • Patients treated within 0 to 5 years of diagnosis had better response rates than those treated with ponatinib 5 to 24 years after di
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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