Dec. 11, 2007 A new drug for chronic myelogenous leukemia works for patients who have developed resistance to frontline therapy and causes fewer side effects than other medications in its class, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports at the 49th annual meeting of the American Society of Hematology.
"Bosutinib has shown good efficacy and very little toxicity compared to other tyrosine kinase inhibitors at this stage of the clinical trial," says lead researcher Jorge Cortes, M.D., professor in M. D. Anderson's Department of Leukemia.
Bosutinib, developed by Wyeth Pharmaceuticals, is being tested in patients in the early or chronic phase of CML whose disease has become resistant to imatinib or who have become intolerant of imatinib's side effects.
So far, 98 patients have enrolled in the relatively new clinical trial, with median duration of treatment at 5.1 months.
Among 23 evaluable patients who had become resistant to imatinib, 17 (74 percent) achieved a complete hematological response - normal blood counts. Of 36 evaluable for cytogenetic response - reduction of the abnormal chromosome that causes the disease - 15 had a major response and 12 of those had a complete response, or absence, of the chromosome.
"These responses are comparable to other drugs at a similar stage of follow-up," Cortes says.
Interestingly, a small number of patients who had also become resistant to second-line treatments nilotinib and dasatinib derived some benefit from taking the new drug. Out of eight such patients, three achieved complete hematologic response and two achieved major cytogenetic response.
The most common side effects were low-grade nausea, vomiting and diarrhea, which improved greatly three or four weeks into therapy. Higher grade side effects such as low counts of platelets, white or red blood cells ranged from 1 to 9 percent of patients. Fluid build-up in the lungs and other organs occurred in only 12 patients and was of low grade.
Cortes says the researchers suspect that the low grade and frequency of side effects is probably a result of the drug's specificity in the proteins that it targets. Bosutinib inhibits SRC and ABL proteins but does not affect platelet derived growth factor receptor or C-Kit, two similar kinases that are affected by other CML drugs.
CML is caused by the Bcr-Abl protein, which results from a chromosomal abnormality called the Philadelphia Chromosome. Bcr-Abl is a tyrosine kinase that fuels an overabundance of white blood cells and immature stem cells called blasts that crowd out red blood cells and platelets.
Tyrosine kinases are a specialized subgroup of protein kinases, which regulate protein behavior by attaching phosphate groups to proteins or small molecules. Bosutinib, like imatinib (Gleevec(r)), dasatinib (Sprycel(r)) and nilotinib (Tasigna(r)), is a tyrosine kinase inhibitor.
The researchers also found that bosutinib is effective against a variety of Bcr-Abl mutants that cause CML and conclude that the drug is effective in imatinib-resistant patients with chronic CML across a range of mutations and after the failure of other tyrosine kinase inhibitors.
Co-authors with Cortes are Hagop Kantarjian, M.D., of M. D. Anderson's Department of Leukemia; Tim Bruemmendorf, M.D., University of Hamburg; H. Jean Khoury, M.D., and Becker Hewes, M.D. of Emory University; Gianantonio Rosti, University of Bologna, Italy; Thomas Fischer, M.D., Johannes Gutenberg University, Mainz, Germany; L. Tornaghi; E.C. Martin of Wyeth Research; and Carlo Gambacorti-Passerini, M.D., and Lucia Tornaghi, both of University of Milano-Bicocca.
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