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.
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.
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.
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.
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.
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.
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.