Leukemia fighter: drug could combat resistant cases.

The drug imatinib, also called Gleevec, is the kind of success story most scientists only dream of. Since its FDA approval in 2001, imatinib has rescued thousands of patients from chronic myeloid leukemia, a lethal blood cancer with limited treatment options short of a bone marrow transplant.

However, some patients taking imatinib have relapsed as their leukemia has become resistant to the drug's effects. In the July 16 Science, researchers report that a new drug aimed specifically at imatinib-resistant leukemia stops the cancer in mice.

First, the scientists induced leukemia in the animals. Most mice recovered when they subsequently received a 2-week treatment of the experimental oral drug. All the mice fed an inert substance showed progressive disease. In a laboratory-dish experiment, the drug thwarted growth of cancerous bone marrow cells taken from patients with chronic myeloid leukemia that was resistant to imatinib.

On the basis of these findings, researchers have begun a safety trial that's providing the new drug, called BMS-354825, to people with imatinib-resistant leukemia, says study coauthor Neil P. Shah of the University of California, Los Angeles.

The new drug stops chronic myeloid leukemia much as imatinib does. Both drugs bind to and disable the same rogue enzyme in the blood. Cells start making the enzyme, called Bcr-Abl, when a piece of one chromosome moves into another. Chronic myeloid leukemia is dependent on this enzyme, which induces white blood cells to proliferate out of control.

Imatinib stops the process, but 10 to 15 percent of the patients eventually relapse, says Brian J. Druker of the Oregon Health and Science University in Portland. "Drugs like [BMS-354825] would be of value there," he says.

Patients relapse because they start making mutant versions of the rogue enzyme to which imatinib molecules can't effectively bind. BMS-354825 molecules are shaped differently from those of imatinib, and in the lab tests, they bound to 14 of 15 known mutant versions of the Bcr-Abl enzyme, Shah and his colleagues report.

Most cases of chronic myeloid leukemia progress slowly before exploding into a crisis stage of cell proliferation, during which mutant versions of the rogue enzyme crop up rapidly. Imatinib has a greatly reduced effect during this stage of the disease. Shah says that the ongoing BMS-354825 trial has already shown encouraging early results in patients in the crisis stage.

If BMS-354825 proves safe in this trial and effective in larger tests, combining it with imatinib might eradicate the Bcr-Abl enzyme from patients at the start of therapy and limit the number of people who relapse and then reach a crisis stage, he says.