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Increasing benefit seen in novel drug that treats Gleevec resistance


An investigational drug is producing powerful responses in patients resistant to Gleevec, the targeted therapy that helps most people diagnosed with chronic myeloid leukemia (CML), an international research team headed by investigators at The University of Texas M. D. Anderson Cancer Center is reporting.

The drug, AMN107, is showing an increasingly strong benefit as doses are being steadily raised, say the researchers, who presented their latest analysis at the annual meeting of the American Association for Cancer Research.

In an ongoing study that has enrolled more than 100 patients, over 90 percent of those with the earlier stage "chronic" phase of CML have had a hematologic response, meaning their blood counts have returned to normal, says Francis Giles, M.D., a professor of medicine in the Department of Leukemia at M. D. Anderson. Additionally, more than 70 percent of patients with the advanced "accelerated" and terminal "blast" stages of the disease have similarly benefited, and the number of complete molecular remissions in patients also is steadily increasing, he says.

Giles can offer only estimates of response because he says that this study employs a new model of clinical trial design in which patients are continuously being given higher doses of the drug. "So the results change daily as patients fare increasingly better on higher doses," he says. "We are seeing benefit at lower doses that will only be fully quantifiable when all patients are on the maximal safe dose - a dose which we have not yet defined."

Clear activity was seen at the very first dose of 50 milligrams offered to the first patients who enrolled in May, 2004, Giles says. "This week everyone is being moved to the latest ceiling, which is 400 milligrams twice a day, and based on its safety and effectiveness, I believe we will soon move to 600 milligrams twice a day.

"If I had to guess, I would think the overall response rate across the whole population will be well over 75 percent," he says. Only within the last month have chronic phase patients been allowed into the study, and Giles estimates response in those patients may reach close to 100 percent because their cancer has not yet had the chance to form new mutations that the drug cannot treat. For that same reason, some patients with more advanced cancer will not respond to the drug, Giles points out.

Despite what he calls very exciting results from the use of AMN107, he stresses that CML patients should not think that they need to switch to this experimental drug. "Gleevec is incredibly powerful and failures are very rare in early phase CML. It is very effective in the great majority of patients," he says. "We are focused on a minority of patients, less than 10 percent of chronic patients, who more than likely need some other form of intervention to give them a normal life span."

CML is caused by the errant swapping of genetic material in bone marrow stem cells that produces an abnormality called the Philadelphia chromosome. This chromosome contains a new fused-together gene, BCR-ABL, which produces an enzyme that switches on uncontrolled growth in the bone marrow cell. Gleevec binds to this Bcr-Abl enzyme, shutting down its activity, which often leads to death of the leukemia cell.

AMN107 is estimated to be up to 30 to 100 times more potent than Gleevec because it was designed to more efficiently bind to Bcr-Abl, including to mutated forms of the enzyme that can produce Gleevec resistance, Giles says.

But the drugs have not been compared head-to-head, so Giles says, "I can’t say that AMN107 is better than Gleevec."

Giles, however, is planning to open a clinical trial at M. D. Anderson this summer to test AMN107 as a "frontline" therapy - the first treatment given - in chronic phase CML patients. Another six clinical trials testing the drug in all three separate phases of CML, as well as in other leukemias in which Gleevec has shown some benefit, also are slated to open soon.

Giles suggests that in the future, both Gleevec and AMN107, as well as perhaps other new tailored agents, may all be used in treating CML, especially if these drugs show a synergistic effect.

M. D. Anderson enrolled patients in the study, as did researchers at the University of Frankfurt in Germany. Giles presented first results of the therapy in fewer patients last December at the annual meeting of the American Society of Hematology.

Nancy Jensen | EurekAlert!
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