'Designer' drug shows activity in leukemia

December 09, 2002

PHILADELPHIA -- An experimental drug aimed precisely at a culprit genetic mutation has shown promising activity in a difficult-to-treat form of leukemia, say researchers from Dana-Farber Cancer Institute and their collaborators.

The scientists, who will present their findings at the annual meeting of the American Society of Hematology (ASH) in Philadelphia (Dec. 9, 11:15 a.m., Room 114), call the results a "proof of concept" even though none of the 15 patients treated with the drug, a Novartis Pharma compound known as PKC-412, went into remission. Thirteen of the patients did respond with reductions in their abnormally high white blood cell counts.

"This is really designer therapy" in that the drug is matched to a specific genetic flaw that distinguishes a particular form of acute myeloid leukemia (AML), says Dana-Farber's Richard Stone, MD, who will present the data at ASH.

The experimental compound is similar in concept to Gleevec, the first of the new "targeted" drugs that take advantage of an explosion of molecular information about cancer cells and their specific abnormalities. Because such drugs are aimed so narrowly, they are less likely to harm normal cells and tissues than conventional chemotherapy drugs with many and often severe side effects.

AML affects about 15,000 children and adults in the United States each year. In about one-third of patients, the cancerous blood cells contain an abnormal gene called FLT3, and those patients have a poorer prognosis than individuals who carry a normal FLT3 gene. The mutant gene transmits a signal that drives the cells into abnormal, excessive proliferation.

Previous work by James Griffin, MD, and Ellen Weisberg, PhD, of Dana-Farber, and Gary Gilliland, MD, PhD, of Brigham and Women's Hospital and Harvard Medical School, had shown that the experimental drug could block the harmful FLT3 growth signal in mice with a leukemia-like disease. The next question was whether it could do the same, and help patients, in a human clinical trial.

The 15 AML patients had either relapsed after treatment, achieved a temporary remission or had disease that was too stubborn to go into remission. They took the drug in pill form for up to 92 days. Nausea was the most common side effect, but otherwise the drug was well-tolerated, the researchers say.

In 13 of the patients, the drug caused abnormally high white cell counts to come down, dramatically in some cases. One patient had a count of 100,000 drop to normal (between 4,000 and 10,000) within a few days, Stone reports.

Although the drug didn't bring about a remission in any patient, "it's a lead," says Stone. "It is not a cure in itself, but combined with chemotherapy it might have a big impact." He says the trial will continue to enroll patients until 20 have undergone treatment with PKC-412. After that, the drug might be paired with a conventional chemotherapy drug to study the effect of the combination, says Stone.
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Dana-Farber Cancer Institute (www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Dana-Farber Cancer Institute

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