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New gene-targeted therapy promises improved cure rates for deadly type of Leukemia

Johns Hopkins Medicine

Researchers at the Johns Hopkins Oncology Center have developed a new gene-based therapy that they hope will transform one of the most lethal types of adult leukemia to one of the most treatable. The test-tube findings, related to the treatment of acute myeloid leukemia (AML), also the most common form of adult leukemia, are reported in the August 1, 2001, issue of Blood.

AML is characterized by the uncontrolled growth of myeloid cells of the blood and bone marrow, which eventually crowds out and destroys normal blood cells. Normally, FLT3 is involved in the growth and maturation of healthy blood cells. In AML patients with FLT3 mutations, the cells acquire an abnormally altered FLT3 gene that promotes the uncontrolled growth.

Existing therapies using chemotherapy cure the disease in fewer than 10 percent of patients who have a mutation of the FLT3 gene. But, researchers say a new treatment that targets and blocks the abnormal action of mutant FLT3 has the potential to dramatically improve the cure rate for these patients.

Still, Donald Small, M.D., Ph.D., associate professor of oncology and director of the research, cautions that the Hopkins studies are preliminary, and the safety and effectiveness of the therapy have yet to be confirmed in animal and human clinical trials.

Specifically, researchers have identified a compound that targets the signaling ability of mutant FLT3 (pronounced: flit three) genes. These mutations occur in and account for up to 40 percent of AML cases and are associated with a more aggressive, less curable form of the disease. Mutant FLT3 genes signal leukemia cells to grow and prevent the cells from dying. The new treatment specifically inhibits this activity, blocking the signal for growth and inducing leukemia cells to die.

In their study, the Hopkins investigators used the drug AG1295 to interfere with abnormal FLT3 signaling. "By blocking the action of the altered FLT3 protein, we can render it powerless. It's as if the mutation no longer exists. This is really proof of concept that a FLT3 inhibitor can kill human leukemia cells," says, Small, the first to clone the human FLT3 gene**.

The investigators tested AG1295 on clusters of human leukemia cells called blasts obtained from 23 AML patients. The compound caused many of the leukemia cells to die, with the most significant activity occurring in the blasts of patients with FLT3 mutations.

"This is the payoff of more than a decade of laboratory research to pinpoint the genetic alterations associated with this type of leukemia. Now, as hoped, we have evidence that the very abnormalities that cause the disease to progress may provide part of the cure," says Small.

The first human trials at Johns Hopkins of a FLT3 inhibitor are currently in planning. AML strikes more than 10,000 adults and children in the U.S. annually making it the most common form of adult leukemia and the second most common childhood leukemia.


In addition to Small, other participants in this study include Mark Levis, Kam-Fai Tse, B. Douglas Smith, and Elizabeth Garrett.

This work was supported by grants from the National Cancer Institute, Leukemia and Lymphoma Society, Children's Cancer Foundation, Alexander and Margaret Stewart Trust, and the National Institutes of Health.

**Small, D., Levenstein, M., Kim, E.K., Carow, C., Amin, S., Rockwell, P., Witte, L., Burrow, C., Ratajczak, M., Gewirtz, A.M., and Civin, C.I. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc. Natl. Acad. Sci. 91: 459-463, 1994.

"A FLT3 Tyrosine Kinase Inhibitor is Selectively Cytotoxic to AML Blasts Harboring FLT3/ITD Mutations." Blood vol. 98, no. 3, August 1, 2001.

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