Sorafenib promising in leukemia with mutant FLT3

February 11, 2008

NEW YORK (Reuters Health) - Acute myeloid leukemia (AML) patients with a mutant variety of the Fms-like tyrosine kinase 3 (FLT3) gene may be particularly receptive to therapy with the kinase inhibitor sorafenib, the results of animal and clinical studies suggest.

Dr. Michael Andreeff of the University of Texas M. D. Anderson Cancer Center, Houston and colleagues note that internal tandem duplication mutations of the FLT3 gene are seen in 30% of AML patients and are associated with poor prognosis.

However, the researchers found that sorafenib was from 1000- to 3000-fold more effective in inducing growth arrest and apoptosis in mutant murine AML cell lines than in those with wild-type FLT3.

In a mouse xenograft model of FLT3-internal tandem duplication mutant leukemia, sorafenib-treated animals survived for a median of 36.5 days versus 16 days for vehicle-treated animals, the researchers report in the February 6th issue of the Journal of the National Cancer Institute.

They also determined that this treatment led to a significant reduction in the median percentage of leukemia blasts, from 81% to 7.5%, in the peripheral blood of patients with FLT3-internal tandem duplication. In bone marrow, the corresponding drop was from 75.5% to 34%. No reductions were seen in patients without the mutation.

"Taken together," the researchers conclude, "our findings imply that sorafenib is a potent antileukemic agent in patients with FLT3-internal tandem duplication mutant AML, a form of AML that responds poorly to traditional chemotherapy."

In comments to Reuters Health, Dr. Andreeff added that "sorafenib should not be used indiscriminately, but combination studies with other agents, including investigational drugs, can now be developed. I am not advocating the use of sorafenib alone," he said, "rather as a platform for mechanism-based combinations."

"Finally, the mutation is also present in AML stem cells," he added, "which raises hope that these cells can also be eliminated with this targeted therapy."