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Treatment of Acute Myeloid Leukemia Cells with Combinations of a FLT3 Inhibitor and Chemotherapeutic Agents



Treatment of Acute Myeloid Leukemia Cells with Combinations of a FLT3 Inhibitor and Chemotherapeutic Agents



Blood 100(11): Abstract No 4603, November 16



Activating mutations of the receptor tyrosine kinase FLT3, consisting of internal tandem duplications (FLT3/ITD) and point mutations (FLT3/KM), are found in roughly one third of patients with acute myeloid leukemia (AML). These FLT3 mutations appear to confer a worse prognosis in a disease that has a cure rate of only 30-40% using conventional treatment approaches. There are now at least 4 small molecule FLT3 inhibitors in early clinical trials as monotherapy for AML. Given that monotherapy with any agent is generally non-curative in hematologic malignancies, we anticipate the need to incorporate FLT3 inhibitor therapy into conventional chemotherapy regimens. CEP-701, an indolocarbazole derivative that potently and selectively inhibits FLT3 autophosphorylation in vitro and in vivo, is cytotoxic to leukemia cells harboring FLT3 activating mutations. This cytotoxic response is associated with a cell cycle arrest at G1/S. Using model cell lines and leukemic blasts from AML patients harboring FLT3/ITD and FLT3/KM mutations, we studied the in vitro cytotoxic responses of leukemia cells to combinations of FLT3 inhibition and different chemotherapeutic agents. Cells were exposed to the CEP-701/chemotherapy combinations both in sequential and simultaneous fashion. Cytotoxicity was then assessed using an MTT proliferation assay. We found that the cytotoxic effects of CEP-701 on both model cell lines and primary AML blasts harboring FLT3 activating mutations were generally additive with the effects of chemotherapeutic agents commonly used to treat AML, such as cytarabine, etoposide, and daunorubicin. Vincristine, in contrast, appeared to antagonize CEP-701-mediated cytotoxicity, an effect that was likely due to interactions between the cell cycle-arresting properties of these different agents. These data suggest that concurrent use of FLT3 inhibitors and chemotherapy may be of clinical benefit.

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