Preclinical activity of FLT3 inhibitors

FLT3 inhibitors induce apoptosis in cell lines harboring activating mutations in FLT3. Each of the inhibitors listed above inhibits Ba/F3 cells transformed with FLT3-ITD, and this effect can be rescued by addition of IL-3. Several of these inhibitors also induce apoptotic cell death in human AML cell lines containing the FLT3-ITD mutation, and in some cases even in AML cell lines overexpressing wild-type FLT3. It is not clear why inhibitors appear to be generally more effective for cells expressing mutant receptors in some studies. These observations indicate that it may be appropriate to test FLT3 inhibitors in AML patients with overexpression of wild-type FLT3 as well as mutant FLT3.

Murine models have also been developed to test FLT3 inhibitors in preclinical analysis, including injection of FLT3-ITD transformed Ba/F3 cells into syngeneic recipient mice and murine bone marrow transplant models of FLT3-ITD-induced disease. In each of the model systems FLT3 inhibitors demonstrate statistically significantly prolonged survival, indicating that these agents are effective in vivo, and have appropriate pharmacokinetic properties for inhibition of FLT3 in vivo.

Based on these data, Phase I/II trials of FLT3 inhibitors have been initiated by several groups in AML. Most trials have fo-cussed on the treatment of relapsed AML patients who have a mutant FLT3. In some cases, FLT3 inhibitors such as PKC412 and CEP-701 have already been tested in Phase I trials for other disease indications, and are currently in Phase II trials for AML. Other agents, such as MLN518, are currently in Phase I trials. Although it is still early in the evaluation process, preliminary indications are that several of these agents have reasonable safety profiles and have activity in this clinical context. Extensive additional testing will be necessary to determine whether these agents will have a place in the armamentarium used to treat AML, whether they can be used in combination or sequentially with available therapies for AML, and whether they will be efficacious in both FLT3 mutant and wild-type AML.

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