FLT3 Inhibitors in Acute Myeloid Leukemia

Khaled el-Shami; Richard M. Stone; B. Douglas Smith


Expert Rev Hematol. 2008;1(2):153-160. 

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Expert Commentary

For almost 30 years, the standard treatment of AML has largely remained unchanged, as have the clinical outcomes. Traditional cytotoxic chemotherapy is effective in causing significant cytoreduction in a large number of patients but cures a minority —generally those with good-risk cytogenetics. Patients with poor-risk features defined by advanced age, adverse cytogenetics, prior myelodysplasia or chemotherapy for another cancer, and molecular features such as FLT3-ITD, are essentially never cured with conventional chemotherapy. Efforts to target one of the noted poor-risk features has been fairly limited prior to the identification of FLT3-ITD. Given the frequency of mutated FLT3 in AML, its location on the cell surface and its clear impact on the biology and natural history of the disease, this mutation is an attractive target. The identification of FLT3 mutations across a range of the cytogenetic subgroups of AML has opened up the possibility of a targeted therapeutic approach with broad applicability. Four agents are currently in clinical trials, all of which displayed both sufficient activity against AML and acceptable toxicity profiles to support continued studies to optimize their use and incorporation into therapeutic regimens for AML. While the agents are generally well tolerated compared with traditional cytotoxic agents, unfortunately, like many tyrosine kinase inhibitors, their single-agent clinical activity has been modest. Preclinical studies point to a tantalizing synergy between effective inhibition, FLT3-mediated signaling and standard cytotoxic chemotherapy. There is also early but strong evidence that the sequence of administration of FLT3 inhibitors with chemotherapy is important to achieve the maximum synergy possible, with concurrent administration being the most appropriate from the point of view of pharmacokinetic interactions between small-molecule kinase inhibitors and cytotoxics. While the absorption and bioavailability of orally administered drugs in the face of chemotherapy-inducedmucositis, nausea and vomiting will be challenging, previous experience with the concurrent combination of 'biologics' and 'cytotoxics' provides proof that it can be done and that synergy, or at least addition, can be maintained.


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