title: The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond.
abstract: Acute myeloid leukemia remains associated with poor outcomes despite advances in our understanding of the complicated molecular events driving leukemogenesis and malignant progression. Those patients harboring mutations in the FLT3 receptor tyrosine kinase have a particularly poor prognosis; however, significant excitement has been generated by the emergence of a variety of targeted inhibitors capable of suppressing FLT3 signaling in vivo. Here we will review results from preclinical studies and early clinical trials evaluating both first- and second-generation FLT3 inhibitors. Early FLT3 inhibitors (including sunitinib, midostaurin, and lestaurtinib) demonstrated significant promise in preclinical models of FLT3 mutant AML. Unfortunately, many of these compounds failed to achieve robust and sustained FLT3 inhibition in early clinical trials, at best resulting in only transient decreases in peripheral blast counts. These results have prompted the development of second-generation FLT3 inhibitors, epitomized by the novel agent quizartinib. These second-generation inhibitors have demonstrated enhanced FLT3 specificity and have been generally well tolerated in early clinical trials. Several FLT3 inhibitors have reached phase III clinical trials, and a variety of phase I/II trials exploring a role for these novel compounds in conjunction with conventional chemotherapy or hematopoietic stem cell transplantation are ongoing. Finally, molecular insights provided by FLT3 inhibitors have shed light upon the variety of mechanisms underlying the acquisition of resistance and have provided a rationale supporting the use of combinatorial regimens with other emerging targeted therapies.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Seth A
authors.initials: SA
authors.lastname: Wander
authors.affiliation: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Levis
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Zero Emerson Place, Suite 118, Boston, MA 02114, USA.
authors.forename: Amir T
authors.initials: AT
authors.lastname: Fathi
keywords: FLT3; acute myeloid leukemia; quizartinib; targeted therapies