FLT3 Inhibitors in the Therapy of Acute Myeloid Leukemia

Richard M. Stone, MD
Acute myeloid leukemia (AML) is a diverse disease biologically; subtypes may be defined on the basis of patients’ blast-cell-specific mutational profile. FLT3 mutations, found in 30%–31% of AML, activate the transmembrane tyrosine kinase and cause it to be able to drive growth in a factor-independent fashion. There are two FLT3 mutation types: point mutation in the tyrosine kinase domain and the more common FLT3 ITD (internal tandem duplication) subtype associated with a higher relapse rate. Small molecule inhibitors of activated FLT3 have been developed. They differ in potency, specificity, and binding. Initial single-agent trials in patients with mutant FLT3 AML yield clear biological activity but few complete remissions. The remission rate with newer, more specific FLT3 inhibitors may be slightly higher, but hematopoietic recovery is rare. Nonetheless, there are two ongoing phase III trials comparing single agent FLT3 inhibitors (gilteritinib and quizartinib) with chemotherapy in advanced mutant FLT3 AML. A clear, bright spot was the result from the CALGB 106/RATIFY trial, which studied the addition of FLT3 inhibitor + multitargeted kinase inhibitor, midostaurin; it showed improved survival when added to chemotherapy in adults aged 18–60 years with FLT3 mutant AML.