A review of FLT3 inhibitors in acute myeloid leukemia

Abstract

FLT3 mutations are the most common genetic aberrations found in acute myeloid leukemia (AML) and associated with poor prognosis. Since the discovery of FLT3 mutations and their prognostic implications, multiple FLT3-targeted molecules have been evaluated. Midostaurin is approved in the U.S. and Europe for newly diagnosed FLT3 mutated AML in combination with standard induction and consolidation chemotherapy based on data from the RATIFY study. Gilteritinib is approved for relapsed or refractory FLT3 mutated AML as monotherapy based on the ADMIRAL study. Although significant progress has been made in the treatment of AML with FLT3-targeting, many challenges remain. Several drug resistance mechanisms have been identified, including clonal selection, stromal protection, FLT3-associated mutations, and off-target mutations. The benefit of FLT3 inhibitor maintenance therapy, either post-chemotherapy or post-transplant, remains controversial, although several studies are ongoing.

Keywords: Acute myeloid leukemia; Crenolanib; FLT3; Gilteritinib; Midostaurin; Quizartinib.

Figure 1.

the FLT3 tyrosine kinase comprimses of five domains: extracellular receptor tyrosine kinase (RTK), juxtamembrane domain, tyrosine kinase domain (TKD), kinase insertion domain, and a C-terminus intracellular domain. Internal tandum duplication (ITD) mutation is located in the juxtamembrane domain and causes a gain-of-function of the RTK. Deletions or mutations in the TKD results in a loss of auto-inhibition. The most common TKD mutation involving residue D835 is located in the activation loop of the TKD and may lead to lower binding affinity of type II inhibitors. Mutation involving the “gate-keeper” residue F691 is also located within TKD and may lead to resistance to both type I and II inhibitors. Both ITD and TKD mutations lead to constitutive activation of downstream proliferative signaling cascades. Type I inhibitors bind to both the active and inactive conformation of FLT3 at the ATP binding site, while type II inhibitors bind to a site adjacent to the ATP binding site in the inactive conformation only.