Targeting FLT-3 Mutations in Acute Myeloid Leukaemia: from Molecular Insights to Clinical Strategies.

Abstract

FMS-like tyrosine kinase 3 (FLT-3) mutations represent one of the most common genetic anomalies in acute myeloid leukaemia (AML), particularly in adults. The two most common types of mutations, internal tandem duplications (ITD) and tyrosine kinase domain (TKD) point mutations, facilitate uncontrolled cellular proliferation and unfavourable patient outcomes. These mutations are linked with a high relapse rate and shorter overall survival, highlighting the need for targeted therapies to be used. Recent advances in the discovery of new agents enabled incorporation of FLT-3 inhibitors into the frontline treatment regimen. First-generation inhibitors, such as midostaurin, provided the foundation for targeted therapy, while recently developed agents such as gilteritinib and quizartinib have shown more selectivity and demonstrated superior clinical efficiency and improved tolerability. This review discusses the significance of FLT-3 mutations, the evolution of targeted therapies, current treatment guidelines, and ongoing challenges such as resistance and high relapse rates. We also discuss the emerging combinations of therapies and novel agents currently in clinical trials that aim to overcome resistance and improve long-term outcomes for patients with FLT-3-mutated AML.