Recent Advances in Therapeutic Strategies for FLT3-Mutated Acute Myeloid Leukemia

FLT3 mutations occur in approximately 25% to 30% of newly diagnosed cases of acute myeloid leukemia (AML) and are typically associated with adverse prognoses characterized by a high risk of relapse. In recent years, the AML therapeutic landscape has been notably reshaped by the introduction of FLT3 inhibitors, including midostaurin, quizartinib, and gilteritinib. The European LeukemiaNet 2022 guidelines classify all FLT3-ITD-positive AML as intermediate risk, regardless of allelic ratios, thereby highlighting the importance of co-mutations and measurable residual disease (MRD). In fit patients (intensive chemotherapy eligible), the current standard therapy incorporates FLT3 inhibitor-based chemotherapy, allogeneic hematopoietic stem cell transplantation during the initial complete remission, and post-transplant maintenance. Long-term follow-up from the RATIFY trial confirmed durable survival benefits using midostaurin (10-year overall survival, 43.7%), whereas the QuANTUM-first study has provided evidence for the marked efficacy of quizartinib in patients with NPM1 and DNMT3A co-mutations. For unfit patients, although azacitidine plus venetoclax remains the standard therapy, early-phase studies evaluating FLT3 inhibitor-containing triplet regimens have revealed complete remission rates exceeding 80%. In addition, for cases of relapsed or refractory FLT3-mutated AML, gilteritinib has been established to provide a median overall survival of 9.3 months and serves as an effective bridge to transplantation, whereas venetoclax combinations can contribute to enhancing the length of remission. Recent advances in characterizing resistance mechanisms, including secondary TKD mutations and RAS/MAPK pathway activation, are contributing to the developments of next-generation covalent and multi-kinase FLT3 inhibitors, and it is anticipated that MRD-guided therapeutic adaptation and genomics-driven precision medicine will facilitate further refinement of future standards of the care.