FLT3-ITD Measurable Residual Disease in Acute Myeloid Leukemia: Implications for FLT3 Inhibitor-Based Therapies

Fms related receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations occur in approximately 20–25% of patients with acute myeloid leukemia (AML) and are associated with increased relapse risk and inferior survival outcomes. Although measurable residual disease (MRD) has become a key prognostic tool for guiding post-remission treatment decisions, FLT3-ITD was historically considered a suboptimal MRD marker because of its subclonal nature, structural heterogeneity and dynamic behavior during disease evolution. Despite its strong diagnostic and prognostic relevance, FLT3-ITD has not yet been fully integrated into routine MRD monitoring also due to methodological limitations, and lack of standardized workflows. Recent evidence supports the use of ultra-high sensitivity (UHS) next-generation sequencing (NGS) approaches to detect FLT3-ITD MRD with improved precision, enabling reliable longitudinal tracking of patient-specific clones at very low variant allele frequencies (VAF), and potentially informing clinical decision-making. Indeed, although MRD evaluation is complicated by clonal heterogeneity and molecular instability, advances in high-sensitivity detection techniques have allowed more accurate monitoring of residual leukemic burden. The present review summarizes the biological underpinnings of FLT3-ITD mutated (FLT3-ITDmut) AML, discusses the methodological challenges of MRD detection, and critically evaluates the evolving role of MRD in refining relapse prediction, supporting post-remission therapy tailoring, and contributing to a harmonized framework for FLT3-ITDmut AML management.