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. In addition, FLT3-ITD has not yet been fully integrated into routine MRD monitoring due to methodological limitations and a lack of standardized workflows. The latest European LeukemiaNet (ELN)-DAVID 2025 recommendations stressed the use of ultra-high sensitivity (UHS) next-generation sequencing (NGS) technologies to detect FLT3-ITD MRD with improved precision, enabling reliable longitudinal tracking of patient-specific clones at very low variant allele frequencies (VAF). Indeed, despite prospective evidence supporting this approach remaining limited, FLT3-ITD-based MRD monitoring is emerging as a clinically relevant prognostic indicator, contributing to the identification of patients at increased risk of relapse and refining risk stratification, while also informing therapeutic decision-making, particularly in the peri-transplant setting. The present review summarizes the biological underpinnings of FLT3-ITD mutated (FLT3-ITD^mut) 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-ITD^mut AML management.