Measurable Residual Disease in IDH ‐Mutated AML : Identifying a Clinically Relevant Threshold for IDH Mutation Monitoring

BACKGROUND: Isocitrate dehydrogenase (IDH) mutations are recurrent in acute myeloid leukemia (AML) and represent promising targets for measurable residual disease (MRD) monitoring. However, clinically validated strategies for IDH-based MRD assessment remain lacking. METHODS: We evaluated the analytical performance and clinical utility of droplet digital PCR (ddPCR) for IDH mutation monitoring in a single-center cohort of patients with IDH-mutated AML treated with curative intent. Healthy controls were included to characterize low-level background signals and identify a clinical threshold. RESULTS: ddPCR showed robust analytical performance, with a limit of detection of 0.01% variant allele frequency (VAF) and strong concordance with NGS. Low-level IDH mutation signals were frequently detected in healthy individuals and in patients in remission. We identified 0.2% VAF as a candidate threshold for clinically relevant IDH MRD. Using this cutoff, post-treatment detectable IDH MRD was associated with a higher 2-year cumulative incidence of relapse (63.6% vs. 20%; p = 0.019) and inferior overall survival (70.6% vs. 92.9%; p = 0.04). Among patients negative by multiparameter flow cytometry, ddPCR identified residual IDH-mutated clones in 56% of cases, who showed higher relapse rates than double-negative patients (50% vs. 0%; p = 0.031). CONCLUSIONS: A 0.2% VAF threshold was associated with clinically distinct outcomes and may provide a useful framework for IDH-based MRD assessment in AML.