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Simple Summary: Measurable residual disease (MRD) monitoring is crucial in managing AML to predict the risk of relapse. A better understanding of which MRD technique and molecular target will have an effective clinical impact on AML is still required. Locked nucleic acid quantitative Real-Time PCR assay (LNA-qPCR) is sensitive and specific for quantifying oncogenetic single-nucleotide variation. We assessed the role of LNA-qPCR in the monitoring of IDH1/2 mutations MRD in eighty-eight AML patients from multiple centers. We found that IDH1/2 LNA-qPCR MRD correlates well with NPM1 qPCR MRD, predicts relapse-free survival and cumulative incidence of relapse, and is a potential MRD technique for IDH1/2-mutated AML patients with reduced IDH1/2 mutant levels after complete remission. Locked nucleic acid quantitative Real-Time PCR (LNA-qPCR) for IDH1/2 mutations in AML measurable residual disease (MRD) detection is rarely reported. LNA-qPCR was applied to quantify IDH1/2 mutants MRD kinetics in bone marrow from 88 IDH1/2-mutated AML patients, and correlated with NPM1-MRD, clinical characteristics, and outcomes. The median normalized copy number (NCN) of IDH1/2 mutants decreased significantly from 53,228 (range 87–980,686)/ALB × 106 at diagnosis to 773 (range 1.5–103,600)/ALB × 106 at first complete remission (CR). IDH1/2 LNA-qPCR MRD was concordant with remission status or NPM1-MRD in 79.5% (70/88) of patients. Younger patients and patients with FLT3 mutations had higher concordance. The Spearman correlation coefficient (rs) and concordance rate between the log reduction of IDH1/2 LNA-qPCR and NPM1-MRD were 0.68 and 81% (K = 0.63, 95% CI 0.50–0.74), respectively. IDH1/2-MRD > 2 log reduction at first CR predicted significantly better relapse-free survival (3-year RFS rates 52.9% vs. 31.9%, p = 0.007) and cumulative incidence of relapse (3-year CIR rates 44.5% vs. 64.5%, p = 0.012) compared to IDH1/2-MRD ≤ 2 log reduction. IDH1/2-MRD > 2 log reduction during consolidation is also associated with a significantly lower CIR rate than IDH1/2-MRD ≤ 2 log reduction (3-year CIR rates 42.3% vs. 68.8%, p = 0.019). LNA-qPCR for IDH1/2 mutation is a potential MRD technique to predict relapse in IDH1/2-mutated AML patients, especially for those with IDH1/2 MRD > 2 log reduction at first CR or a concurrent FLT3 mutation. [ABSTRACT FROM AUTHOR]