Personalized Circulating Tumor DNA Profiling Enables Superior and Universal Residual Disease Detection in Acute Myeloid Leukemia

Relapsed and/or refractory disease remains the leading cause of death in AML, highlighting the need for broadly applicable, high-sensitivity approaches to MRD detection. We developed AML-CAPP-Seq (Cancer Personalized Profiling by Deep Sequencing), a personalized hybrid-capture assay that tracks both canonical AML drivers and patient-specific variants identified by whole-exome sequencing. In 56 patients with longitudinal plasma and matched peripheral blood and bone marrow samples, AML-CAPP-Seq enabled universal MRD assessment and resolution of clonal dynamics using a median of 30.5 variants per patient. Plasma ctDNA outperformed cellular compartments for MRD detection and more strongly predicted relapse-free (HR 17.8, p<0.0001) and overall survival (HR 17.0, p<0.0001) than standard-of-care MRD methods. Among 29 allogeneic transplant recipients, peri-transplant ctDNA-MRD dynamics markedly improved relapse risk stratification (HR 36.0, p=0.0009). Together, these results establish personalized ctDNA profiling as a minimally invasive, highly sensitive, and generalizable platform for enhanced clinical MRD detection and clonal surveillance in AML.