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.

Significance Statement We present a personalized blood test for acute myeloid leukemia that tracks patient-specific circulating tumor DNA, enabling sensitive, universal, noninvasive detection of residual disease. It outperforms standard-of-care marrow and cell-based methods for predicting relapse and survival, including after transplant, reveals clonal dynamics, and supports individualized disease monitoring and risk-adapted treatment.

The authors have declared no competing interest.

This work was funded by the National Institutes of Health (K08CA248940 to T.Y.Z.; K08CA241076 to D.M.K.) and the Stanford Cancer Institute (T.Y.Z., D.M.K.). R.G. has received support from the Stanford Division of Hematology (T32 HL120824, Dr. Steven Coutre Fellowship), the American Society of Hematology (Research Training Award for Fellows), the Stanford Cancer Institute Fellowship, and the Association for Northern California Oncologists.

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The study was approved by the Stanford Institutional Review Board (protocol #18329) in accordance with the Declaration of Helsinki, and all patients provided written informed consent, including consent for genomic sequencing analyses.

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Genotypic data generated in this study will be deposited in Figshare and made publicly available upon publication. Due to patient confidentiality and restrictions in the informed consent approved by the Stanford Institutional Review Board, raw sequencing data are considered protected health information and are not publicly available. Additional processed data and analysis outputs are available from the corresponding author upon reasonable request. For inquiries, please contact the corresponding author at tzhang8stanford.edu.