Ruwan Gunaratne

Relapsed and/or refractory disease remains the leading cause of death in acute myeloid leukemia (AML), highlighting the need for broadly applicable, high-sensitivity approaches to measurable residual disease (MRD) detection. We developed AML-Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq), 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 circulating tumor DNA (ctDNA) outperformed cellular compartments for MRD detection and more strongly predicted relapse-free survival [hazard ratio (HR), 17.8; P < 0.0001] and overall survival (HR, 17; P < 0.0001) than standard-of-care (SOC) MRD methods. Among 29 allogeneic transplant recipients, peritransplant ctDNA-MRD dynamics markedly improved relapse risk stratification (HR, 36; 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:We present a personalized blood test for AML that tracks patient-specific ctDNA, enabling sensitive, universal, and noninvasive detection of residual disease. It outperforms SOC 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.

This workbook contains the genomic coordinates of all hybrid capture probes used in the AML-CAPP-Seq study.

This workbook contains the processed whole-exome sequencing (WES) variant data used for personalized panel design in the AML-CAPP-Seq study.

This workbook contains the longitudinal clinical annotations, sample metadata, sequencing quality metrics, and MRD assessments for all samples included in the AML-CAPP-Seq study.

This workbook contains the processed variant lists used for personalized measurable residual disease (MRD) tracking in the AML-CAPP-Seq study.

Flow cytometric purification of AML blasts and matched T cells for whole-exome sequencing and identification of patient-specific somatic variants.

Longitudinal comparison of personalized ctDNA-MRD and standard-of-care molecular MRD assessments in individual patients.

Performance of personalized ctDNA-MRD for relapse-free and overall survival in patients with adverse-risk AML.

Performance of personalized ctDNA-MRD stratified according to availability of approved molecular MRD markers.

Comparison of prognostic performance between ctDNA-MRD and cellular compartment–based MRD assessment.