Personalized Circulating Tumor DNA Profiling Enables Superior and Universal Residual Disease Detection in Acute Myeloid Leukemia
Ruwan Gunaratne, Crystal M. Zhou, Sanjeeth Rajaram, Jesse W. Tai, Kailee L. Tanaka, Charu Tiwari, Emily Y. Yang, Sky Kim, Grace Gao, Raymond Yin, Mia Carleton, Matthew S. Alkaitis, Matthew Schwede, Brian J. Sworder, Gabriel N. Mannis, Michael S. Khodadoust, Ravindra Majeti, David M. Kurtz, Tian Yi. ZhangAbstract
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.