High-Sensitivity Genomic Minimal Residual Disease Detection Reveals Multiclonal Hematopoiesis and Is Associated with Survival in Adult AML

• Published in: Blood 2015-12, Vol.126 (23), p.225-225
• Main Authors: Parkin, Brian, Londoño Joshi, Angelina, Kang, Qing, Rhim, Andrew D., Malek, Sami N.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.225.225

▪ Introduction: Minimal residual disease (MRD) measurement is emerging as a prognostic marker of relapse-free survival (RFS) and overall survival (OS) in acute myelogenous leukemia (AML). In order to improve the technical feasibility of MRD detection and to enable broad, ultra-sensitive mutational profiling of residual AML, we optimized a droplet-based digital PCR (ddPCR) approach capable of detecting mutated alleles in most recurrently mutated genes in AML in as few as 5 in 100,000 cells. We subsequently analyzed bone marrow specimens of AML patients in early complete remission (CR) and correlated MRD levels with outcome. Methods: Fifty-two consecutively enrolled patients with AML at a single center who had paired diagnostic and CR bone marrow specimens were studied. First, genomic DNA from FACS-purified leukemic cells of diagnostic samples underwent Sanger resequencing of NPM1, IDH1, IDH2, NRAS, KRAS, FLT3, TP53, DNMT3A, TET2, ASXL1, BCORL1, CEBPA, and RUNX1. For cases with 1% VAF in 85% (11 of 13) (range 1.6-34.6%) and 50% (5 of 10) (range 2.3-15.1%) of cases, respectively, including in patients with subsequent durable remissions (>1000 days). Conversely, 94% (15 of 16) and 100% (5 of 5) of NPM1 and NRAS mutations, respectively, were reduced to