Abstract
Acute myeloid leukemia (AML) is driven by diverse genetic abnormalities. We investigated clinical and molecular differences between clinically defined secondary AML following antecedent MDS, molecularly defined secondary type AML (st-AML), molecularly defined MDS/AML (st-MDS/AML; 10%-19% blasts) and other newly diagnosed AML (de novo AML). We also examined the prognostic value of molecular measurable residual disease (MRD) in st-AML. This retrospective cohort study included 2684 intensively treated patients with AML. Diagnostic (n = 2684) and complete remission (CR; n = 436) samples were sequenced using a 54-gene panel targeting frequently mutated genes in AML. Odds ratios were calculated to show the association between mutated genes and clinically defined sAML or de novo AML. Clinical outcomes of interest were overall survival (OS) and cumulative incidence of relapse (CIR). Not only the established mutations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 but also ETV6 was significantly associated with clinically defined sAML, which defined the molecular signature for st-MDS/AML and st-AML. No OS differences were observed between st-MDS/AML and st-AML. Molecularly defined st-AML, now combined with st-MDS/AML, had worse OS compared with ELN2022 favorable- (5-year OS 39.9% vs 70.4%; P< .001) and intermediate-risk (5-year OS 39.9% vs 48.9%; P = .005) patients with AML. MRD based solely on secondary type mutations lacked predictive value, whereas MRD of non-DTA mutations in CR was associated with increased CIR in st-AML (subdistribution hazard ratio [SHR] 3.25; P< .001). Molecularly defined st-AML, including st-MDS/AML, defines a distinct AML category with a unique genetic, clinical and treatment response profile, in which next-generation sequencing (NGS)-based MRD holds markedly prognostic significance.