MDS/AML and AML with myelodysplasia-related gene mutations: clinical and molecular similarities.

Acute myeloid leukemia (AML) is driven by diverse genetic abnormalities. We investigated clinical and molecular differences between clinically-defined secondary AML following antecedent MDS (sAML), 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) detection in st-AML. This retrospective cohort study included 2,684 intensively treated AML patients. Bone marrow and peripheral blood samples collected at diagnosis (n=2,684) and complete remission (CR) (n=436) were sequenced using a 54-gene panel targeting the most 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 cases, had considerably worse OS compared to ELN2022 favorable (5-yr OS 39.9%vs.70.4%;p<0.001) and intermediate risk (5-yr OS 39.9%vs.48.9;p=0.005) AML patients. MRD of secondary type mutations alone lacks predictive value, yet MRD of non-DTA mutations in CR is associated with increased CIR in st-AML (SHR MRDpos vs. MRDneg 3.25; p<0.001). Molecularly-defined st-AML, including st-MDS/AML, defines a distinct AML category with a unique genetic, clinical and treatment response profile, in which NGS-based MRD holds markedly prognostic significance.