Clinico‐Genomic Interrogation of Secondary‐Type Acute Myeloid Leukemia: Response and Outcomes to Contemporary Therapies

ABSTRACT Ontogeny of acute myeloid leukemia (AML) provides prognostic information, however closer interrogation with respect to AML characteristics, genomics, and various treatments are warranted. We defined untreated clinical secondary (CS) AML as AML with a diagnosis of antecedent myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MDS‐MPN) without exposure to hypomethylating agents or chemotherapy; genomic secondary (GS) AML included patients with myelodysplasia related cytogenetics (MRC) or myelodysplasia related mutations (MRM) without a known antecedent myeloid neoplasm or prior chemo‐radiotherapy for non‐myeloid neoplasms. Among newly diagnosed AML patients classified as untreated CS‐AML ( n = 133) or GS‐AML ( n = 389), median relapse‐free survival (RFS) (11.9 vs. 12.4 months, p = 0.36) and overall survival (OS) (11.6 vs. 14.4 months, p = 0.75) were similar. No difference in RFS and OS between these groups treated with low‐intensity therapy (LIT) and venetoclax regimens was seen, but both were inferior to de novo (DN) AML without secondary‐type genomics (pure DN‐AML). GS‐AML defined by the presence of only MRM had superior OS compared with MRM ± MRC with LIT+ venetoclax therapy (RFS 19.5 vs. 6.8 months [ p < 0.01] and OS 29.6 vs. 8.4 [ p < 0.01]) and had similar RFS (29.8 months, p = 0.48) and OS (32.0 months, p = 0.48) to pure DN‐AML treated with LIT+ venetoclax. On multivariate analysis in patients treated with LIT+ venetoclax, untreated CS‐AML (vs. GS‐AML), adverse cytogenetics and ELN 2024 adverse‐risk disease (mutated TP53 ) were associated with higher hazard of death. Adverse cytogenetics was the strongest prognostic variable predicting survival. Mutation‐driven genomic ontogeny of newly diagnosed AML with MRM appears less prognostic than cytogenetic‐driven ontogeny with venetoclax‐based therapy.