Outcomes of Patients With Treated Secondary Acute Myeloid Leukemia: A High‐Risk Subtype That Warrants an Independent Prognostic Designation

ABSTRACT Patients who develop acute myeloid leukemia (AML) after having received treatment for myelodysplastic syndrome (MDS) or related conditions have particularly poor outcomes. This study analyzed adult patients with newly diagnosed AML who previously had MDS, chronic myelomonocytic leukemia (CMML), or MDS/myeloproliferative neoplasm (MPN) overlap syndrome, and who had received hypomethylating agents, chemotherapy, and/or allogeneic stem cell transplantation (HSCT) for these antecedent disorders. From January 2012 to August 2023, we included 673 patients with a median age of 70 years (range, 19–94); 536 (80%) had transformed from MDS, and the remainder from CMML or MDS‐MPN. Additionally, 149 patients (22%) had prior therapy for nonmyeloid malignancies. Among 497 evaluable patients, 289 (58%) had adverse‐risk (AR) cytogenetics, 34% had TP53 mutation/s, and 71% were classified as AR by the ELN 2017 criteria. Most patients (67%) received low‐intensity therapy (LIT) for AML, and 27% were treated with venetoclax. The overall response rate was 37%, and venetoclax improved the odds of response (OR = 2.5, 95% CI 1.6–3.7) in LIT–treated patients. At a median follow‐up of 43 months, the median relapse‐free survival (RFS) and overall survival (OS) were 4.6 and 4.8 months, respectively. Multivariate analysis showed that prior therapy for nonmyeloid disorders (HR = 1.30), ≥ 2 lines of therapy for antecedent myeloid disorders (HR = 1.23), and ELN AR risk (HR = 1.47) increased the hazards of death, while HSCT (HR = 0.50) was beneficial and validated on gradient‐boosted regression. TS‐AML is associated with poor outcomes irrespective of AML genomics and treatment, highlighting the need for its inclusion as an independent AR category for accurate prognostication and clinical trial reporting.