Validation of ELN 2024 genetic classification in patients with AML treated with HMA-based regimens: PETHEMA registry study.

The 2024 European LeukemiaNet (ELN 2024) genetic risk classification was proposed to assess prognosis in patients with acute myeloid leukemia (AML) receiving less-intensive hypomethylating agent (HMA)-based regimens. However, its applicability to real-world patients remains unclear. We retrospectively analyzed 669 adult patients with AML from the PETHEMA registry treated in routine practice with HMA monotherapy (n = 414) or HMA-venetoclax (VEN) (n = 255). Molecular profiling was performed centrally among the Programa Español de Tratamientos en Hematología (PETHEMA) laboratory network. Median age was 75 years, and 48% had secondary AML (s-AML). Across the full cohort, ELN 2024 stratified patients into prognostic groups across both regimens, but overall survival (OS) was consistently shorter with HMA monotherapy than with HMA-VEN (median OS, 6.5 vs 11.2 months). Favorable risk patients treated with HMA-VEN achieved a median OS exceeding 18.4 months, whereas adverse risk patients had an OS of 7.7 months. ELN 2024 provides meaningful stratification in nonintensive AML, especially with HMA-VEN. However, prognostic accuracy is limited in HMA monotherapy and s-AML, particularly those arising from a myeloid neoplasm (sM-AML). Incorporating cytogenetic risk and sM-AML as adverse risk improved discrimination (area under the curve at 24 months, 0.71 vs 0.76). Refinement incorporating clinical history, cytogenetics, emerging mutations, and treatment response is needed to improve risk prediction in real-world populations.