Validation and Refinement of the European LeukemiaNet 2022 Genetic Risk Stratification of AML

PURPOSE The 2022 European LeukemiaNet (ELN22) genetic risk stratification for AML makes critical changes, including removal of FLT3- internal tandem duplications (ITD) allelic ratio and inclusion of mutations in myelodysplasia-related (MR) genes and in-frame bZIP CEBPA mutations. We evaluated the applicability of ELN22 in a uniformly treated younger AML cohort and explored refinements to improve risk prediction. METHODS We retrospectively analyzed 473 adult patients with AML treated with intensive therapy. A combination of cytogenetics and next-generation sequencing was used to stratify patients into the ELN17 and ELN22 risk. In addition, we also evaluated leukemic stem cell (LSC) burden at diagnosis and postinduction measurable residual disease by multiparametric flow cytometry. RESULTS A total of 77 cases (16.3%) were reclassified from ELN17, primarily because of changes associated with FLT3 -ITD, CEBPA , and MR gene mutations. As per ELN22, 56.7% of patients were classified as favorable, 28.3% intermediate, and 15.0% adverse risk. ELN22 adverse-risk patients had significantly inferior overall survival and relapse-free survival compared with intermediate- and favorable-risk patients. High LSC burden at diagnosis, presence of WT1 mutations, and DNMT3A-FLT3 -ITD comutated NPM 1 dichotomized the ELN22 intermediate-risk group. CONCLUSION We conclude that ELN22 is prognostically valid in intensively treated younger patients with AML. Incorporation of WT1 mutation status, triple-mutated NPM1 , and LSC burden may improve risk stratification, particularly within the heterogeneous intermediate-risk category.