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

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• The 2022 European LeukemiaNet (ELN22) guidelines introduced significant changes to acute myeloid leukemia (AML) genetic risk stratification.
• These changes include modifications to FLT3-internal tandem duplications (ITD) allelic ratio criteria and the inclusion of myelodysplasia-related (MR) genes and CEBPA mutations.

Purpose of the Study:

• To evaluate the applicability of the ELN22 risk stratification in a cohort of younger adult patients with AML uniformly treated with intensive therapy.
• To explore potential refinements to the ELN22 criteria to enhance risk prediction accuracy.

Main Methods:

• Retrospective analysis of 473 adult AML patients treated with intensive chemotherapy.
• Stratification using cytogenetics and next-generation sequencing according to ELN17 and ELN22 criteria.
• Assessment of leukemic stem cell (LSC) burden at diagnosis and measurable residual disease (MRD) post-induction using multiparametric flow cytometry.

Main Results:

• 16.3% of patients were reclassified under ELN22 compared to ELN17, mainly due to FLT3-ITD, CEBPA, and MR gene mutation status.
• ELN22 classified patients as: 56.7% favorable, 28.3% intermediate, and 15.0% adverse risk.
• Adverse-risk patients by ELN22 had significantly worse overall survival and relapse-free survival.
• High LSC burden, WT1 mutations, and DNMT3A-FLT3-ITD comutations in NPM1 defined a high-risk subgroup within the ELN22 intermediate-risk category.

Conclusions:

• The ELN22 genetic risk stratification demonstrates prognostic validity in intensively treated younger adult AML patients.
• Integrating WT1 mutation status, triple-mutated NPM1, and LSC burden could further improve risk stratification, especially for the heterogeneous intermediate-risk group.