Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia

Abstract

The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18-86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients (n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel's C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53-mutated patients with complex karyotypes as "very adverse". In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017.

Fig. 1. Patient distribution according to ELN-2017 and 2022.

A ELN-2022 categories stratified by age group (<60 y vs. ≥60 y). B ELN 2022 classification stratified by sex. C ELN-2022 classification compared to ELN-2017.

Fig. 2. Outcomes of patients according to the ELN-2022 risk groups.

A Relapse-free survival and B overall survival in the entire cohort of 1118 patients. (age range: 18–86).

Fig. 3. Multivariate analyses of outcomes according to the ELN-2022 genetic risk groups and further pretreatment prognostic variables.

A Forest plot showing odds ratios from a logistic regression model for achievement of complete remission. B Forest plot showing hazard ratios from a Cox proportional hazards model for relapse-free survival. C Forest plot showing hazard ratios from a Cox proportional hazards model for overall survival. Interaction P values refer to an interaction between the ELN-2022 risk groups and the respective variable.

Fig. 4. Outcomes of patients according to the ELN-2017 and ELN-2022 risk groups.

A relapse-free survival, and B overall survival in the entire cohort of 1118 patients (age range: 18–86). Dashed lines represent ELN-2017 risk groups, solid lines represent ELN-2022 risk groups.

Fig. 5. Outcomes of patients newly classified as adverse due to presence of a myelodysplasia-related mutation compared to ELN-2022 risk groups.

A Relapse-free survival and B overall survival in the entire cohort of 1118 patients (age range: 18–86). The adverse risk group is divided into patients newly classified as adverse due to presence of a myelodysplasia-related mutation (gold) and all other adverse risk patients (orange).

Fig. 6. Outcomes of patients according to the proposed refinement of the ELN-2022 classification.

A Relapse-free survival and B overall survival in the entire cohort of 1 118 patients.