Validation of the revised 2022 European LeukemiaNet risk stratification in adult patients with acute myeloid leukemia

Abstract

In 2022, the European LeukemiaNet (ELN) risk stratification for patients with acute myeloid leukemia (AML) has been updated. We aimed to validate the prognostic value of the 2022 ELN classification (ELN22) by evaluating 1570 patients with newly diagnosed AML (median age, 56 years) treated with cytarabine-based intensive chemotherapy regimens. Compared with 2017 ELN classification (ELN17), which allocated 595 (38%), 413 (26%), and 562 patients (36%) to the favorable-, intermediate-, and adverse-risk categories, ELN22 classified 575 (37%), 410 (26%), and 585 patients (37%) as favorable, intermediate, and adverse risk, respectively. Risk group allocation was revised in 340 patients (22%). Most patients were reclassified into the ELN22 intermediate- or ELN22 adverse-risk group. The allocation of patients according to the ELN22 risk categories resulted in a significantly distinct event-free survival (EFS), relapse-free survival, and overall survival (OS). Compared with ELN17, reallocation according to the ELN22 recommendations resulted in a significantly improved prognostic discrimination for OS (3-year area under the curve, 0.71 vs 0.67). In patients with ELN22 favorable-risk AML, co-occurring myelodysplasia-related (MR) gene mutations did not significantly affect outcomes. Within the ELN22 adverse-risk group, we observed marked survival differences across mutational groups (5-year OS rate of 21% and 3% in patients with MR gene mutations and TP53 mutations, respectively). In patients harboring MR gene mutations, EZH2-, STAG2-, and ZRSR2-mutated patients showed an intermediate-like OS. In patients with secondary AML and those who underwent allogeneic hematopoietic cell transplantation, EFS and OS significantly differed between ELN22 risk groups, whereas the prognostic abilities of ELN17 and ELN22 classifications were similar. In conclusion, ELN22 improves prognostic discrimination in a large cohort of intensively treated patients with AML. Given the heterogeneous outcome in patients with MR gene alterations, ranging between those of intermediate and adverse risk patients, we suggest re-evaluation of risk allocation in these patients.

Graphical abstract

Figure 1.

Sankey plot showing reallocation of patients in ELN22 compared with ELN17. ADV, adverse; FAV, favorable; INT, intermediate.

Figure 2.

Outcome of patients (N = 1570) stratified according to the ELN22 recommendations. (A) RFS. (B) OS.

Figure 3.

Multivariate analyses of outcomes according to the ELN22 risk stratification. Forest plot showing hazard ratios from a Cox proportional hazards model for OS (A), EFS (B), and RFS (C). AIC, Akaike information criterion.

Figure 3.

Multivariate analyses of outcomes according to the ELN22 risk stratification. Forest plot showing hazard ratios from a Cox proportional hazards model for OS (A), EFS (B), and RFS (C). AIC, Akaike information criterion.

Figure 4.

Outcome of patients with ELN22 favorable-risk AML. (A) Outcome of patients with NPM1 mutations, patients with CBF leukemia and patients with CEBPA bZIP in-frame mutations within the ELN22 favorable risk category. (B) Outcome of patients with ELN22 favorable-risk AML with or without MR gene comutations (ie, mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2). (C) Outcome of patients with ELN22 favorable-risk AML with or without MR gene comutations, stratified by age (≤/>60 years). (D) Outcome of patients with ELN22 favorable-risk NPM1-mutated AML with or without MR gene mutations. mut, mutated.

Figure 5.

Outcome of patients with ELN22 adverse risk AML. (A) Outcome of patients with MR gene mutations (ie, mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2) compared with patients with TP53 mutations within the ELN22 adverse-risk group. (B) Outcome of patients with ASXL1 and/or RUNX1 mutations and patients with MR gene mutations other than ASXL1 and/or RUNX1 within the ELN22 adverse-risk category. (C) Outcome of patients with MR gene mutations, stratified by MR gene mutation VAF. (D) Outcome of patients with evidence of mutations in EZH2, STAG2, U2AF1, and ZRSR2. w/o, without.

Figure 6.

Performance of the revised ELN22 classification. (A) Comparison of outcome in patients stratified by either ELN17 or ELN22. (B) Comparison of time-dependent ROC curves for OS between ELN17 and ELN22.

Figure 7.

Risk stratification and outcome in patients who underwent alloHCT (n = 504). (A) Comparison of outcome in patients stratified according to either ELN17 or ELN22. (B) Outcome of patients with MR gene mutations compared with patients with TP53 mutations within the ELN22 adverse-risk category. (C) Comparison of prognostic discrimination as assessed by time-dependent ROC curves for OS between ELN17 and ELN22.