Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia

Abstract

Risk stratification in acute myeloid leukemia (AML) remains principle for survival prognostication and treatment selection. The 2022 European LeukemiaNet (ELN) recommendations were recently published, with notable updates to risk group assignment. The complexity of risk stratification and comparative outcomes between the 2022 and 2017 ELN guidelines remains unknown. This comparative analysis evaluated outcomes between the 2017 and 2022 ELN criteria in patients enrolled within the multi-center Beat AML cohort. Five-hundred thirteen patients were included. Most patients had one (36% [N=183]) or two (31% [N=159]) ELN risk-defining abnormalities. In patients with two or more ELN-risk defining mutations (58% [N=297]), 44% (N=132) had mutations spanning multiple ELN risk categories. Compared to ELN 2017 criteria, the updated ELN 2022 guidelines changed assigned risk group in 15% (N=75) of patients, including 10% (N=16/160), 26% (N=29/112), and 6% (N=13/224) of ELN 2017 favorable, intermediate, and adverse-risk patients. Median OS across ELN 2022 favorable, intermediate, and adverse-risk groups was not reached (estimated 5-year OS: 53% [standard error: 0.06%]), 16.8 (95% CI: 11-48) and 9.7 (95% CI: 8.3-10.8) months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate or adverse-risk AML treated with IC (HR: 1.58 [95% CI: 1.12-2.25], p-value: 0.01) compared to ELN 2017 guidelines (HR 1.27 [95% CI: 0.88-1.85], p-value: 0.20). The updated ELN 2022 guidelines better stratify survival, namely between patients with intermediate or adverse-risk AML treated with IC. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification.

Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia: an appraisal of the new WHO and IC classifications and ELN risk stratification

“…Among 42 patients, mutations of MR/RUNX1 genes were present in 14 de novo AML and 28 MR-Hx AML, resulting in a positive predictive value of only 66% for MR-Hx. This is similar to our entire cohort (positive predictive value 51/80, 64%, specificity 74%) regardless of NGS panels used (Figure 2) as well as other studies 28,30 . If RUNX1 mutations are excluded, the positive predictive value and specificity of MR gene mutations for MR-Hx is 70% and 75%, respectively.…”

“…The discrepancy may be due to different cohorts but is more likely related to misclassification. The suboptimal specificity of MR gene mutations has also been observed in a few recent studies 28,30 . This questions the approach of classifying these MR genes into one entity largely aiming to replace MR-Hx or AML-MRC WHO2016 .…”

“…Several studies have demonstrated inferior outcomes in AML with MR gene mutations, but its independent prognostic value in de novo AML has been controversial [21][22][23]44 . Recent studies have shown that MR gene mutations in a favorable-risk group (mostly de novo) do not affect outcome 30,45 . Our findings indicate that the outcome of AML with MR gene mutations in ELN2017 intermediate/adverse risk group is stratified by ontogeny and de novo patients had an OS not inferior to intermediate risk group.…”

“…We next focused on MR/RUNX1 mutated AML. Although a previous study had suggested that MR gene mutations are highly specific to MR-Hx (with 95% specificity) 17 , the specificity of these gene mutations to MR-Hx remains controversial 28,30 . We decided to address these issues with our well-annotated cohort.…”

Assessment of 2022 European LeukemiaNet risk classification system in real‐world cohort from China

“…However, the ELN‐2022 risk classification systems remain controversial. Using the Beat AML database cohort, Lachowiez et al 13 show that the ELN‐2022 guidelines classify patients treated with idarubicin plus cytarabine better, whereas Cancer and Leukemia Group B (CALGB) frontline treatment data show no prognostic advantage for patients with de novo AML compared to ELN‐2017 14 . Both the German AML Cooperative Group trial data and Spanish real‐world data show that more AML patients are classified as adverse‐risk due to MR‐gene mutation, resulting in inappropriately better survival in the adverse‐risk group of ELN‐2022 compared to ELN‐2017 15,16 .…”