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

Abstract

Risk stratification in acute myeloid leukemia (AML) remains principle in 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 multicenter Beat AML cohort. Five hundred thirteen patients were included. Most patients had 1 or 2 ELN risk-defining abnormalities. In patients with ≥2 ELN risk-defining mutations, 44% (n = 132) had mutations spanning multiple ELN risk categories. Compared with ELN 2017 criteria, the updated ELN 2022 guidelines changed the assigned risk group in 15% of patients, including 10%, 26%, and 6% of patients categorized as being at ELN 2017 favorable-, intermediate-, and adverse-risk, respectively. The median overall survival across ELN 2022 favorable-, intermediate-, and adverse-risk groups was not reached, 16.8, and 9.7 months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy compared with ELN 2017 guidelines. The updated ELN 2022 guidelines better stratify survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification.

Graphical abstract

Figure 1.

Distribution of ELN risk defining mutations within the Beat AML Cohort. (A) Correlation plot demonstrating relationship of ELN risk-defining mutations. NPM1 frequently associated with FLT3 ITD mutations, both of which were associated with diploid karyotypes. Conversely, adverse-risk cytogenetics and TP53 mutations tended to correlate with each other. Size of circles indicates the frequency (larger circles indicate increasing and smaller circles indicate decreasing frequency) of co-occurrence. Only correlations with P < .001 are displayed. (B) Percentage of patients with no identifiable, 1 identifiable, or multiple identifiable ELN risk–defining mutations. Colored bars indicate percentage of patients with multiple ELN risk–defining mutations spanning different (ie, favorable and adverse) risk groups. (C) Number of ELN risk–defining mutations identified per patient across ELN 2022 risk groups. Red circles indicate cases that were reclassified based on the updated ELN 2022 guidelines. (D-E) Bar plot demonstrating the percentage of patients reclassified according to ELN 2022 risk group (D) and overall (E). Patients listed as ambiguous ELN include 17 patients with co-occurring NPM1 and FLT3 ITD mutations in whom the FLT3 ITD allelic ratio was unknown.

Figure 2.

Proposed workflow using hierarchal classification of ELN risk–defining abnormalities. Notably, instances in which a favorable-risk and adverse-risk mutation co-occurred (ie, core binding factor AML with mutated TP53) without clear risk group assignment were infrequent.

Figure 3.

OS of patients based on 2017 and 2022 ELN classifications for all treatments and IC treatment subgroup. (A-B) OS based on ELN 2017 (A) and ELN 2022 (B) criteria in all treated patients. Although both criteria appropriately identified patients with favorable-risk AML, the 2022 criteria more effectively stratified survival between patients with intermediate and adverse-risk AML. (C-D) Similar findings were observed when limited to the population of patients treated with intensive chemotherapy, in which the ELN guidelines are most well validated.

Figure 4.

OS of patients with co-occurring mutations spanning multiple risk groups compared with patients with mutation(s) in a single ELN risk group. (A-D) Patients with mutations in ELN favorable and adverse-risk categories (B) had survival similar to that of patients classified as ELN favorable-risk, whereas patients with other combinations of mutations, such as ELN favorable– and intermediate–risk (predominantly comprised of patients with co-occurring NPM1 and FLT3 ITD mutations) (A); favorable-, intermediate-, and adverse-risk (C); and intermediate- and adverse-risk (D) had inferior outcomes.