Additional gene mutations may refine the 2017 European LeukemiaNet classification in adult patients with de novo acute myeloid leukemia aged <60 years

Abstract

The European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) have become an important tool to assess patients' prognosis and guide treatment. We tested the prognostic impact of the 2017 ELN classification in a large cohort of 863 AML patients aged <60 years similarly treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology studies. Based on multivariable models within each ELN genetic-risk group, we identified additional gene mutations that may refine the 2017 ELN risk classification. BCOR- or SETBP1-mutated favorable-risk patients with non-core-binding factor AML and IDH-mutated adverse-risk patients had intermediate-risk outcomes. Outcomes of NPM1/WT1 co-mutated patients and those of ZRSR2-mutated patients resembled outcome of adverse-risk patients. Moreover, FLT3-ITD^high allelic ratio conferred adverse rather than intermediate-risk irrespective of the NPM1 mutation status, and DNMT3A mutations associated with very poor survival. Application of these refinements reclassified 9% of current favorable-risk patients and 53% of current intermediate-risk patients to the adverse-risk group, with similar poor survival as current adverse-risk patients. Furthermore, 4% of current favorable-risk patients and 9% of adverse-risk patients were reclassified to the intermediate-risk group.

Figure 1.

Oncoprint of genes most frequently mutated in younger acute myeloid leukemia patients categorized into genetic-risk groups according to the 2017 European LeukemiaNet (ELN) classification (green color, Favorable-risk; yellow, Intermediate-risk; red, Adverse-risk). Each column represents an individual patient. Black color indicates genes found to be mutated, light gray indicates wild-type status of the gene, and dark gray indicates missing values.

Figure 2.

Line graphs showing the impact of gene mutations found to be prognostically significant in multivariable models for a Non-core-binding factor acute myeloid leukemia (non-CBF-AML) patients in the 2017 European LeukemiaNet (ELN) Favorable-risk group, b CBF-AML Favorable-risk patients, c Intermediate-risk patients and d Adverse-risk patients on complete remission rates (left panel), 3-year disease-free survival rates (middle panel) and 3-year overall survival rates (right panel). The percentages are depicted for both wild-type (wt) and mutated (mut) patients, relative to the median rates according to the ELN genetic-risk classification (blue vertical bars). * mutated versus Intermediate-risk, P≤0.05 (adjusted for multiple comparisons); ** mutated versus Adverse-risk, P≤0.05 (adjusted for multiple comparisons).

Figure 3.

a Disease-free survival (DFS, upper graph) and overall survival (OS, lower graph) of NPM1-mutated (blue line) and NPM1-wild-type (red line) patients who were either FLT3-ITD-negative or harbored FLT3-ITD^low. b DFS (upper graph) and OS (lower graph) of NPM1-mutated (blue line) and NPM1-wild-type (red line) patients who harbored FLT3-ITD^high.

Figure 4.

Kaplan-Meier curves depicting the disease-free (left panel) and overall survival (right panel) of NPM1-mutated/WT1-mutated patients (red line), NPM1-mutated/WT1 wild-type patients (blue line), NPM1 wild-type/WT1-mutated patients (black line), and NPM1 wild-type/WT1 wild-type patients (green line).

Figure 5.

a Kaplan-Meier curves depicting the disease-free (DFS, left panel) and overall survival (OS, right panel) of younger (aged <60 years) adult patients with acute myeloid leukemia classified into proposed Favorable-risk (blue line), Intermediate-risk (black) and Adverse-risk (red) 2017 European LeukemiaNet (ELN) groups after the proposed refinement of the ELN classification. b DFS (left graph) and OS (right graph) of younger patients classified into the original ELN genetic-risk groups.