Clinical and Molecular Characteristics of NPM1 MT De Novo AML ( NPM1 MT dnAML) Differ from NPM1 MT therapy-associated AML ( NPM1 MT tAML)

Background: NPM1-mutated AML accounts for 30% of all adult AML cases and frequently carries a favorable prognostic impact when enriched by a normal karyotype and the absence of FLT3-ITD mutations. Although the clinical and molecular characteristics of NPM1-mutated de novo AML ( NPM1MT dnAML) are well known, the impact of NPM1MT within the context of therapy-associated AML ( NPM1MT tAML) remains controversial. Recent work by Othman et al. suggests NPM1MT tAML may represent a biologically de novo leukemia, displaying similar clinical, genomic, and transcriptional profile to NPM1MT dnAML and should be treated as a single disease entity. We sought to externally validate this by analyzing the clinical outcomes, mutational landscape, and molecular features of a large cohort of patients with NPM1-mutated AML. Methods: We conducted a large retrospective analysis of adult AML patients with NPM1MT by screening public databases, cBioPortal (Cerami et al., 2012) and AACR GENIE (v 13.1), and expanded with a published metanalytic cohort of various sub-studies from Cleveland Clinic Foundation from 2012-2021 (Awada et al., Blood 2021 and Kewan et al., Nature Communications, 2023). Baseline clinical and molecular characteristics were noted. We analyzed the molecular data in the context of overall survival (OS), clinical parameters, coexisting mutations, karyotype, AML subtypes, ELN-favorability, and gene expression data. Results: We screened a total of 15,742 adult AML patients, and 4,135 eligible patients were separated into 5 cohorts: 2,156 patients (52%) with NPM1MT dnAML, 1233 patients (30%) with NPM1WT sAML, 289 patients (7%) with NPM1MT sAML, 397 patients (10%) with NPM1WT tAML, and 60 patients (1.5%) with NPM1MT tAML. NPM1MT dnAML and NPM1MT sAML patients had a median age of 60 and 72 yrs. [18-91 vs 27-91 yrs., p =