Evaluation of ELN2022 Risk Stratification in NPM1 Mutated AML: A Study from the Fred Hutch and SWOG
Authors: Liu Vivian M. , Othus Megan , Ries Rhonda E. , Naru Jasmine , Pogosova-Agadjanyan Era L. , Appelbaum Frederick R. , Beppu Lan W. , Chauncey Thomas R. , Erba Harry P. , Godwin John E. , Fitzgibbon Matthew , Fang Min , Lee Stanley C. , Moseley Anna B. , Radich Jerald P. , Willman Cheryl L. , Wu Feinan , Meshinchi Soheil , Stirewalt Derek L. 
Published: December 2024

NPM1 mutations (NPM1+) are found in about 30% of adult AML. While NPM1+ are generally associated with favorable risk, prior studies have shown that NPM1+ older patients, defined as ≥ 65 years, have significantly worse outcomes. The updated European Leukemia Net 2022 (ELN22) now classifies NPM1+ AML patients with FLT3-ITD (ITD+) and MDS-associated mutations (MDSm+) as adverse-risk, while NPM1+/ITD-/MDSm+ patients remain favorable-risk unless they have an adverse-risk karyotype. A recent report (Chan et al., Blood Adv 2024) found MDSm+ conferred worse OS only in patients ≥ 60 years; however another report (Othman et al., Blood 2024) did not find MDSm+ were significantly associated with adverse outcomes in a larger cohort of NPM1+ patients.
To further assess this question, we examined the mutational landscape in a large cohort of pre-treatment, diagnostic specimens from 456 patients enrolled in SWOG clinical trials (SWOG-9031, SWOG-9333, S0106, and S0112) and 126 patients from the UW/FHCC Hematopoietic Repository (Total N=582). Patients were treated with curative intent as per standard practice or clinical trials. Out of the 582 patients, 191 were NPM1+ (33%), of which 148 patients had cytogenetic and long-term outcome data. Kaplan-Meier and cumulative incidence estimates were estimated. C-statistics and AUC for Cox, cause-specific and logistic regression models for overall survival (OS), event-free survival (EFS), time to relapse (TTR, calculated in n=106 who achieved complete remission [CR], death in remission analyzed as a competing risk) and CR were calculated for age, ELN17, and ELN22, as well as ELN17 and ELN22 adjusting for age.
ELN17 favorable-risk patients reclassified as adverse-risk (N=5 of 108) demonstrated significantly shorter EFS (HR=2.50, p=0.05) and CR rate (OR=0.20, p=0.024), although with similar OS (HR 1.30, p=0.66) and TTR (HR=1.20, p=0.86). ELN17 favorable-risk patients reclassified as ELN22 intermediate-risk (N=23 of 108) did not show a significant difference in OS (HR 1.47, p=0.20), EFS (HR 1.35, p=0.12), CR rate (OR 0.75, p=0.46), or TTR (HR=1.64, p=0.11) compared to ELN22 favorable-risk. For ELN17 intermediate-risk (N=40), 5 patients were reclassified as ELN22 adverse-risk (12.5%) and had significantly shorter EFS (HR 2.89, p=0.037) compared to ELN22 intermediate risk, although there was not a significant difference in CR rate (OR 0.31, p=0.23) or OS (HR 0.81, p=0.67). We next compared the prognostic significance of age relative to ELN risk classification. Age was associated with higher C-statistics (OS=0.65, TTR=0.57 and EFS=0.60) and AUC (CR=0.64) compared to both ELN17 (OS=0.56, TTR=0.54, EFS=0.54, CR=0.54) or ELN22 (OS=0.57, TTR=0.57, EFS=0.57, CR=0.58). The combination of age and ELN22 resulted in the highest C-statistics for OS, TTR, and EFS (OS=0.68, TTR=0.60, EFS=0.64).
To further assess the impact of MDSm on risk-stratification of NPM1+ AML, we performed multivariable analyses adjusting for FLT3-ITD, MDSm, and age in patients without adverse-risk disease. These analyses showed MDSm did not have a significant association with OS when controlling for age or FLT3-ITD. We also compared ELN22 favorable-risk patients with and without MDSm (MDSm+ N=18; MDSm- N=61). Compared with the MDSm-, there was a trend toward an inferior OS (HR 1.85, p=0.054) for MDSm+ patients but not EFS (HR 1.38, p=0.3) or TTR (HR 1.2, p=0.64). When stratified by age (&lt;65, N=53 vs. ≥65, N=26), MDSm+ in younger patients did not show a difference for OS (HR 0.96, p=0.96), EFS (HR 0.63, p=0.53) or TTR (HR 0.4, p=0.37). Older ELN22 favorable-risk patients (≥65) had similarly poor OS (MDSm- HR 3.33 and MDSm+ 3.27, respectively, p=0.001 for both) and EFS (MDSm- HR 3.11 and MDSm+ 2.39, p=0.001 and 0.01) compared to younger MDSm- patients.
In our study, the ELN22 guidelines incrementally improve risk stratification for EFS in NPM1+ patients. However, age remains the most prognostic factor, and patients ≥ 65 years have similar adverse clinical outcomes, whether classified as favorable risk by ELN17, ELN22, or incorporating MDSm. Moreover, MDSm do not confer a worse prognosis in NPM1+ patients when accounting for age or FLT3-ITD status. These findings differ from a recent report by Chan et al. and are in keeping with the report by Othman et al. Therefore, further understanding of the underlying biology of age and its effect on NPM1+ AML is needed to improve outcomes for older patients.