What type of study is this?

This is a Cohort Study study (also classified as: Pre-Registered Trial).

What question did this study set out to answer?

This research investigates the prognostic role of NPM1 in the presence of RAS mutations among older patients with AML.

December 8, 2025Open Access

RAS mutations negate the favorable impact of NPM1 in older patients with newly diagnosed Acute Myeloid Leukemia treated with ven/HMA

YHYing HuangFujian Medical University RWRina Li WelkieThe Ohio State University RSRonan SwordsOregon Health & Science University

Key Points

This research investigates the prognostic role of NPM1 in the presence of RAS mutations among older patients with AML.
Retrospective study of older patients (≥60 years) with newly diagnosed AML treated with VEN+HMA.
Data collected from two cohorts: Beat AML trial and Flatiron Health database.
Mutation analysis performed at diagnosis using next-generation sequencing or PCR.
Overall survival estimated with Kaplan-Meier method.
NPM1 mutations associated with improved survival; RAS mutations negated this benefit.
Median overall survival for patients with NPM1 mutations was higher compared to those without.
In presence of RAS mutations, NPM1's positive prognosis significantly decreased.

Abstract

Abstract Background: Activating RAS mutations play an important role in the pathogenesis of acute myeloid leukemia (AML) and occur in approximately 15-20% of patients with newly diagnosed (ND) AML. Although RAS mutations do not independently impact survival, the 4-gene molecular prognostic risk signature (mPRS) that is used to risk-stratify clinical outcomes in patients treated with venetoclax (VEN) and azacitidine and led to the updated ELN 2024, considered RAS mutations intermediate-risk. Furthermore, NPM1 was no longer favorable prognostic when co-occurring with signaling gene (SG) mutations (i.e., FLT3, NRAS, KRAS). However, given the small number of patients with a co-occurring NPM1and RAS mutation (n=8) or FLT3-ITD (n=16), it is unclear whether these patients truly have worse outcome compared with those without SG mutations. We aimed to investigate the prognostic impact of NPM1 alone and in the co-presence of RAS and/or FLT3-ITD mutations, among patients with favorable- or intermediate-risk AML per ELN 2024, in two independent cohorts of older patients (≥60 years) treated with VEN in combination with a hypomethylating agent (HMA). Methods: This retrospective study included data from two different cohorts of patients aged ≥60 years with ND AML who were treated with first-line (1L) VEN+HMA and were enrolled in the Beat AML trial (NCT03013998) or who were included in the US-based Flatiron Health research database. Mutation analysis (next-generation sequencing or polymerase chain reaction) was performed at diagnosis. Overall survival (OS) was estimated using the Kaplan-Meier method. OS was defined as the date of consent (Beat AML) or from start of 1L (Flatiron) to the date of death, allogeneic cell transplantation, or last follow-up. Results: A total of 187 patients enrolled on the Beat AML trial with favorable- (n=128) or intermediate-risk AML (n=59) per ELN 2024 were included. The median age was 74 years (range, 61-89). Forty (21%) patients were NPM1mut, 41 (21%) were RASmut, and 21 (11%) patients were FLT3-ITDpos. The median OS was 48.6 weeks with a 2-yr OS of 40%. NPM1mutwas associated with a trend toward increased OS compared to NPM1wt (2-yr OS 54% vs 37%, p=0.12). NeitherRASmut (p=0.2), nor FLT3-ITD (p=0.84) impacted outcome. NPM1mutwithout RASmut (n=29) had a non-significant superior 2-yr OS of 58% compared to NPM1mutwith RASmut(n=11), NPM1wtwith RASmut(n=30) and NPM1wtwithout RAS(n=117) patients(30%, 38%, 39%, respectively; p=0.22). NPM1mutwithout SG (n=20) was also associated with non-significant improved 2-yr OS of 59% compared to NPM1mutwith SGmut(n=20), NPM1wtSGmut(n=39), NPM1wtSGwt(n=108) patients(45%, 29% and 40%, respectively; p=0.27). Due to the small number of patients, a similar analysis was performed in a larger real-world cohort of ND AML patients (n=803). The median age was 76 years (range, 60-84), 645 (80%) patients were favorable- and 158 (20%) were intermediate-risk per ELN 2024. One hundred twenty-six patients had NPM1mut, 155 had RASmut (113 NRASmut, 64 KRASmut) and 104 patients were FLT3-ITDpos. The median OS was 40 weeks (range, 0-390). NPM1mutwas associated with significantly longer OS compared to NPM1wt (p=0.0078) and RASmut was associated with a shorter OS compared to RASwt (p=0.0001), irrespective of KRAS (p=0.055) or NRAS (p=0.0001). FLT3-ITD did not impact outcome (p=0.12). Stratified by the presence of RAS mutation, 2-yr OS of NPM1mutRASmut was inferior compared to NPM1mutRASwt(2-yr OS 27% vs 51%, p=0.001). NPM1mut in the co-presence of SGmutwas also associated with inferior 2-yr OS compared to NPM1mut in the absence of SGmut(2-yr OS 35% vs 49%, p=0.036), however, when we compared NPM1mut with or without FLT3-ITD, outcome was not impacted (p=0.29). Conclusions: SG mutations are common in older patients with AML, often with NPM1 co-mutations. We demonstrated that while NPM1mutwere prognostically favorable, the presence of co-occurring SG mutations negates the favorable effect of NPM1mut in ND older adults with AML, particularly RASmutrather than FLT3-ITD. These findings warrant investigation of new therapies, such as the addition of menin inhibitors to VEN/AZA, in the subset of NPM1mutRASmutFLT3-ITDneg patients. Phase 3 trials are currently underway, and benefit to this patient subset should be analyzed.

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