Nucleophosmin ( <i>NPM1</i> ) genomic alterations (GA) in acute myeloid leukemia (AML): A genomic landscape study.

Abstract

6528 Background: NPM1 GA characterize a clinically important subset of AML cases which relapse in more than 50% of treated patients despite being generally sensitive to conventional chemotherapy regimens. In AML, the interactions between GA in NPM1 , KMT2A and menin protein have been linked to leukemogenesis and represent new potential targets for anti-tumor therapies. Methods: 4,206 cases of AML underwent comprehensive genomic profiling from 2019 through 2024, using the FoundationOne Heme combined hybrid capture based DNA and RNA sequencing assay. All classes of relevant GA were evaluated. The tumor mutation burden (TMB), homologous recombination deficiency signature (HRDsig) and microsatellite Stability (MSS) status were determined from the sequenced data. Results: 633 (15.1%) of the 4,206 AML featured NPM1 GA (NPM1mut). Short variant mutations were found in &gt;99% of the NPM1mut AML with the W288fs*12 frameshift base substitution accounting for 92.4% of cases. An NPM1 - MLF1 fusion was identified in 1.3% of NPM1mut cases. The NPM1mut+ were more frequently associated with female patients (53.4% vs 41.5%; p&lt;.0001) and had a slightly higher median age compared to the NPM1 wild type (NPM1wt) AML patients (62yrs vs 60yrs; p&lt;.0001). Majority of patients (&gt;60%) were from European decent. There were greater NPM1 GA in patients with European (77.1% vs 68.5%; p&lt;.0001) and lower with African ancestry (9.2% vs 10.2%; p&lt;.0001). MSI High (0% in both groups) status, HRDsig+ (0—0.1%) and elevated TMB (median &lt; 1 mutation/Mb) were extremely uncommon in both groups. GA more frequent in NPM1mut AML compared to the NPM1wt AML cohort included DNMT3A (39.2% vs 12.6%; p&lt;.0001), FLT3 (54.5% vs 14.7%; p&lt;.0001) , IDH1 (16.1% vs 5.6%; p&lt;.0001), IDH2 (19.0% vs 9.0%; p&lt;.0001), TET2 (23.4% vs 13.5%; p&lt;.0001) and WT1 (12.5% vs 9.4% p=.02). GA more frequent in NPM1wt AML included ASXL1 (17.1% vs 3.6%; p,.0001), BCOR (7.5% vs 1.6%; p&lt;.0001), KMT2A (14.7% vs 0.2%; p&lt;.0001), RUNX1 (22.5% vs 1.9%; p-,.0001), STAG2 (6.9% vs 1.6%; p&lt;.0001) and TP53 (19.1% vs 4.1%; p&lt;.0001). Conclusions: The development of menin inhibitors has recently identified GA in NPM1 as a promising target of therapy for AML patients. Other therapy targets in AML such as FLT3 and IDH1/2 are more frequently identified in NPM1mut than NPM1wt AML, while KMT2A is more frequently identified in NPM1wt AML. This genomic landscape study reveals significant differences in important GA associated with AML in NPM1mut and NPM1wt cases which may enrich our understanding of the molecular profile in AML and identify additional targets for therapy. Pathogenic genomic alterations in NPM1mut and NPM1wt AML. NPM1wt AML (n=3573) NPM1mut AML (n=633) P-value ASXL1 17.1% 3.6% &lt;.0001 CEBPA 6.4% 8.2% NS DNMT3A 12.6% 39.2% &lt;.0001 FLT3 14.7% 54.5% &lt;.0001 IDH1 5.6% 16.1% &lt;.0001 IDH2 9.4% 19.0% &lt;.0001 KMT2A 14.7% 0.2% &lt;.0001 RUNX1 22.5% 1.9% &lt;.0001 TET2 13.5% 23.4% &lt;.0001 TP53 19.1% 4.1% &lt;.0001