Variant Topography of Npm1 Mutations in Acute Myeloid Leukemia

Document Type

Conference Proceeding

Publication Date

6-10-2026

Publication Title

HemaSphere

Keywords

DNA methyltransferase 3A, acute myeloid leukemia, adult, aged, clinical outcome, cohort analysis, conference abstract, controlled study, data analysis software, female, human, major clinical study, male, therapy, topography

Abstract

Background Despite its favorable prognosis in the absence of FLT3 mutations, NPM1 mutated AML frequently relapses. Current risk stratification models approach all NPM1 subtypes (ST) uniformly. Evaluating Type A, B, D and non-ABD NPM1 variants may elucidate the biological heterogeneity driving the discordance between predicted risk and clinical outcomes. Aims To evaluate the molecular intricacies of NPM1 variants and their co-mutational profiles in AML. Methods Patient data from Karmanos Cancer Institute, published meta-analytic cohorts (Awada et al., 2021; Kewan et al., 2023), cBioPortal and AACR GENIE (v17) (Cerami et al., 2012; Gao et al., 2013; de Bruijn et al., 2023) were evaluated. Clinical and genomic characteristics of NPM1MT AML were reviewed. NPM1 mutations were classified as Type A, B, D or non-ABD according to nucleotide insertion sequencing. Statistical analysis was performed via GraphPad Prism. Results Of 7653 patients, 1540 had NPM1 mutated AML. Type A was most common (74%), followed by non-ABD (18%), B (4.8%) and D (4.7%). Type A was the most proliferative, with a median bone marrow blast count of 79%, compared to 54% in non-ABD (p<0.0001). B had the highest NPM1 VAF (37.6 vs 30.9% in non-ABD, p <0.0001). The most common co-mutation with NPM1 was DNMT3A (48%). Type A was enriched for DNMT3A compared to other ST (54% vs 34%, p<0.00001). Type A and D had more IDH1, IDH2, and NRAS mutations than B and non-ABD (17% vs 10%, p=0.01; 23% vs 9%, p<0.00001; 16% vs 10%, p=0.03, respectively). B and non-ABD were more enriched in WT1 compared to A and D (12% vs 4%, p=0.00002). Non-ABD was more enriched for FLT3 mutations than other ST (39% vs 24%, p=0.00012). DNMT3AR882 was enriched in high VAF (HV) compared to low VAF (LV) NPM1 (54% vs 46%, p=0.01). FLT3 was more common in HV NPM1 (34% vs 17%, p<0.0001). NPM1 was often a subclone (82%), but was more likely to be dominant in B (29%, p=0.001). The median OS of NPM1MT AML was 19 mo. OS was numerically higher in D (26 mo) and non-ABD (25 mo). LV NPM1 (Q1 ≤22.8%) had a significantly better OS than HV (Q3 ≥38%): 21 vs 10 mo (p<0.0001). This trend was observed across ST and was most pronounced in D and non-ABD (D: 58 vs 10 mo, p=0.009; non-ABD: 29 vs 7 mo, p=0.005). Summary/Conclusion While NPM1 variants are distinct in disease presentation, outcomes appear to be shaped by complex interactions with co-mutational patterns and clonal hierarchy rather than subtype alone. Future work will evaluate whether variant topography actively shapes permissive co-mutational landscapes and disease ontogeny, thereby driving clinical behavior and MRD dynamics.

Volume

10

Find It @ Sladen

Share

COinS