Acute Myeloid Leukemia with Normal Cytogenetics and NPM1-Mutation: Impact of Mutation Topography on Outcomes

<b>Background</b>: About half of adults with acute myeloid leukemia with normal cytogenetics (CN-AML) have <i>NPM1</i> mutations. There is controversy regarding their prognosis and best therapy. <b>Methods</b>: We studied 150 subjects with these features using targeted regional sequencing. Prognostic stratification was carried out based on risk factors, and we assessed the effects of two post-remission strategies with and without transplant across risk cohorts. <b>Results</b>: In multi-variable analyses, a positive MRD test after the second consolidation cycle (HR = 6.00; 95% CI [3.31, 10.85]; <i>p</i> < 0.001), <i>DNMT3A</i> mutations (HR = 3.01 [1.57, 5.78]; <i>p</i> < 0.001), <i>FLT3</i>-ITD mutation with high variant allele frequency (HR = 4.40 [1.89, 10.24]; <i>p</i> < 0.001) and <i>DDX11</i> mutations (HR = 4.38 [2.38, 8.04]; <i>p</i> < 0.001) were independently correlated with higher cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) (HR = 5.49 [3.01, 10.04]; <i>p <</i> 0.001; HR = 2.99 [1.60, 5.62]; <i>p <</i> 0.001; HR = 4.20 [1.87, 9.40]; <i>p <</i> 0.001; and HR = 4.22, 95% CI [1.99, 8.95], <i>p <</i> 0.001). Subjects with ≥1 high-risk co-variate who received a transplant had a lower CIR and better LFS, whereas others did not. <b>Conclusions</b>: We identified co-variates associated with CIR and LFS in subjects of <i>NPM1</i>-mutated CN-AML.