: NPM1-mutated AML represents a WHO leukemia entity with unique pathological and clinical features. Little is known about the characteristics of "therapy-related" NPM1-mutated AML. We compared the genetics, transcriptional profile and clinical outcome of therapy-related NPM1-mutated AML (t-NPM1 AML), de-novo NPM1-mutated AML (dn-NPM1 AML) and therapy-related AML with wild-type NPM1 (t-AML). A normal karyotype was more frequent in t-NPM1 AML (n=78/96 cases, 88%) and dn-NPM1 (n=1986/2394,88%) than in t-AML (n=103/390,28%; p <0.001). DNMT3A and TET2 were mutated in 43% and 40% of t-NPM1 AML (n=107), similar to dn-NPM1 (n=88, 48% and 30%; p-values >0.1), but more frequently than t-AML (n=162; 14% and 10%; p-values <0.001). TP53 and PPM1D, typically mutated in t-AML, were consistently wild-type in t-NPM1 AML (97% and 96%). t-NPM1 and dn-NPM1 AML were transcriptionally similar, displaying upregulation of HOX genes and down-regulation of CD133 and CD34. With a median follow-up of 62 months, 3-year overall survival (OS) for t-NPM1 AML (n=96), dn-NPM1 AML (n=2394) and t-AML (n=390) was 54%, 60% and 31%. In multivariable analysis OS was similar for the two NPM1-mutated groups (HR 0.9, 95%CI 0.65-1.25, p=0.45) but better in t-NPM1 AML than t-AML (HR 1.86, 95%CI 1.30-2.68, p<0.001). Relapse-free survival did not differ between t-NPM1 and dn-NPM1 AML (HR 1.02, 95%CI 0.72-1.467, p=0.90) but was significantly higher in t-NPM1 AML than t-AML (HR 1.77, 95%CI 1.19-2.64, p=0.0045).t-NPM1 and dn-NPM1 AML have similar clinical, genomic and transcriptomic features, suggesting that they should be classified as a single disease entity.
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