NPM1-mutated myeloid neoplasms (NPM1+ MNs) with <20% blood or bone marrow blasts are rare and have been previously shown in limited case series to exhibit an aggressive clinical course. We assembled the largest cohort of NPM1+ MN cases to date (n = 45) and compared it with NPM1- MN (n = 95) and NPM1+ de novo acute myeloid leukemia (AML; n = 119) patients. Compared with NPM1- MN, NPM1+ MN were associated with younger age (P = .007), a normal karyotype (P < .0001), more frequent mutations involving DNMT3A (P = .01) and PTPN11 (P = .03), and fewer involving ASXL1 (P = .003), RUNX1 (P = .0004), and TP53 (P = .02). Mutations involving IDH1 or IDH2 (IDH1/2) (P = .007) and FLT3 (internal tandem duplication, P < .0001; noninternal tandem duplication, P = .01) were less frequent in NPM1+ MN than in NPM1+ AML. In multivariable analyses performed in patients with myelodysplastic syndrome only, total mutation count (hazard ratio [HR], 1.3; P = .05), NPM1 mutation (HR, 3.6; P = .02), TP53 mutation (HR, 5.2; P = .01), and higher International Prognostic Scoring System-R score (HR, 1.7; P = .0003) were independently associated with shorter overall survival, whereas stem cell transplant conferred a favorable effect (HR, 0.1; P < .0001). These data suggest that NPM1+ MN are biologically distinct from NPM1- MN. Similar to NPM1+ AML, patients with NPM1-mutated myelodysplastic syndrome may benefit from more intensive therapeutic regimens.
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