Clinicopathologic and genetic characterization of nonacute NPM1 -mutated myeloid neoplasms.

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.
(© 2019 by The American Society of Hematology.)