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Clinicopathologic and genetic characterization of nonacute NPM1-mutated myeloid neoplasms

Sanjay S. Patel, Caleb Ho, Ryan N. Ptashkin, Sam Sadigh, Adam Bagg, Julia T. Geyer, Mina L. Xu, Thomas Prebet, Emily F. Mason, Adam C. Seegmiller, Elizabeth A. Morgan, David P. Steensma, Eric S. Winer, Waihay J. Wong, Robert P. Hasserjian and Olga K. Weinberg

Key Points

  • Nonacute NPM1-mutated myeloid neoplasms are biologically distinct from nonacute NPM1 wild-type myeloid neoplasms.

  • Nonacute NPM1-mutated myeloid neoplasms are associated with poorer survival compared with NPM1-mutated AML and NPM1-WT myeloid neoplasms.

Abstract

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.

  • Submitted February 26, 2019.
  • Accepted April 3, 2019.
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