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Blood Adv. 2019 May 14;3(9):1540-1545. doi: 10.1182/bloodadvances.2019000090.

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

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Department of Pathology, Brigham and Women's Hospital, Boston, MA.
Division of Hematopathology, Memorial Sloan Kettering Cancer Center, New York, NY.
Division of Hematopathology, Department of Pathology, Hospital of the University of Pennsylvania and Perelman School of Medicine, Philadelphia, PA.
Division of Hematopathology, Weill Cornell Medical College, New York, NY.
Department of Pathology and Laboratory Medicine and.
Division of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Department of Pathology, Massachusetts General Hospital, Boston, MA; and.
Department of Pathology, Boston Children's Hospital, Boston, MA.


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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