Recent work has identified distinct molecular subgroups of acute myeloid leukemia (AML) with implications for disease classification and prognosis. AML with mutated NPM1 (AML-NPM1) represents a distinct entity in the revised 2017 World Health Organization classification, but relatively little work has examined the clinical significance of phenotypic and genetic heterogeneity within this group. A multi-institutional cohort of 239 AML-NPM1 cases included 3 phenotypic groups: cases with blasts showing monocytic differentiation (n = 93; monocytic AML-NPM1), cases lacking monocytic differentiation (n = 72; myeloid AML-NPM1), and cases where blasts were negative for both CD34 and HLA-DR (n = 74; double-negative [DN] AML-NPM1). Genotypic diversity typical of AML-NPM1 was seen, with comutations occurring most commonly in DNA methylation genes (81% of cases), FLT3 (48%; including internal tandem duplication and tyrosine kinase domain mutations), and RAS pathway genes (30%). However, the comutation pattern differed by blast phenotype. TET2 and IDH1/2 mutations were significantly more common in DN AML-NPM1 (96% of cases) than in myeloid (39%) or monocytic AML-NPM1 (48%; P < .0001). Conversely, DNMT3A mutations were significantly less common in DN AML-NPM1 (27%) than in myeloid (44%) or monocytic cases (54%; P = .002). Furthermore, the 3 phenotypic groups showed significant differences in outcome, with DN AML-NPM1 showing significantly longer relapse-free (RFS) and overall survival (OS) (64.7 and 66.5 months, respectively) than monocytic AML-NPM1 (RFS, 20.6 months; OS, 44.3 months) or myeloid AML-NPM1 (RFS, 8.4 months; OS, 20.2 months; P < .0001 and P = .01 for RFS and OS, respectively). Our findings highlight biologic differences within immunophenotypically defined subgroups of NPM1-mutated AML that may impart prognostic significance.
© 2019 by The American Society of Hematology.