Npm1 Mutations As An Independent Prognosticator For Older Cytogenetically Normal Acute Myeloid Leukemia (Cn Aml)

7000 Background: In younger CN AML without FLT3-ITD, NPM1 mutations predict favorable outcome. Their prognostic impact in older [≥60 years (y)] patients (pts) requires further evaluation. Methods: Pretreatment marrow was studied in 189 older CN AML pts [median age 69 y (60 - 83 y); 162 de novo & 27 secondary (s; prior hematologic disorders) cases] enrolled on CALGB 9720 (n=106) & 10201 (n=83). Both protocols had standard-dose (100 mg/m2/d) cytarabine (AraC)/daunorubicin (DN)-based induction; consolidation was based on standard-dose AraC/DN/etoposide (1 cycle) in 9720 & intermediate-dose (2 g/m2/d) AraC (2 cycles) in 10201. Pts transplanted in 1st complete remission (CR) were excluded. Median follow-up was 3.3 y for pts alive. Analyses of NPM1 exon 12 by direct sequencing, gene & microRNA (miR) expression profiling by Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays, & other markers (FLT3-ITD, FLT3-TKD, WT1mut) were performed centrally. Results: In de novo CN AML, NPM1 mutated (NPM1mut) pts (54%) had more CRs (85% v 45%, P<.0001) & longer relapse-free (RFS) (P=.02; 3 y rates 23% v 10%) & overall survival (OS) (P<.0001; 3 y 34% v 7%) than NPM1 wild-type (NPM1wt) pts. In multivariable models, NPM1 mutations independently predicted favorable outcome (Table) - NPM1mut pts had 10-fold higher odds of CR & 64% reduction in relapse risk. In genome-wide analyses, miR-10 & miR-16 were upregulated in NPM1mut pts, accompanied by highly expressed HOX genes & downregulated BCL2, respectively. NPM1mut were rare in sAML pts (15%), precluding study of their impact. Conclusions: NPM1 mutations independently predict better outcome in older CN AML. Upregulation of proapoptotic microRNAs & downregulation of antiapoptotic microRNA targets may explain the impact of NPM1 mutations. [Table: see text] No significant financial relationships to disclose.