Low Meningioma 1 (MN1) gene expression to predict outcome in cytogenetically normal acute myeloid leukemia (CN-AML): A Cancer and Leukemia Group B (CALGB) study

Abstract

7011 Background: Expression of the MN1 gene, which encodes a transcription co-activator implicated in myeloid leukemogenesis, has been shown to predict outcome in CN-AML patients (pts) in 1 study (Heuser et al. Blood 2006;108:3898). Here we present the first validation of the prognostic impact of MN1 expression in CN-AML in the context of not only mutated (mut) FLT3 and NPM1 and MLL-partial tandem duplication but also other established prognostic markers (i.e., CEBPAmut, WT1mut, ERG and BAALC expression levels). Methods: MN1 expression was measured by quantitative real-time RT-PCR in pretreatment bone marrow samples from 119 de novo CN-AML adult pts <60 years with material available for MN1 expression analyses who were treated on CALGB protocols 9621 and 19808. MN1 copy numbers were measured and normalized to ABL (internal control) copy numbers. Pts were dichotomized at the MN1 median expression and analyzed for outcome. Results: At diagnosis, low MN1 expression was associated with NPM1mut (P<0.0001) and the molecular low risk group (FLT3-internal tandem duplication (ITD)negative and NPM1mut; P<0.001). Complete remission (CR) rate was higher in low MN1 pts (93% v 73%); low MN1 pts were 6 times more likely to achieve a CR than high MN1 pts (P=0.005), once adjusting for hemoglobin (P=0.01) (Table). With a median follow-up of 4.6 years, low MN1 pts also had longer disease-free survival (DFS) (P<0.005; 3-year DFS: 60% v 32%) and overall survival (OS) (P<0.001; 3-year OS: 68% v 40%) than high MN1 pts. In multivariable analyses, MN1 expression independently predicted for DFS (P=0.01) and OS (P=0.03). For low MN1 pts, the risk for an event was reduced by approximately 50% compared with high MN1 pts (Table). Conclusions: MN1 expression predicts outcome independent of other established molecular markers in CN-AML pts. Particularly, low MN1 expression defines a group of CN-AML pts with favorable clinical outcome. Multivariable analyses for achievement of CR, DFS and OS Variables in Final Models CR DFS OS OR * P HR ** P HR ** P MN1 expression, low v high 6.4 0.005 0.46 0.01 0.54 0.03 WT1, mutated v wild-type – – 5.6 <0.0001 7.0 <0.0001 FLT3-ITD/NPM1 status, high v low risk – – – – 3.0 0.005 WBC, each 50 unit increase – – 2.1 0.002 1.7 <0.0001 Hemoglobin 1.7 0.01 – – – – * OR: odds ratio; ** HR: hazard ratio. Variables considered in the models were those significant at α=0.20 in univariable analyses as follows: for CR, MN1 expression, FLT3-ITD/NPM1 status (molecular high risk is FLT3-ITDpositive and/or NPM1wt; molecular low risk is FLT3-ITDnegative and NPM1mut), WBC, hemoglobin, age, race; for DFS, MN1 expression, FLT3-ITD/NPM1 status, ERG expression, WT1 and CEBPA mutations, WBC, race; for OS, MN1 expression, FLT3-ITD/NPM1 status, ERG and BAALC expression, WT1 mutations, WBC, age, race, hemoglobin, % blood blasts, extramedullary involvement. No significant financial relationships to disclose.