[104] Gene and microRNA (miRNA) Expression Signatures and Prognostic Significance of CEBPA Mutations in Cytogenetically Normal (CN) Acute Myeloid Leukemia (AML) with High-Risk Molecular Features: A Cancer and Leukemia Group B (CALGB) Study. Session Type: Oral Session

Guido Marcucci, Kati Maharry, Michael D. Radmacher, Krzysztof Mrózek, Tamara Vukosavljevic, Peter Paschka, Susan P. Whitman, Christian Langer, Claudia D. Baldus, Amy S. Ruppert, Bayard L. Powell, Andrew J. Carroll, Michael A. Caligiuri, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA; CALGB, Chicago, IL, USA

Although CEBPA mutations (CEBPA+) have been reported to predict favorable outcome in CN-AML, their prognostic value has not been evaluated in the context of such established prognostic molecular markers in CN-AML as the combination of FLT3-ITD and NPM1 mutational status and BAALC and ERG expression. 169 adults aged <60 years (yrs) with untreated, de novo CN-AML, enrolled on CALGB protocols 9621 or 19808 that included autologous stem cell transplantation for consolidation, were analyzed for CEBPA+ by DNA PCR amplification/direct sequencing. Testing for BAALC and ERG expression, FLT3-ITD, FLT3-TKD, MLL-PTD and NPM1 mutations (NPM1+) was performed centrally in pretreatment marrow or blood samples. Unexpectedly, CEBPA+ patients (pts) were more likely to have FLT3-ITD/NPM1 high-risk molecular features [ie, FLT3-ITD+ and/or NPM1 wild-type (NPM1wt)] than low-risk molecular features (FLT3-ITD-/NPM1+; 26 v 3 pts, respectively; P=.001). Thus, we focused subsequent analyses on FLT3-ITD/NPM1 high-risk pts (n=109) that included 90% of the CEBPA+ pts. In this group, a microarray gene-expression signature of 2,342 probes, 59% of which were downregulated in CEBPA+ pts, separated CEBPA+ and CEBPA wild-type (CEBPAwt) pts [false discovery rate (FDR)=.01]. Among the 20 most downregulated probes in CEBPA+ pts, 9 corresponded to Homeobox genes (HOXA3, A5, A9, A10, B2, B3, MEIS1). Also downregulated in CEBPA+ pts were other Homeobox genes (HOXA1, A2, A4, A6, A7, B4, B5, B6), FLT3, RUNX1 and RAS superfamily members, while CEBPA and GATA1 were upregulated. Additionally, a 13-probe microRNA (miRNA) expression signature distinguished CEBPA+ from CEBPAwt pts (FDR=.11). This signature shared features with a previously reported miRNA-signature predictive of clinical outcome in FLT3-ITD/NPM1 high-risk CN-AML (Radmacher et al. JCO 2007;25:359s). Eight miRNA probes for miRNA 181 family members were upregulated in CEBPA+ pts; an association between miRNA 181 family upregulation and good outcome was a major feature of the previously reported outcome miRNA signature. A probe for miRNA 194, whose downregulation was associated with good outcome in the prior outcome signature, was also downregulated in CEBPA+ pts. Consistent with these findings, CEBPA+ status predicted better outcome in the FLT3-ITD/NPM1 high-risk group. CEBPA+ pts had a better event-free survival (EFS) than CEBPAwt pts (P<.0001), with estimated 3-yr EFS rates of 57% and 17%, respectively. In a multivariable analysis, CEBPA+ independently predicted longer EFS (P=.0004; hazard ratio=0.30; 95%CI=0.15-0.58), after adjusting for ERG expression (P=.03). In summary, we report that CN-AML pts with CEBPA+ mostly have FLT3/NPM1 high-risk molecular features, and that the FLT3/NPM1 high-risk group can be subdivided based on the presence or absence of CEBPA+ into 2 subsets characterized by strong gene- and miRNA-expression signatures and different outcome. It is likely that testing for CEBPA+ at diagnosis will improve molecular risk-based classification of de novo CN-AML and aid in risk-adapted treatment stratification. Gene- and miRNA-expression profiling may provide insights into disease biology leading to development of novel therapies.
Abstract #104 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: Acute Myeloid Leukemia|C/EBP|Prognostic Factor
Disclosure: No relevant conflicts of interest to declare.

Sunday, December 9, 2007 4:45 PM

Session Info:  Simultaneous Session: Molecular Signatures in AML (4:30 p.m.-6:00 p.m.)