Outcome prediction in adult core binding factor (CBF) acute myeloid leukemia (AML) with gene expression profiling: A Cancer and Leukemia Group B (CALGB) study
7011 Background: In CBF AML with t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) [abbreviated inv(16)], KIT mutations (mutKIT) and, in inv(16), trisomy 22 predict outcome and may guide the development of novel risk-adapted therapies. However, prognosis of patients (pts) lacking the aforementioned markers is less clear. Therefore, we profiled gene expression in t(8;21) (n=22) or sole inv(16) (n=25) pts who lacked mutKIT to identify signatures predictive of outcome. All pts were treated on CALGB trials incorporating consolidation therapy with multiple courses of higher dose cytarabine. Methods: Gene expression profiling was performed using Affymetrix U133 plus 2.0 arrays on diagnostic samples. As differences in gene expression distinguished all t(8;21) pts from all inv(16) pts, indicating two different biological entities, we pursued outcome prediction separately for each cytogenetic group. Gene expression-based outcome predictors for event-free survival (EFS) were constructed using a cross-validated prediction algorithm. Results: Among t(8;21) pts, EFS for predicted good (n=13) and poor (n=9) outcome groups differed strikingly (P=0.005; estimated 3-year EFS rates: 69% v 11%). Prediction was correct for 77% of pts. Among sole inv(16) pts, EFS for predicted good (n=18) and poor (n=7) outcome groups also differed (P=0.08; 3-year EFS rates: 78% v 29%). Prediction was correct for 76% of pts. FLT3 mutations appeared not to account for differences in EFS between the predicted groups; only the predicted outcome groups were associated with EFS (all baseline clinical characteristics at P>0.10). Pts with predicted poor outcome had higher expression of genes with leukemogenic potential such as WT1 [t(8;21) and inv(16)], CCNA1 [t(8;21)] and the oncogene MYCN [inv(16)]. Conclusions: Gene expression profiling improves outcome prediction in CBF AML pts lacking the known prognostic markers. Future studies should explore the clinical usefulness of targeting products of over- expressed genes, such as WT1 encoding a potential target for immunotherapy in AML. No significant financial relationships to disclose.