Aberrant Gene Expression of BAALC and ERG in Older [≥60 Years (y)] De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): A Cancer and Leukemia Group B (CALGB) Study.

Abstract 214 BAALC & ERG are aberrantly expressed in younger (<60 y) adult CN-AML patients (pts), where expression levels of these genes are also associated with clinical outcome. Whether aberrant BAALC & ERG expression also occurs in older (≥60 y) CN-AML pts is unknown. To assess the BAALC & ERG expression levels in older CN-AML & their impact on outcome we studied pts ≥60 y (median age, 68 y; range 60–83) enrolled on cytarabine/daunorubicin-based protocols [CALGB 10201, 9720, 9420, 8923, 8525], with diagnostic blood samples available for quantitative RT-PCR analysis (n=158), that were also characterized for other molecular prognosticators ( FLT3 -ITD, FLT3 -TKD, NPM1 & WT1 mutations). BAALC & ERG expression values were normalized to an internal control ( ABL1 ), & the median gene expression value was used to define high & low expressers for BAALC & ERG . Gene (GEP) & microRNA (MEP) expression profiling were done using, respectively, Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays. At diagnosis, lower BAALC expression was associated with mutated NPM1 (P<.001) & low ERG expression (P<.001). Lower BAALC expressers had a higher complete remission rate (CR; 86% v 54%, P<.001) & longer disease-free (DFS; P=.006; 3y rates 19% v 12%) & overall survival (OS; P<.001; 3y 29% v 10%) than higher expressers. Lower ERG expression was associated with lower WBC (P=.005), % marrow (BM; P=.001) & blood (P<.001) blasts & absent FLT3 -ITD (P<.001) & low BAALC expression (P<.001). Lower ERG expression also associated with longer DFS (P=.001; 3y 18% v 14%) & OS (P<.001; 3y 24% v 15%). In multivariable models ([Table 1][1]), low BAALC expression independently associated with CR & longer DFS. BAALC & ERG expression were the only factors associated with OS. Comparison of age-groups (60-69 y v ≥70 y; [Table 2][2]) showed BAALC expression had a stronger prognostic impact in ≥70 y pts; lower expression was associated with higher CR rates & longer DFS & OS. ERG expression had instead stronger prognostic impact in 60-69 y pts ([Table 2][2]); lower expression was associated with longer DFS & OS. GEP (482 probes) & MEP (22 probes) differentiated low from high BAALC expressers. Low BAALC expressers had down-regulation of stem cell markers ( CD34, CD133) & unfavorable outcome predictors ( HGF, MN1, CD200) , & up-regulation of HOX genes & miR-10a & miR-10b . GEP (1554 probes) & MEP (11 probes) differentiating low from high ERG expressers showed low ERG expressers had down-regulation of DNMT3B & up-regulation of topoisomerase 1 ( TOP1 ), which is associated with enhanced chemotherapy sensitivity. Among up-regulated microRNAs in low ERG expressers was miR-208a , which is predicted to target ERG . In conclusion, lower expression of both BAALC & ERG associated with better outcome in older CN-AML pts even in the context of other established prognostic molecular markers, but have different impact on age-groups. GEP & MEP provided novel information that may elucidate how differential expression levels of these genes contribute to leukemogenesis & aid in developing novel risk-adapted therapies. | Variables in the final model | CR | DFS | OS | |:-------------------------------:| ---- | -------- | ---- | ----------- | | OR[*][3] | P | HR[†][4] | P | HR[†][4] | P | | BAALC , low v high (median cut) | 4.32 | <.001 | 0.64 | .03 | 0.49 | <.001[‡][5] | | ERG , low v high (median cut) | - | - | - | - | 0.69 | .03 | | WBC, each 50 unit increase | 0.68 | .02 | - | - | - | - | | NPM1 , mutated v wild-type | 2.34 | .04 | - | - | - | - | | FLT3 -ITD, any ITD v no ITD | - | - | 1.79 | <.001[‡][5] | - | - | | Age, each 10 year increase | - | - | 0.65 | .047 | - | - | * [↵][6]* OR, odd ratio, >1 (<1) mean higher (lower) CR rate for the 1st category listed for the dichotomous variables & for the higher values of the continuous variables. * [↵][7]† HR, hazard ratio, 1) indicate lower (higher) risk for an event for the first category listed for the dichotomous variables & for the higher values of the continuous variables. Variables considered in the models were those significant at α=0.20 in univariable analyses. * [↵][8]‡ Variable did not meet the proportional hazards assumption, a covariate was used to account for time dependence. Table 1: Multivariable analyses for CR, DFS & OS | Clinical endpoint | BAALC expression | ERG expression | |:-------------------:| ---------------- | ------------------ | ---------------- | | 60-69 y Pts (n=86) | ≥70 y Pts (n=72) | 60-69 y Pts (n=86) | ≥70 y Pts (n=72) | | Low | High | P | Low | High | P | Low | High | P | Low | High | P | | % achieving CR | 84 | 71 | .19 | 88 | 37 | <.001 | 80 | 76 | .80 | 71 | 53 | .15 | | DFS, % in CR at 3 y | 16 | 10 | .10 | 23 | 14 | .03 | 19 | 6 | <.001 | 17 | 25 | .48 | | OS, % alive at 3 y | 24 | 12 | .01 | 35 | 8 | <.001 | 24 | 12 | .006 | 23 | 18 | .03 | * The age-group clinical endpoints significantly associated with BAALC or ERG expression levels are denoted by bold type. Table 2: Age-Group comparison for CR, DFS & OS Disclosures: No relevant conflicts of interest to declare. [1]: #T1 [2]: #T2 [3]: #fn-1 [4]: #fn-2 [5]: #fn-3 [6]: #xref-fn-1-1 [7]: #xref-fn-2-1 [8]: #xref-fn-3-1