Abstract
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), 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) 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); 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* . | P . | HR† . | P . | HR† . | P . | |
BAALC, low v high (median cut) | 4.32 | <.001 | 0.64 | .03 | 0.49 | <.001‡ |
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‡ | - | - |
Age, each 10 year increase | - | - | 0.65 | .047 | - | - |
Variables in the final model . | CR . | DFS . | OS . | |||
---|---|---|---|---|---|---|
OR* . | P . | HR† . | P . | HR† . | P . | |
BAALC, low v high (median cut) | 4.32 | <.001 | 0.64 | .03 | 0.49 | <.001‡ |
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‡ | - | - |
Age, each 10 year increase | - | - | 0.65 | .047 | - | - |
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.
HR, hazard ratio, <1 (>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.
Variable did not meet the proportional hazards assumption, a covariate was used to account for time dependence.
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 |
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.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
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