Abstract
Cytogenetics remain the most powerful prognostic factor in acute myeloid leukemia (AML). However, 50–60 % of those patients (pts) are included in intermediate or unknown karyotypic risk groups. Molecular markers might improve risk classification and recently, 2 groups have reported that the expression of BAALC and EVI1 might be associated with a poor outcome, especially in pts with normal karyotype (Blood.2003;102:1613; Blood2003;101:837). Thus, we retrospectively analyzed the prognostic significance of the expressions level of these genes, by real time quantitative PCR (RQ-PCR) in AML.
Patients and methods: 189 adult pts were analyzed: median age was 49 years (range, 19-65), median WBC counts 19 Giga/L (range, 0-602). FAB classification was: M0=22, M1=41,M2=44,M4=37,M5=26,M6=7,M7=1 and unclassified =11. Karyotype was prognostically favorable (n=28), intermediate (n=115, including 80 normal), unfavorable (n=39) and unknown (n=7). All pts received anthracycline-AraC chemotherapy according to French ALFA group multicenter trials (Castaigne et al, Blood 2004; May 13, Epub ahead of print). Complete remission rate was 83 %, median overall survival: 22 months, range 0.1 to 123. RQ-PCR was performed according to the 2 previous paper recommendations. However the housekeeping gene used in this work was TBP (TF2D). Results were expressed using ΔCt method. High levels of EVI1 were defined by ΔCt lower than 11. BAALC (+) pts and (−) pts were defined by ΔCt value lower or higher than 2.45 (ie the median ΔCt for BAALC expression).
Results: 24/189 (13%) pts had high expression of EVI1. By comparison to pts without high EVI1 expression, pretreatment variables other than karyotype (including age, WBC counts, FAB classification) were similar in pts with high EVI1 expression. Patients with high EVI1 expression had significantly worse karyotype: none had favorable karyotype, only 4 (17%) had 3q26 abnormalities ((associated with other adverse abnormalities in 3 cases (i.e. -7/7q-)), 3 had 11q23 abnormalities and 9/24 (37.5%) pts normal karyotype. No significant diferencies between pts with high and low EVI1 expression was found for CR rates and DFS, but high EVI1 expression was associated with poorer overall survival ( median:11.7 months versus 26.9 months; p=0.0372). No pretreatment parameters, including karyotype, differed between BAALC (+) (ie pts with BAALC expression lower than the ΔCt median value) and BAALC (−) pts (ie pts with expression greater than the ΔCt median value). Overall CR rate, DFS, OS were similar in BAALC (+) and BAALC (−) pts. However, in the intermediate cytogenetic subgroup (n=115 pts), BAALC (+) pts had lower median DFS (9.7 months versus 19.8 months; p=0.0316) and EFS (4.1 months versus 11.8 months; p=0.0027) than BAALC (−) pts and a trend for poorer OS:16 months versus 27 months (p=0.07).
In conclusion: In adult AML patients, high expression of EVI and BAALC are associated with poorer outcome. Determination at diagnosis of the level of those two genes could be helpful for treatment adjustment, especially in the intermediate cytogenetic subgroup. Correlation between EVI1 and BAALC results and those of other molecular markers (CEBPA, RAS, FLT3) mutations will be presented.
Molecular Evaluation of DNMT3A and IDH1/2 Gene Mutation: Frequency, Distribution Pattern and Associations with Additional Molecular Markers in Normal Karyotype Indian Acute Myeloid Leukemia Patients
