Significance of BAALC, MN1, ERG, CEBPa Gene Expression as New Prognostic Factors, in the Context of Other Molecular Markers in Intermediate Risk AML Group According to Cytogenetics, Including Patients Younger Than 60 Years

Background: High expression of BAALC,MN1, ERG and low CEBPA have been shown to be an adverse risk factor in cytogenetically normal acute myeloid leukemia (CN-AML). However intermediate (IM) risk group of AML includes not only patients with normal karyotype, but also with other aberrations, of unknown clinical significance. That’s why it is important to evaluate prognostic impact of the above mentioned markers in the IM group of AML patients as total. So far, the prognostic significance of expression level of the studied markers has not been yet compared with each other, as well as evaluated in the context of other molecular biomarkers, such as FLT3 ITD (internal tandem duplication), MLL-PTD (partial tandem duplication) mutations, and EVI1 expression level.

Aims: To evaluate the prognostic impact of BAALC,MN1, ERG, CEBPA expression in the context of FLT3-ITD, MLL-PTD and EVI1 expression on the complete response to induction therapy (CR), and the relapse rate in the patients group representing intermediate risk group of AML according to cytogenetics.

Methods: 86 patients (16 to 60 years of age) with untreated primary IM-risk AML were included in this study: 55 with normal karyotype, and 31 with other aberrations. Patients were treated similarly according to the Polish Acute Leukemia Group (PALG) protocol (induction chemotherapy: daunorubicin, cytarabine plus fludarabine or cladribine, and two cycles of consolidation high-dose cytarabine with mitoxantrone and high- dose cytarabine). BAALC, MN1, ERG, CEBPA expressions were evaluated in the bone marrow cells from IM-AML patients by real-time RT-PCR technique, using TaqMan probes, as recently described.

Results: High and low BAALC, as well asERGandMN1 expression was determined by dichotomizing delta Ct values at the median (high expression of ERG, MN1 referred further as negative or positive cases). High BAALC correlated significantly with the group positive for MN1 (p=0.01), ERG (p=0.01) as well as MLL-PTD (p=0.045), while no correlation was found between: high BAALC and FLT3-ITD, as well as CEBPA. There was a trend towards significance towards lower CR rates in the groups with high BAALC, positive MN1, positive EVI1 expression or MLL-PTD, while low CEBPA showed negative correlation with CR rate (p=0.02). Next we analysed cumulative presence of the subsequent markers: MLL-PTD, positive ERG, positive MN1, and positive EVI1. Cases negative for all of above markers presented 85 % of CR rate, patients with one or two markers present: 55% CR rate, and a group with more than three of them positive: only 20% CR rate. Further comparing DFS after 2nd and 3rd year of follow up, with each marker separately did not show significant correlation, although a trend towards significance was observed for most of them. However again, cumulative presence of high BAALC, positive MN1, positive ERG, positive EVI1, and MLL-PTD showed significant correlation with 2 and 3 years’ DFS (respectively 70% for the cases with 0 –2 markers, while 22% for the group with more than 2 markers present; p=0.035).

Conclusions: In our study, we analysed a series of patients with intermediate risk according to the cytogenetics (NC and other aberrations). Cumulative presence of high BAALC, and positiveERG, MN1, EVI1 expression levels as well as MLL-PTD, showed their prognostic significance.