Prognostic Impact of BAALC Expression in the Context of Other Molecular Markers in Cytogenetically Normal Acute Myeloid Leukemia.
Authors: Dohner Konstanze , Corbacioglu Andrea , Eiwen Karina , Ewert Judith , Frohling Stefan , Bullinger Lars , Krauter Juergen , Schlegelberger Brigitte , Ganser Arnold , Dohner Hartmut , Schlenk Richard F. 
Published: October 2019

Abstract
Background: In previous studies, high blood expression values of BAALC (brain and acute leukemia cytoplasmic) have been shown to be an adverse risk factor in cytogenetically normal acute myeloid leukemia (CN-AML). So far, the prognostic value of BAALC expression has not been evaluated in the context of other relevant molecular markers such as mutations (mut) in the NPM1 or CEBPA genes.
Aims: To evaluate the prognostic impact of BAALC expression in the context of NPM1, FLT3-ITD (internal tandem duplication)/TKD (tyrosine kinase domain mutations at codons 835/836), CEBPA, and MLL-PTD (partial tandem duplication) mutation status on response to induction therapy, relapse-free (RFS) and overall survival (OS).
Methods: Patients (pts) 16 to 60 years of age were entered on three treatment trials conducted by the German-Austrian AML Study Gorup (AML HD93, AML HD98A, AML04–07). In all three trials, a genetic randomization was performed assigning all pts with an HLA-matched family donor to allogeneic stem cell transplantation (SCT) in first complete remission (CR). BAALC expression was determined in peripheral blood from 339 CN-AML pts by real-time RT-PCR as recently described; gene mutation screening was performed as previously reported.
Results: BAALC expression levels were heavily scattered in the 339 pts, with a median of 4,716 (range 11–1,120,212). High and low BAALC expression was determined by dichotomizing BAALC at the median. Correlation of BAALC expression levels with FLT3-ITD/TKD, NPM1, CEBPA and MLL-PTD mutation status revealed high BAALC expression to be significantly associated with FLT3-ITDpos (p=0.001), NPM1WT (p<0.0001) and CEBPAmut (p=0.006). In addition, when correlating BAALC expression levels with the combined FLT3-ITD/NPM1 genotypes that recently have been shown to be of prognostic relevance in CN-AML, a significant correlation of low BAALC expression and the favorable FLT3-ITDneg/NPM1mut (p<0.0001) genotype was present. In contrast, high expression levels were significantly correlated with the other unfavorable genotypes. There was a trend towards a lower CR rate in high BAALC expressers (p=0.07). However, in a multivariable logistic regression model, BAALC was not significant (p=0.75); the only significant variables for induction success were the FLT3-ITDneg/NPM1mut (p=0.03) and CEBPAmut genotypes (p=0.04), as well as logarithm of white blood cell count (WBC, p=0.03). In univariable analyses for OS and RFS, high BAALC expressers had significantly inferior clinical outcome (p=0.05 and p=0.02, respectively). Again, multivariable Cox proportional hazard models for RFS and OS revealed no significant impact of BAALC expression (p=0.15 and p=0.96, respectively); significant variables for OS and RFS were the FLT3-ITDneg/NPM1mut (p<0.0001 and p<0.0001) genotype, availability of an HLA-matched family donor (p=0.02 and p=0.001), and WBC (p=0.0002 and p=0.0001); in addition, the CEBPAmut genotype was a significant variable for OS (p=0.002).
Conclusions: In our study on a large series of molecularly well characterized CN-AML, BAALC expression levels were significantly correlated with FLT3-ITD/NPM1 genotypes. In the context of these genotypes, BAALC expression lost its independent prognostic impact.