title: Monoallelic CEBPA mutations in normal karyotype acute myeloid leukemia: independent favorable prognostic factor within NPM1 mutated patients.
abstract: We and others have shown that cytogenetically normal (CN)-AML patients with biallelic CEBPA gene mutations (biCEBPA) represent a molecularly distinct group with a favorable prognosis. Patients carrying a monoallelic CEBPA mutation (moCEBPA), however, show no different outcome compared to patients with wildtype CEBPA, and these mutations are frequently associated with mutated NPM1 or FLT3-ITD. So far, no molecular or clinical hallmark has been identified to prognostically distinguish moCEBPA patients from patients with wildtype CEBPA. Therefore, we used the data of 663 CN-AML patients treated within the AMLCG 1999 trial to explore the prognostic value of moCEBPA in the context of concomitant clinical and molecular markers (mutated NPM1, FLT3-ITD). Multiple Cox regression in 515 patients adjusting for all available potential confounders revealed that the NPM1 mutation modified the prognostic value of moCEBPA with respect to overall survival (OS, p = 0.017) and event-free survival (EFS, p = 0.011). MoCEBPA was beneficial in NPM1 mutated patients: adjusted OS-hazard ratio (HR) 0.09, 95% confidence interval (CI) 0.01-0.63, p = 0.016; EFS-HR (95% CI) 0.16 (0.04-0.65), p = 0.010. In contrast, moCEBPA had no prognostic impact in patients with wildtype NPM1: OS-HR (95% CI) 1.08 (0.59-1.97), p = 0.804; EFS-HR (95% CI) 1.12 (0.64-1.96), p = 0.682. We found no prognostic effect modification for moCEBPA by FLT3-ITD. The presence of a moCEBPA mutation was shown to be associated with prolonged survival in NPM1 mutated CN-AML patients. Confirmation of these results in larger studies will clarify whether an additional moCEBPA mutation influences the risk stratification of patients with an NPM1 mutated/FLT3-ITD positive genotype.
authors.affiliation: Laboratory for Leukemia Diagnostics, Department of Medicine III, University of Munich-Grosshadern, Marchioninistr.15, 81377, Munich, Germany. annika.dufour@med.uni-muenchen.de
authors.forename: Annika
authors.initials: A
authors.lastname: Dufour
authors.forename: Friederike
authors.initials: F
authors.lastname: Schneider
authors.forename: Eva
authors.initials: E
authors.lastname: Hoster
authors.forename: Tobias
authors.initials: T
authors.lastname: Benthaus
authors.forename: Bianka
authors.initials: B
authors.lastname: Ksienzyk
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schneider
authors.forename: Purvi M
authors.initials: PM
authors.lastname: Kakadia
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: Sauerland
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wörmann
authors.forename: Jan
authors.initials: J
authors.lastname: Braess
authors.forename: Marion
authors.initials: M
authors.lastname: Subklewe
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006720:Homozygote; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D012307:Risk Factors; D055815:Young Adult
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin