Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations.
OBJECTIVE
To determine the clinical relevance of mutations in the CCAAT/enhancer binding protein alpha (CEBPA) gene in acute myeloid leukemia (AML) and to examine factors that might modify prognostic impact.


METHODS
The entire CEBPA coding sequence was screened in 1,427 young adult patients with AML, excluding acute promyelocytic leukemia, using denaturing high-performance liquid chromatography and direct sequencing.


RESULTS
Of 107 patients (7%) with CEBPA mutations, 48 patients (45%) had one mutation (CEBPA-single), and 59 patients (55%) had two mutations (CEBPA-double). The incidence of CEBPA-double patients was similar in intermediate cytogenetic risk patients with and without a normal karyotype (6% and 5%, respectively). CEBPA-double patients had evidence of a lower coincidence with FLT3/ITDs (P = .04) and were highly unlikely to have an NPM1 mutation (P < .0001). CEBPA-double but not CEBPA-single patients had a significantly better overall survival (OS) at 8 years (34%, 31%, and 54% for CEBPA-wild-type [WT], CEBPA-single, and CEBPA-double, respectively, P = .004). This benefit was lost in the presence of a FLT3/ITD (OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-negative patients: 36%, 35%, 59%, respectively, P = .002; OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-positive patients: 26%, 21%, 14%, respectively, P = .05). There was no evidence of any additional favorable benefit for a CEBPA-single mutation in the presence of an NPM1 mutation (OS, 45%, 44%, and 56%, P = .2, for NPM1-positive/CEBPA-WT, NPM1-positive/CEBPA-single, and NPM1-negative/CEBPA-double patients, respectively).


CONCLUSIONS
Screening for CEBPA mutations can be restricted to patients with intermediate-risk cytogenetics lacking an FLT3/ITD or NPM1 mutation. Only the presence of a CEBPA-double mutation should be used for therapy risk stratification.
Green
Claire L
CL
Department of Haematology, UCL Cancer Institute, University College London, 72 Huntley St., London, UK.
Koo
Kenneth K
KK
Hills
Robert K
RK
Burnett
Alan K
AK
Linch
David C
DC
Gale
Rosemary E
RE
D000328:Adult; D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D016026:Bone Marrow Transplantation; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D015331:Cohort Studies; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012737:Sex Factors; D016019:Survival Analysis; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D022763:CCAAT-Enhancer-Binding Protein-alpha; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D051941:fms-Like Tyrosine Kinase 3