The favorable impact of CEBPA mutations in patients with acute myeloid leukemia is only observed in the absence of associated cytogenetic abnormalities and FLT3 internal duplication

Abstract

Mutations of the CCAAT/enhancer binding protein alpha (CEBPA) gene have been associated with a favorable outcome in patients with acute myeloid leukemia (AML), but mainly in those with a normal karyotype. Here, we analyzed the impact of associated cytogenetic abnormalities or bad-prognosis fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in 53 patients with CEBPA ؉ de novo AML treated in the Acute Leukemia French Association trials. We found that only those with a normal karyotype and no FLT3-ITD displayed the expected favorable outcome. In this context, relapsefree, disease-free, and overall survival were significantly longer than in corresponding patients without the CEBPA mutation (P ‫؍‬ .035, .016, and .047, respectively). This was not observed in the context of an abnormal karyotype or associated FLT3-ITD. Furthermore, after adjustment on age, trial, and mutation type, these features were independently predictive of shorter overall survival in the subset of patients with CEBPA ؉ AML (multivariate hazard ratio ‫؍‬ 2.7; 95% confidence interval, 1.08-6.7; and 2.9; 95% confidence interval, 1. IntroductionThe prognosis of patients with acute myeloid leukemia (AML) has been deeply refined because of the impact of new molecular markers. If standard cytogenetics remains a strong factor for both complete remission (CR) achievement and relapse, several gene mutations have been described and demonstrated as significantly influencing the outcome of these patients. 1 In this new context, most cooperative groups recommend to screen for some gene mutations at diagnosis, including the fms-like tyrosine kinase 3 (FLT3), the nucleophosmine (NPM1), and the CCAAT/enhancer binding protein alpha (CEBPA) genes. 2 We have previously reported that CEBPA mutations are associated with a favorable outcome in younger patients with newly diagnosed AML. 3 This was confirmed by other groups, but mainly in patients with cytogenetically normal (CN) AML. [4][5][6][7] The issue of whether this favorable impact is still observed in patients with AML carrying cytogenetic abnormalities remains open. Another open issue is to determine whether cooperating bad-prognosis FLT3 internal tandem duplication (FLT3-ITD) may alter the prognosis of CEBPA mutated (CEBPA ϩ ) AML. 3,5,7 Finally, it has been recently reported that only CEBPA double mutations, but not single, might be associated with a good outcome. 8 In the present study, we thus analyzed the role of these factors in 53 patients with CEBPA ϩ AML treated in Acute Leukemia French Association (ALFA) trials. MethodsA total of 1529 patients (15-70 years of age) with newly diagnosed AML entered the ALFA-9000, ALFA-9801, and ALFA-9802 trials between 1990 and 2006. Trial designs have been already reported. [9][10][11] Briefly, the first ALFA-9000 trial demonstrated the superiority of an intensified timedsequential over a standard (3 ϩ 7) induction in terms of relapse incidence in the subgroup of patients 50 years of age or younger. 9 From 1998, these younger patients were thus treated...

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

“…13 --15 CN-AML with CEBPA mutations define another subgroup of patients also associated with a favorable prognosis. 11,12,16 More recently, several studies have demonstrated that only AML with biallelic CEBPA mutations (most of them being double CEBPA mutations) should be regarded as favorable. 17 --21 Mutations in NPM1, CEBPA and FLT3-ITD allowed a refined prognostic classification of CN-AML and improved risk stratification in this subset of AML patients.…”

Prevalence and Prognostic Impact of CEBPA Gene Mutation (Simplified Assay Technique) in Egyptian Acute Myeloid Leukemia Patients with Normal Cytogenetics

“…Cytogenetically normal AML (CN-AML) represents 40-50 % of all AML cases and currently is considered separate entity in WHO classification [3]. The identification of molecular markers that precisely differentiate a patient's risk could improve treatment outcome and deeply refine the prognosis of patients with CN-AML [4,5].…”

“…It was originally isolated from rat liver that bound to viral enhancer sequences CCAAT [1,4,5]. CEBPA is the original member of the basic region leucine zipper (bZIP) class of transcription factors [6].…”

“…CEBPA mutations have been reported in approximately 5-14 % of all AML with predominance in CN-AML [5,10,11]. It has been reported that suppressed CEBPA function characterizes CN-AML with favorable outcome [11,12].…”

“…It has been reported that suppressed CEBPA function characterizes CN-AML with favorable outcome [11,12]. Accurate testing for CEBPA mutations is important for identification of this prognostically significant AML subtype which is now considered as a distinct disease entity in the 2008 World Health Organization classification of leukemia's [5,7].…”