Laboratory evaluation and prognostication among adults and children with CEBPA‐mutant acute myeloid leukemia

Abstract

CEBPA‐mutant acute myeloid leukemia (AML) encompasses clinically and biologically distinct subtypes of AML in both adults and children. CEBPA‐mutant AML may occur with monoallelic (moCEBPA) or biallelic (biCEBPA) mutations, which can be somatic or germline, with each entity impacting prognosis in unique ways. BiCEBPA AML is broadly associated with a favorable prognosis, but differences in the type and location of CEBPA mutations as well as the presence of additional leukemogenic mutations can lead to heterogeneity in survival. Concurrent FLT3‐ITD mutations have a well‐documented negative effect on survival in adult biCEBPA AML, whereas support for a negative prognostic effect of mutations in TET2, DNMT3A, WT1, CSF3R, ASXL1, and KIT is mixed. NPM1 and GATA2 mutations may have a positive prognostic impact. MoCEBPA AML has similar survival outcomes compared to AML with wild‐type CEBPA, and risk stratification is determined by other cytogenetic and molecular findings. Germline CEBPA mutations may lead to familial biCEBPA AML after acquisition of second somatic CEBPA mutation, with variable penetrance and age. BiCEBPA AML in children is likely a favorable‐risk diagnosis as it is in adults, but the role of a single CEBPA mutation and the impact of concurrent leukemogenic mutations are not clear in this population. Laboratory evaluation of the CEBPA gene includes PCR‐based fragment‐length analysis, Sanger sequencing, and next‐generation sequencing. Phenotypic analysis using multiparameter flow cytometry can also provide additional data in evaluating CEBPA, helping to assess for the likelihood of mutation presence.

Mutational Landscape of CEBPA in Mexican Pediatric Acute Myeloid Leukemia Patients: Prognostic Implications

“…Heterogeneity in relapse rates and survival outcomes has been reported in CEBPA POS patients despite the favorable impact of CEBPA BI mutations on OS ( 36 ). Concurrent mutations in other genes and a differential impact of CEBPA mutations according to their location would contribute to the observed heterogeneity ( 15 , 37 ). We searched for concurrent mutations in FLT3 , NPM1 , CSF3R among CEBPA POS patients; however, statistical tests could not be run due to the small sample size.…”

“…FLT3 was mutated with VF > 30% in 3 out of 10 CEBPA POS patients (one CEBPA BI and two CEBPA MONO ). We had previously reported that FLT3 mutations have a negative impact on clinical outcomes in Mexican pediatric AML patients, and OS is significantly lower in patients with FLT3 mutations than in FLT3 NEG (17,37). Akin et al reported that 2 out of 3 patients who carried concurrent CEBPA and FLT3 mutations died during treatment (38).…”

Rare Hematologic Malignancies and Pre-Leukemic Entities in Children and Adolescents Young Adults

“…Briefly described below are the rare entities among these syndromes. These rare disorders are characterized by either CEBPA or DDX41 mutations and are often inherited in families without a pre-existing platelet disorder or organ dysfunction [156][157][158][159]. Patients with familial AML with germline CEBPA mutations are typically younger at presentation than patients with de novo disease, with a median age of 25 years and without antecedent MDS or cytopenias [158].…”

A review of granulocyte colony-stimulating factor receptor signaling and regulation with implications for cancer

“…Mutation of this region reduces promoter activity by 75%. Additionally, C/EBPα physically interacts with and activates PU.1 distal enhancer in myeloid differentiation, suggesting an additional level of transcriptional complexity ( 64 ). Interestingly, when promoter activity was monitored by luciferase assay, activity increases were observed in NB4 and HL60 leukemic cell lines but not in the non-myeloid cell lines, Jurkat or BJAB ( 65 – 67 ).…”