Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group

Abstract

CEBPA mutations have been associated with improved outcome in adult acute myeloid leukemia (AML). We evaluated the prevalence and prognostic significance of CEBPA mutations in 847 children with AML treated on 3 consecutive pediatric trials. Two types of CEBPA mutations-N-terminal truncating mutations and in-frame bZip-domain mutationswere detected in 38 (4.5%) of 847 patients tested; 31 (82%) of 38 patients with mutations harbored both mutation types. Mutation status was correlated with laboratory and clinical characteristics and clinical outcome. CEBPA mutations were significantly more common in older patients, patients with FAB M1 or M2, and patients with normal karyotype. Mutations did not occur in patients with either favorable or unfavorable cytogenetics. Actuarial eventfree survival at 5 years was 70% versus 38% (P ‫؍‬ .015) with a cumulative incidence of relapse from complete remission of 13% versus 44% (P ‫؍‬ .007) for those with and without CEBPA mutations. The presence of CEBPA mutations was an independent prognostic factor for improved outcome (HR ‫؍‬ 0.24, P ‫؍‬ .047). As CEBPA mutations are associated with lower relapse rate and improved survival, CEBPA mutation analysis needs to be incorporated into initial screening for risk identification and therapy allocation at diagnosis.

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…Of these mutations, only WT1 mutations were found in MLL-rearranged AML, and these even at a low frequency. [93][94][95][96] In more than 60% of cases a molecular aberration has not been identified, which could indicate that an MLL rearrangement on its own could be sufficient to induce leukemia. However, 40% of cases do harbor a secondary aberration and therefore it is conceivable that Gilliland's hypothesis is still a valid model for at least the large subset of MLL-rearranged pediatric AML.…”

Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML

“…CD33 expression was also correlated with molecular prognostic factors. [16][17][18][19] FLT3/ITD, NPM1, and CEBPA mutations were detected in 15%, 6%, and 6% of evaluable samples, respectively. There was a statistically significant increase in FLT3/ITD prevalence with increasing CD33 expression when analyzed by quartiles (8% for Q1, 10% for Q2, 20% for Q3, and 22% for Q4; P Ͻ .001, Figure 1B) and for NPM1 mutations (1% for Q1, 5% for Q2, 7% for Q3, and 10% for Q4; P ϭ .001), but there was no definitive trend in CEBPA prevalence among quartiles (Table 1).…”

Pediatric Acute Myeloid Leukemia

“…(Balgobind, et al 2011a) The NPM1 and CEBPA double mutations confer good clinical outcome, allowing risk-stratification with the "good risk" cytogenetic subgroups. (Brown, et al 2007, Ho, et al 2009, Hollink, et al 2011, Hollink, et al 2009c In addition, the following type-1 mutations were identified: FLT3-internal tandem duplications (FLT3-ITD), found in ~30-40% of cases, FLT3-tyrosine kinase domain mutations (FLT3-TKD) in ~2% and N-or K-RAS mutations in ~15-20% of CN-AML cases. (Balgobind, et al 2011a, Goemans, et al 2005 WT1 mutations were found in 20-25% of pediatric CN-AML cases, in approximately half of the cases together with a FLT3-ITD, and in a quarter together with a RAS-mutation.…”

“…(Balgobind, et al 2011a, Marcucci, et al 2011 NPM1 and CEBPA gene mutations confer good clinical outcome, whereas mutations in the FLT3 and WT1-genes confer poor clinical outcome. (Ho, et al 2009, Ho, et al 2010b, Hollink, et al 2011, Hollink, et al 2009a, Hollink, et al 2009c, Zwaan, et al 2003a Figure 2 shows the distribution of type 1 and 2 abnormalities, as identified in >400 cases of pediatric AML. We have arbitrarily included the WT1 mutations as type I aberrations, however, their role in AML still has to be elucidated.…”