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Prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group.

Matsuo H, Kajihara M, Tomizawa D, Watanabe T, Saito AM, Fujimoto J, Horibe K, Kodama K, Tokumasu M, Itoh H, Nakayama H, Kinoshita A, Taga T, Tawa A, Taki T, Tanaka S, Adachi S - Blood Cancer J (2014)

Bottom Line: We found that 47 (14.9%) of the 315 evaluable patients harbored mutations in CEBPA; 26 cases (8.3%) harbored a single mutation (CEBPA-single) and 21 (6.7%) harbored double or triple mutations (CEBPA-double).After excluding core-binding factor-AML cases, patients harboring CEBPA mutations showed better overall survival (OS; P=0.048), but not event-free survival (EFS; P=0.051), than wild-type patients.CEBPA-double remained an independent favorable factor for EFS (HR: 0.28; P=0.04) in the normal karyotype cohort.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Health Sciences, Kyoto University, Kyoto, Japan.

ABSTRACT
CCAAT/enhancer-binding protein alpha (CEBPA) mutations are a favorable prognostic factor in adult acute myeloid leukemia (AML) patients; however, few studies have examined their significance in pediatric AML patients. Here we examined the CEBPA mutation status and clinical outcomes of pediatric AML patients treated in the AML-05 study. We found that 47 (14.9%) of the 315 evaluable patients harbored mutations in CEBPA; 26 cases (8.3%) harbored a single mutation (CEBPA-single) and 21 (6.7%) harbored double or triple mutations (CEBPA-double). After excluding core-binding factor-AML cases, patients harboring CEBPA mutations showed better overall survival (OS; P=0.048), but not event-free survival (EFS; P=0.051), than wild-type patients. Multivariate analysis identified CEBPA-single and CEBPA-double as independent favorable prognostic factors for EFS in the total cohort (hazard ratio (HR): 0.47 and 0.33; P=0.02 and 0.01, respectively). CEBPA-double was also an independent favorable prognostic factor for OS (HR: 0.30; P=0.04). CEBPA-double remained an independent favorable factor for EFS (HR: 0.28; P=0.04) in the normal karyotype cohort. These results suggest that CEBPA mutations, particularly CEBPA-double, are an independent favorable prognostic factor in pediatric AML patients, which will have important implications for risk-stratified therapy.

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Kaplan–Meier survival curves showing EFS and OS from the time of diagnosis according to CEBPA mutation status. (a) EFS and (b) OS of patients harboring CEBPA mutations, patients harboring WT CEBPA (excluding core-binding factor-acute myeloid leukemia (CBF-AML) cases (WT non-CBF)) and patients with CBF-AML. (c) EFS and (d) OS of patients harboring a single CEBPA mutation (CEBPA-single), patients harboring double or triple CEBPA mutations (CEBPA-double), WT patients (excluding CBF-AML cases (WT non-CBF)) and patients with CBF-AML. P-values were determined using the log-rank test.
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fig2: Kaplan–Meier survival curves showing EFS and OS from the time of diagnosis according to CEBPA mutation status. (a) EFS and (b) OS of patients harboring CEBPA mutations, patients harboring WT CEBPA (excluding core-binding factor-acute myeloid leukemia (CBF-AML) cases (WT non-CBF)) and patients with CBF-AML. (c) EFS and (d) OS of patients harboring a single CEBPA mutation (CEBPA-single), patients harboring double or triple CEBPA mutations (CEBPA-double), WT patients (excluding CBF-AML cases (WT non-CBF)) and patients with CBF-AML. P-values were determined using the log-rank test.

Mentions: We first analyzed the clinical outcomes of patients harboring CEBPA mutations and then compared them with the outcomes of CBF-AML patients and patients without CBF or CEBPA mutations (denoted ‘WT non-CBF') (Figure 2). The CBF-AML group included AML patients harboring t(8;21)(q22;q22) along with inv(16)(p13.1q22) or its variant t(16;16)(p13.1;q22). Seven CBF-AML patients harboring CEBPA mutations were categorized as ‘CEBPA-mutant'. Patients harboring CEBPA mutations showed better OS (P=0.048), but not EFS (P=0.051), than WT non-CBF patients (Figures 2a and b). However, patients with CEBPA mutations showed poorer OS (P=0.0006) than patients with CBF-AML. Furthermore, we examined whether the number of CEBPA mutations had an impact on prognosis (Figures 2c and d). CEBPA-double patients did not show significantly better EFS and OS than CEBPA-single patients (P=0.33 each). There was also no significant difference in EFS and OS between CEBPA-double patients and WT non-CBF patients (P=0.055 and P=0.057, respectively).


Prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group.

Matsuo H, Kajihara M, Tomizawa D, Watanabe T, Saito AM, Fujimoto J, Horibe K, Kodama K, Tokumasu M, Itoh H, Nakayama H, Kinoshita A, Taga T, Tawa A, Taki T, Tanaka S, Adachi S - Blood Cancer J (2014)

Kaplan–Meier survival curves showing EFS and OS from the time of diagnosis according to CEBPA mutation status. (a) EFS and (b) OS of patients harboring CEBPA mutations, patients harboring WT CEBPA (excluding core-binding factor-acute myeloid leukemia (CBF-AML) cases (WT non-CBF)) and patients with CBF-AML. (c) EFS and (d) OS of patients harboring a single CEBPA mutation (CEBPA-single), patients harboring double or triple CEBPA mutations (CEBPA-double), WT patients (excluding CBF-AML cases (WT non-CBF)) and patients with CBF-AML. P-values were determined using the log-rank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219441&req=5

fig2: Kaplan–Meier survival curves showing EFS and OS from the time of diagnosis according to CEBPA mutation status. (a) EFS and (b) OS of patients harboring CEBPA mutations, patients harboring WT CEBPA (excluding core-binding factor-acute myeloid leukemia (CBF-AML) cases (WT non-CBF)) and patients with CBF-AML. (c) EFS and (d) OS of patients harboring a single CEBPA mutation (CEBPA-single), patients harboring double or triple CEBPA mutations (CEBPA-double), WT patients (excluding CBF-AML cases (WT non-CBF)) and patients with CBF-AML. P-values were determined using the log-rank test.
Mentions: We first analyzed the clinical outcomes of patients harboring CEBPA mutations and then compared them with the outcomes of CBF-AML patients and patients without CBF or CEBPA mutations (denoted ‘WT non-CBF') (Figure 2). The CBF-AML group included AML patients harboring t(8;21)(q22;q22) along with inv(16)(p13.1q22) or its variant t(16;16)(p13.1;q22). Seven CBF-AML patients harboring CEBPA mutations were categorized as ‘CEBPA-mutant'. Patients harboring CEBPA mutations showed better OS (P=0.048), but not EFS (P=0.051), than WT non-CBF patients (Figures 2a and b). However, patients with CEBPA mutations showed poorer OS (P=0.0006) than patients with CBF-AML. Furthermore, we examined whether the number of CEBPA mutations had an impact on prognosis (Figures 2c and d). CEBPA-double patients did not show significantly better EFS and OS than CEBPA-single patients (P=0.33 each). There was also no significant difference in EFS and OS between CEBPA-double patients and WT non-CBF patients (P=0.055 and P=0.057, respectively).

Bottom Line: We found that 47 (14.9%) of the 315 evaluable patients harbored mutations in CEBPA; 26 cases (8.3%) harbored a single mutation (CEBPA-single) and 21 (6.7%) harbored double or triple mutations (CEBPA-double).After excluding core-binding factor-AML cases, patients harboring CEBPA mutations showed better overall survival (OS; P=0.048), but not event-free survival (EFS; P=0.051), than wild-type patients.CEBPA-double remained an independent favorable factor for EFS (HR: 0.28; P=0.04) in the normal karyotype cohort.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Health Sciences, Kyoto University, Kyoto, Japan.

ABSTRACT
CCAAT/enhancer-binding protein alpha (CEBPA) mutations are a favorable prognostic factor in adult acute myeloid leukemia (AML) patients; however, few studies have examined their significance in pediatric AML patients. Here we examined the CEBPA mutation status and clinical outcomes of pediatric AML patients treated in the AML-05 study. We found that 47 (14.9%) of the 315 evaluable patients harbored mutations in CEBPA; 26 cases (8.3%) harbored a single mutation (CEBPA-single) and 21 (6.7%) harbored double or triple mutations (CEBPA-double). After excluding core-binding factor-AML cases, patients harboring CEBPA mutations showed better overall survival (OS; P=0.048), but not event-free survival (EFS; P=0.051), than wild-type patients. Multivariate analysis identified CEBPA-single and CEBPA-double as independent favorable prognostic factors for EFS in the total cohort (hazard ratio (HR): 0.47 and 0.33; P=0.02 and 0.01, respectively). CEBPA-double was also an independent favorable prognostic factor for OS (HR: 0.30; P=0.04). CEBPA-double remained an independent favorable factor for EFS (HR: 0.28; P=0.04) in the normal karyotype cohort. These results suggest that CEBPA mutations, particularly CEBPA-double, are an independent favorable prognostic factor in pediatric AML patients, which will have important implications for risk-stratified therapy.

Show MeSH
Related in: MedlinePlus