Comprehensive Genetic Screening of Chronic Myelomonocytic Leukemias (CMML)
Raphaël ItzyksonOlivier KosmiderAline RennevilleMargot MorabitoCéline BerthonLionel AdèsPierre FenauxOdile Beyne‐RauzyThorsten BraunF. DreyfusNicholas C.P. CrossClaude PreudhommeOlivier BernardMichaëla FontenayWilliam VainchenkerNathalie DroinÉric Solary
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Keywords:
Chronic myelomonocytic leukemia
NPM1
CEBPA
Sanger sequencing
Decitabine
To evaluate the frequency of the nucleophosmin (NPM1) gene and the CCAAT/enhancer binding protein α gene (CEBPA) through polymerase chain reaction (PCR) array in pediatric patients with cytogenetically normal acute myeloid leukemia (CN-AML) and explore the clinical significances of these mutations.Between August 2009 and December 2012, 30 children (<16 years old) with newly diagnosed CN-AML were included. The clinical characteristics were analyzed in these patients. PCR combined with direct sequencing was used to detect NPM1, CEBPA gene mutations. All the data were statistically analyzed using SPSS17.0 software.The gene mutations were detected in each of the 30 patients. NPM1 mutation was positive in three patients (10%) with type A mutation, while CEBPA mutation was positive in two patients (6.7%) with double mutations (TAD, bZIP) . Besides, FLT3/ITD mutation was positive in three patients. Patients with NPM1 or FLT3/ITD had a significantly elevated diagnostic WBC count with a median diagnostic WBC count of 102.80×10(9)/L compared with 18.56×10(9)/L for the patients without mutations(t = 2.353, P = 0.043), as well as the marrow blast percentage (94.0% vs. 80.0%, t = 3.804, P = 0.002). The complete remission was achieved in all the 3 patients with NPM1 mutations and 2 patients with CEBPA mutations. All the patients with these mutations also achieved 2-year event-free survival (EFS) and 2-year overall survival (OS), while 2-year EFS and 2-year OS of the other patients were (40.1 ± 11.2)% and (51.8 ± 10.9)% (P = 0.044, 0.091, respectively).NPM1 and CEBPA mutations may indicate a favorable prognosis in pediatric CN-AML.
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Summary Older adult patients (≥60 years) with acute myeloid leukaemia ( AML ) are generally considered to be poor‐risk and there is limited information available regarding risk stratification based on molecular characterization in this age group, particularly for the double‐mutant CEBPA ( CEBPA DM ) genotype. To investigate whether a molecular favourable‐risk genotype can be identified, we investigated CEBPA , NPM1 and FLT3 status and prognostic impact in a cohort of 301 patients aged 60 years or more with intermediate‐risk cytogenetics, all treated intensively. Overall survival ( OS ) at 1 year was highest in the 12 patients (4%) that were CEBPA DM compared to the 76 (28%) with a mutant NPM1 and wild‐type FLT3 ( NPM1 MUT FLT3 WT ) genotype or all other patients (75%, 54%, 33% respectively), with median survival 15·2, 13·6 and 6·6 months, although the benefit was short‐term ( OS at 3 years 17%, 29%, 12% respectively). Combination of the CEBPA DM and NPM1 MUT FLT3 WT genotype patients defined a molecular group with favourable prognosis ( P < 0·0001 in multivariate analysis), with 57% of patients alive at 1 year compared to 33% for all other patients. Knowledge of genotype in older cytogenetically intermediate‐risk patients might influence therapy decisions.
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While a substantial amount of data on gene mutations related to acute myeloid leukemia (AML) prognosis from western and other populations have been reported, these studies largely describe one or two genes. Additionally, in southwest China, only insufficient data exist regarding FLT3-ITD, FLT3-TKD, NPM1, C-KIT, DNMT3A, and CEBPA mutations have been widely used in clinical settings. Therefore, a comprehensive study about these mutations of clinical importance in the prognosis of AML in western China is necessary. In a cohort of 255 patients with de novo AML, we retrospectively analyzed the prevalence of the six gene mutations, and then we assessed the results in conjunction with clinical characteristics and treatment responses. As for the frequencies of these mutations, the NPM1 mutation occurred most frequently (17.7 %; 42/237), followed by the CEBPA mutation (15.0 %; 19/127) and the FLT3-ITD mutation (10.2 %; 25/244). The frequencies of the FLT3-TKD, DNMT3A, and C-KIT mutations were 3.7 % (9/234), 4.0 % (9/225) and 4.2 % (10/238), respectively. These mutations were closely related to clinical characteristics including FAB classification, gender and age, hemogram, blasts (%), fusion genes, and immunophenotypes. Additionally, a higher complete remission (CR) rate was found in NPM1-mutated patients. The occurrence of these mutations is variable among different countries and regions worldwide, which may provide clues to the etiology of AML. Besides, we identified new clinical characteristics that advance our understanding of these mutations and further clarify the involvement of these mutations in the development of leukemia.
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ObjectivesTo explore NPM1, FLT3-ITD, CEBPA, and c-kit mutations in patients with acute myeloid leukemia (AML) from Chinese population.MethodsIn this study, we retrospectively analyzed the prevalence and clinical profile of NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 patients with de novo AML.ResultsThe frequencies of NPM1, FLT3-ITD, c-kit, and CEBPA mutations were 15.4, 14.0, 7.64, and 25.6%, respectively. The occurrence rate of NPM1 mutations increased with age in patients younger than 60 years. NPM1, c-kit, and CEBPA mutations were all associated with French-American-British subtypes. Patients with NPM1 mutations and FLT3-ITD presented with higher peripheral white blood cell counts and marrow blast percentages.ConclusionBoth this and previous studies may suggest low frequencies of NPM1 and FLT3-ITD mutations in AML patients from the Chinese population, and they may have a synergistic function in stimulating proliferation of leukemia cells.
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Hypomethylating agents have activity in myelodysplastic syndrome (MDS) and have received approval for the treatment of both MDS and chronic myelomonocytic leukemia (CMML). The specific efficacy in CMML has not been detailed in a large number of patients. The aim of the study was to evaluate the activity and safety of decitabine in CMML.Nineteen adults with a diagnosis of CMML treated on decitabine studies were analyzed. Decitabine was given at 100 mg/m(2) per course every 4 weeks. The median number of courses given was 9 (range, 1-18).Overall, 11 patients (58%) achieved complete response (CR) and 2 (11%) had hematologic improvement (HI), for an overall response rate of 69% according to the modified International Working Group (IWG) criteria. Median survival was 19 months. Severe (grade 3-4) extramedullary side effects were rare.Decitabine is active in CMML. Studies of combinations of decitabine with topoisomerase I inhibitors or other active anti-CMML agents are indicated.
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Abstract BACKGROUND. Therapy for patients with myelodysplastic syndrome (MDS) with hypomethylating agents, like decitabine and 5‐azacitidine, has produced favorable results. In this study, the authors update their experience with decitabine in patients with MDS and analyze the cytogenetic response patterns and prognostic factors associated with decitabine therapy. METHODS. One hundred fifteen patients with higher risk MDS who received treatment with decitabine were reviewed. Patients received decitabine 100 mg/m 2 per course every 4 weeks in 3 different schedules: 1) 20 mg/m 2 intravenously daily × 5, 2) 20 mg/m 2 subcutaneously daily × 5, and 3) 10 mg/m 2 intravenously daily × 10. Decitabine was given for a median of ≥7 courses (range, 1–23 courses). RESULTS. Overall, 80 patients (70%) achieved a response according to the modified International Working Group criteria (IWG): complete response (CR), 40 patients (35%); partial response, 2 patients (2%); bone marrow CR with or without other hematologic improvements (HI), 26 patients (23%); and other HI, 12 patients (10%). Cytopenias were improved in 50% of patients. The median remission duration was 20 months, and the median survival was 22 months. Mortality was 3% at 6 weeks and 7% at 3 months. In a multivariate analysis, poor prognostic factors for achieving IWG CR were MDS (vs chronic myelomonocytic leukemia), longer duration of MDS, and prior MDS therapy. For survival, independent adverse prognostic factors were chromosome 5 and/or 7 abnormalities, older age, and prior MDS therapy (excluding growth factors). CONCLUSIONS. The longer term experience with decitabine in MDS was favorable. Pretreatment prognostic factors may predict the outcome of patients who receive decitabine therapy for MDS. Cancer 2007. © 2006 American Cancer Society.
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