CEBPA Mutations in Younger Adults With Acute Myeloid Leukemia and Normal Cytogenetics: Prognostic Relevance and Analysis of Cooperating Mutations

2004 ◽  
Vol 22 (4) ◽  
pp. 624-633 ◽  
Author(s):  
Stefan Fröhling ◽  
Richard F. Schlenk ◽  
Ina Stolze ◽  
Jörg Bihlmayr ◽  
Axel Benner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hazard Ratio ◽  
Younger Adults ◽  
Prognostic Relevance ◽  
Remission Duration ◽  
Flt3 Mutations ◽  
Cebpa Mutations ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Purpose To assess the prognostic relevance of mutations in the CEBPA gene encoding CCAAT/enhancer binding protein alpha (C/EBPα) in a large prospective series of younger adults with acute myeloid leukemia (AML) and normal cytogenetics. Patients and Methods The entire CEBPA coding region was sequenced in diagnostic samples from 236 AML patients 16 to 60 years of age with normal cytogenetics who were uniformly treated on two consecutive protocols of the AML Study Group Ulm, and CEBPA mutation status was correlated with clinical outcome. Results CEBPA mutations were detected in 36 (15%) of 236 patients. Twenty-one (9%) of 236 patients had mutations predicted to result in loss of C/EBPα function. Remission duration and overall survival (OS) were significantly longer for the 36 patients with CEBPA mutations (P = .01 and P = .05, respectively). On multivariate analysis, wild-type CEBPA was an independent prognostic marker affecting remission duration (hazard ratio, 2.85; P = .01) and OS (hazard ratio, 1.87; P = .04). Analysis of cooperating mutations (both types of activating FLT3 mutations and MLL partial tandem duplications) showed that FLT3 mutations had no significant prognostic influence in patients with CEBPA mutations. Furthermore, there was no significant overlap between the subgroup of patients with CEBPA mutation with predicted loss of C/EBPα function and patients with FLT3 or MLL mutations, suggesting that CEBPA loss-of-function mutations define a distinct biologic subclass of AML with normal cytogenetics. Conclusion Mutant CEBPA predicts favorable prognosis and may improve risk stratification in AML patients with normal cytogenetics.

Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4372-4380 ◽  
Author(s):  
Stefan Fröhling ◽  
Richard F. Schlenk ◽  
Jochen Breitruck ◽  
Axel Benner ◽  
Sylvia Kreitmeier ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Serum Lactate Dehydrogenase ◽  
High Dose ◽  
Remission Duration ◽  
Flt3 Mutations ◽  
High Dose Cytarabine ◽  
Postremission Therapy ◽  
Normal Cytogenetics ◽  
Acute Myeloid

To assess the prognostic relevance of activating mutations of theFLT3 gene in homogeneously treated adults 16 to 60 years of age with acute myeloid leukemia (AML) and normal cytogenetics, pretreatment samples from 224 patients entered into 2 consecutive multicenter treatment trials were analyzed for FLT3internal tandem duplications (ITDs) and Asp835 mutations. Treatment included intensive double-induction therapy and postremission therapy with high cumulative doses of high-dose cytarabine. ITDs were detected in 32% of the patients and were related to de novo AML and to high white blood cell (WBC) counts, percentages of peripheral blood (PB) and bone marrow (BM) blasts, and serum lactate dehydrogenase levels. Asp835 mutations were present in 14% of the patients and were associated with WBC counts and percentages of PB and BM blasts that were higher than those of patients without FLT3mutations. With a median follow-up of 34 months, remission duration and overall survival (OS) were significantly shorter for patients with Asp835 mutations or an ITD than for those without FLT3 mutations (P = .03 and P = .0004, respectively). These results were attributable mainly to the negative prognostic effect of FLT3 ITDs. On multivariate analysis, mutantFLT3 was an independent marker affecting remission duration and OS (hazard ratio, 2.35 and 2.11, respectively). Fluorescence in situ hybridization did not detect monoallelicFLT3 deletions in ITD-positive patients. FLT3mutations identify a subset of young AML patients with normal cytogenetics who do not benefit from intensive chemotherapy, including double-induction and postremission therapy with high-dose cytarabine.

Patients with FLT3 Negative Acute Myeloid Leukemia and Normal Cytogenetic who Have the Combination Mutations (NPM1-/CEBPA-) Have Better Survival Than Patients Who Have the Combination Mutations (NPM1+/CEBPA+)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4874-4874
Author(s):  
Shamail Butt ◽  
Pascal Akl ◽  
Himanshu Bhardwaj ◽  
Samer A Srour ◽  
Terry Dunn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Intermediate Risk ◽  
Cebpa Mutations ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Abstract 4874 Introduction: Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults. About 50% of patients with AML have normal karyotype, and are categorized as intermediate risk group. However, the clinical behavior and response to treatment in this group is heterogeneous. As a result, there is strong interest in characterizing molecular genetic features in the intermediate-risk AML patients that might rectify their stratification risk. In this group, FLT3-ITD (Internal Tandem Duplication) and FLT3-TKD (Tyrosine Kinase Domain) mutations are known to confer unfavorable risk whereas NPM1 and CEBPA mutations are known to be favorable risk markers. The purpose of this study is to analyze the combination of NPM1 and CEBPA mutations in presence or absence of FLT3 mutations on prognosis of AML patients referred to the State's largest tertiary care center over a period of 10 years for the treatment of leukemia. Patients and Method: We performed a retrospective chart review of all patients with AML evaluated at University of Oklahoma Health Sciences Center between January 2000 and December 2010. Patient's age, gender, race, laboratory and clinical data as well as bone marrow biopsy and aspirate findings were reported. PCR and Fragment Analysis were conducted on all available DNA preserved bone marrow materials to test the FLT3, NPM1 and CEBPA mutations. For statistical analysis, Kaplan-Meyer curve was used. Results: A total of 239 patients were evaluated. Male to female ratio was 2/1. Median age at diagnosis was 46y. 21 out of the 239 patients were less than 18 year old. DNA samples were present on 132 patients and mutation analysis for FLT3, CEBPA and NPM1 was performed. Correlation between mutations and AML prognosis was determined. 67/132 (50.8 %) patients were categorized into intermediate risk group (majority of patients had normal cytogenetics). 14/67 (20.9%) pts were FLT3+ (FLT3-ITD or FLT3-TKD mutation). 17/67 (23.9%) were NPM1+. 7/67 (10.4%) were CEBPA +. Kaplan-Meier curve was used to identify cumulative proportion surviving over time. FLT3 presence or absence itself was not identified to be statistically significant (p 0.416) in terms of overall survival. Interestingly, presence or absence of combined NPM1/CEBPA mutation in FLT3 negative patients, among intermediate risk group, was found to be statistically significant (p<0.05) in determining overall survival. In this subgroup, presence of NPM1/CEBPA combination (NPM1+/CEBPA+) was associated with poor prognosis (figure 2, lower curve), while absence of NPM1/CEBPA combination (NPM1-/CEBPA-) carries a better prognosis (figure 2, upper curve). Conclusion: Results of our study highlight the importance of performing combinations of mutation analysis in evaluation of overall prognosis in AML patients. FLT3-/NPM1+ profile in patients with normal cytogenetics is thought to confer a favorable prognosis. We demonstrated in this study that using combination mutation analysis in patients with FLT3- can change the risk stratification in patients with intermediate risk group and might affect therapeutic interventions in this patient population. Larger prospective studies are needed in the future for further validation of our findings. Disclosures: No relevant conflicts of interest to declare.

Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3740-3746 ◽  
Author(s):  
Konstanze Döhner ◽  
Richard F. Schlenk ◽  
Marianne Habdank ◽  
Claudia Scholl ◽  
Frank G. Rücker ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Multivariable Analysis ◽  
Gene Mutations ◽  
Human Leukocyte ◽  
High Dose ◽  
Younger Adults ◽  
Normal Cytogenetics ◽  
Acute Myeloid

To assess the prognostic relevance of mutations in the NPM1 gene encoding a nucleocytoplasmic shuttle protein in younger adults with acute myeloid leukemia (AML) and normal cytogenetics, sequencing of NPM1 exon 12 was performed in diagnostic samples from 300 patients entered into 2 consecutive multicenter trials of the AML Study Group (AMLSG). Treatment included intensive double-induction therapy and consolidation therapy with high cumulative doses of high-dose cytarabine. NPM1 mutations were identified in 48% of the patients including 12 novel sequence variants, all leading to a frameshift in the C-terminus of the nucleophosmin 1 (NPM1) protein. Mutant NPM1 was associated with specific clinical, phenotypical, and genetic features. Statistical analysis revealed a significant interaction of NPM1 and FLT3 internal tandem duplications (ITDs). NPM1 mutations predicted for better response to induction therapy and for favorable overall survival (OS) only in the absence of FLT3 ITD. Multivariable analysis for OS revealed combined NPM1-mutated/FLT3 ITD–negative status, CEBPA mutation status, availability of a human leukocyte antigen (HLA)–compatible donor, secondary AML, and lactate dehydrogenase (LDH) as prognostic factors. In conclusion, NPM1 mutations in the absence of FLT3 ITD define a distinct molecular and prognostic subclass of young-adult AML patients with normal cytogenetics.

Prevalence and Prognostic Significance of FLT3 Mutations in Acute Myeloid Leukemia: Association of ITDs with Poor Outcome in Patients with Normal Cytogenetics.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2017-2017
Author(s):  
Michela Palmisano ◽  
Emanuela Ottaviani ◽  
Tiziana Grafone ◽  
Nicoletta Testoni ◽  
Stefania Paolini ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Wild Type ◽  
Poor Prognostic Factor ◽  
Flt3 Mutations ◽  
Blast Cells ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Acute Myeloid Leukemia (AML) is a difficult disease to treat, and better treatments are needed. Molecular targeted therapy represents a novel therapeutic approach. Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately one third of patients with de novo AML and have been implicated in its pathogenesis. The leukemic blasts of most AML patients have the internal tandem duplications (ITDs) in the juxtamembrane region or point mutations in Asp835 and Iso836 codons in the activation loop of the kinase domain (TKD) of the FLT3 receptor. Both mutations result in constitutive FLT3 receptor activity and may play a significant role in leukemogenesis. In this study we have analyzed the incidence and type of FLT3 mutations in a large series of newly diagnosed AML patients. Furthermore, we have evaluated the prognostic impact of FLT3 mutations. The FLT3/ITD was determined by polymerase chain reaction (PCR). The mutations of D835 and I836 codons were determined by PCR followed by restriction enzyme digestion (PCR-RFLP). For the estimation of the statistic significance of the differences in the clinical-biological characteristics, between the mutated patients and wild-type patients, it has been used the Student’s test t for independent data. The probabilities of overall survival (OS) and disease free survival (DFS) were analysed by Kaplan-Meier method; the differences of OS and DFS, between the mutated patients and wild-type patients, were assessed using the log-rank test. Both FLT3/ITD and FLT3/TKD mutations were found in 15%. Dual mutations were found in 2% of 126 patients. Among the FAB subtypes of AML, the rate of FLT3 aberrations was higher in M4 (27%) and M5 (26%). FLT3/ITD was associated to leukocytosis (106.8x10(e)9/l vs 30x10(e)9/l in FLT3-wt, p=0.015) and high percentage of circulating blast cells (82% vs 42% in FLT3-wt, p<0.0001). Differently, FLT3/TKD mutations were not associated with high white blood cells count and blast cells percentage. FLT3 mutations were more prevalent in patients with normal karyotype (51%). In this group, DFS and OS were significantly inferior for patients with FLT3/ITD than patients withouth mutations (0 vs 5, p=0.0032; 5 vs 9, p=0.049, respectively). We have identified the FLT3/ITD as an independent poor prognostic factor in AML patients with normal cytogenetics. Therefore, targeting FLT3 mutations represents a potential therapeutic target for AML. These results suggest that new treatment modalities, such as therapy with a FLT3 tyrosine kinase inhibitor, are clearly needed for this group of patients with “standard risk” profile.

Prognostic Significance of Partial Tandem Duplications of the MLL Gene in Adult Patients 16 to 60 Years Old With Acute Myeloid Leukemia and Normal Cytogenetics: A Study of the Acute Myeloid Leukemia Study Group Ulm

2002 ◽  
Vol 20 (15) ◽  
pp. 3254-3261 ◽  
Author(s):  
Konstanze Döhner ◽  
Karen Tobis ◽  
Regina Ulrich ◽  
Stefan Fröhling ◽  
Axel Benner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Adult Patients ◽  
Mll Gene ◽  
Remission Duration ◽  
Normal Cytogenetics ◽  
Tandem Duplications ◽  
Acute Myeloid

PURPOSE: To evaluate the incidence and clinical significance of partial tandem duplications (PTDs) of the mixed lineage leukemia (MLL) gene in a large series of newly diagnosed adult patients (16 to 60 years old) with acute myeloid leukemia (AML) intensively treated within the multicenter treatment trials AML-HD93 and AML-HD98A. PATIENTS AND METHODS: Identification of MLL PTD was performed centrally using Southern blot analysis in pretreatment samples from 525 of 683 assessable patients. PTD was confirmed by polymerase chain reaction (PCR) and sequencing of the PCR products. RESULTS: MLL PTD was identified in none of the 129 patients with t(8;21), inv(16), and t(15;17); in 19 (7.7%) of 247 patients with normal karyotype; and in 10 (8.5%) of 119 patients with all other abnormalities, with 30 cases of t(11q23) excluded. In the group of patients with a normal karyotype, there was no difference in the presenting clinical features between the PTD-positive and the PTD-negative cases. Sixteen (89%) of the 18 assessable PTD-positive patients and 158 (78%) of the 203 PTD-negative patients achieved a complete remission. After a median follow-up time of 19 months, 11 of the 16 PTD-positive patients relapsed compared with 54 of the 158 PTD-negative patients; the median remission durations of the PTD-positive and the PTD-negative groups were 7.75 months and 19 months, respectively (P < .001). Multivariate analysis identified the MLL PTD status as the single prognostic factor for remission duration. CONCLUSION: Within the subgroup of young adult AML patients with normal karyotype, MLL PTD is associated with short remission duration.

scholarly journals Characterization of CEBPA Mutations and Polymorphisms and their Prognostic Relevance in De Novo Acute Myeloid Leukemia Patients

2015 ◽  
Vol 16 (9) ◽  
pp. 3785-3792 ◽  
Author(s):  
Santhi Sarojam ◽  
Sureshkumar Raveendran ◽  
Sangeetha Vijay ◽  
Jayadevan Sreedharan ◽  
Geetha Narayanan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Relevance ◽  
Cebpa Mutations ◽  
Acute Myeloid

Outcome of Induction and Postremission Therapy in Younger Adults With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study

2005 ◽  
Vol 23 (3) ◽  
pp. 482-493 ◽  
Author(s):  
Sherif S. Farag ◽  
Amy S. Ruppert ◽  
Krzysztof Mrózek ◽  
Robert J. Mayer ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
High Dose ◽  
Younger Adults ◽  
Group I ◽  
Postremission Therapy ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Purpose Evaluate the outcome of induction and postremission therapy in adults younger than 60 years with normal cytogenetics acute myeloid leukemia (AML). Patients and Methods In 490 patients, induction included cytarabine and daunorubicin (AD) or cytarabine and escalated doses of daunorubicin and etoposide ± PSC-833 (ADE/ADEP). Intensification included one cycle of high-dose cytarabine (HDAC) followed by etoposide/cyclophosphamide and mitoxantrone/diaziquone (group I), three HDAC cycles (group II), four intermediate-dose cytarabine (IDAC) or HDAC cycles (group III), or one HDAC/etoposide cycle and autologous stem-cell transplantation (ASCT; group IV). Results Of 350 patients receiving AD, 73% achieved complete remission (CR), compared with 82% of 140 receiving ADE/ADEP (P = .04). Splenomegaly was associated with a lower CR rate (P < .001), and ADE/ADEP, with a higher CR rate in younger patients (P = .005). The 5-year disease-free survival (DFS) rate was 28% each for intensification groups I and II, compared with 41% and 45% for groups III and IV, respectively (P = .02). The 5-year cumulative incidence of relapse (CIR) was 62% and 67% for groups I and II, respectively, compared with 54% and 44% for groups III and IV, respectively (P = .049). The type of postremission intensification remained significant for DFS and CIR in multivariable analysis. Conclusion In younger adults with normal cytogenetics AML, splenomegaly predicts a lower CR rate, and the postremission strategies of either four cycles of I/HDAC or one cycle of HDAC/etoposide followed by ASCT are associated with improved DFS and reduced relapse compared with therapies that include fewer cycles of cytarabine or no transplantation.

scholarly journals Nanopore Targeted Sequencing for Rapid Gene Mutations Detection in Acute Myeloid Leukemia

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1026 ◽  
Author(s):  
Cumbo ◽  
Minervini ◽  
Orsini ◽  
Anelli ◽  
Zagaria ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Cost ◽  
Gene Mutations ◽  
Predictive Biomarkers ◽  
Molecular Testing ◽  
Sequencing Analysis ◽  
Cebpa Mutations ◽  
Targeted Gene Sequencing ◽  
Acute Myeloid

Acute myeloid leukemia (AML) clinical settings cannot do without molecular testing to confirm or rule out predictive biomarkers for prognostic stratification, in order to initiate or withhold targeted therapy. Next generation sequencing offers the advantage of the simultaneous investigation of numerous genes, but these methods remain expensive and time consuming. In this context, we present a nanopore-based assay for rapid (24 h) sequencing of six genes (NPM1, FLT3, CEBPA, TP53, IDH1 and IDH2) that are recurrently mutated in AML. The study included 22 AML patients at diagnosis; all data were compared with the results of S5 sequencing, and discordant variants were validated by Sanger sequencing. Nanopore approach showed substantial advantages in terms of speed and low cost. Furthermore, the ability to generate long reads allows a more accurate detection of longer FLT3 internal tandem duplications and phasing double CEBPA mutations. In conclusion, we propose a cheap, rapid workflow that can potentially enable all basic molecular biology laboratories to perform detailed targeted gene sequencing analysis in AML patients, in order to define their prognosis and the appropriate treatment.

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