scholarly journals Favorable Prognostic Impact ofNPM1Mutations in Older Patients With Cytogenetically Normal De Novo Acute Myeloid Leukemia and Associated Gene- and MicroRNA-Expression Signatures: A Cancer and Leukemia Group B Study

2010 ◽  
Vol 28 (4) ◽  
pp. 596-604 ◽  
Author(s):  
Heiko Becker ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Expression Profiles ◽  
Age Groups ◽  
Microrna Expression ◽  
Prognostic Impact ◽  
Group B ◽  
Leukemia Group ◽  
Acute Myeloid

PurposeTo analyze the prognostic significance of NPM1 mutations, and the associated gene- and microRNA-expression signatures in older patients with de novo, cytogenetically normal acute myeloid leukemia (CN-AML) treated with intensive chemotherapy.Patients and MethodsOne hundred forty-eight adults age ≥ 60 years with de novo CN-AML, enrolled onto Cancer and Leukemia Group B protocols 9720 and 10201, were studied at diagnosis for NPM1, FLT3, CEBPA, and WT1 mutations, and gene- and microRNA-expression profiles.ResultsPatients with NPM1 mutations (56%) had higher complete remission (CR) rates (84% v 48%; P < .001) and longer disease-free survival (DFS; P = .047; 3-year rates, 23% v 10%) and overall survival (OS; P < .001; 3-year rates, 35% v 8%) than NPM1 wild-type patients. In multivariable analyses, NPM1 mutations remained independent predictors for higher CR rates (P < .001) and longer DFS (P = .004) and OS (P < .001), after adjustment for other prognostic clinical and molecular variables. Unexpectedly, the prognostic impact of NPM1 mutations was mainly observed in patients ≥ 70 years. Gene- and microRNA-expression profiles associated with NPM1 mutations were similar across older patient age groups and similar to those in younger (< 60 years) patients with CN-AML. These profiles were characterized by upregulation of HOX genes and their embedded microRNAs and downregulation of the prognostically adverse MN1, BAALC, and ERG genes.ConclusionNPM1 mutations have favorable prognostic impact in older patients with CN-AML, especially those age ≥ 70 years. The gene- and microRNA-expression profiles suggest that NPM1 mutations constitute a marker defining a biologically homogeneous entity in CN-AML that might be treated with specific and/or targeted therapies across age groups.

scholarly journals BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5660-5669 ◽  
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Expression Profiles ◽  
Microrna Expression ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Distinct Gene ◽  
Acute Myeloid

AbstractBAALC and ERG expression levels are prognostic markers in younger (< 60 years) cytogenetically normal acute myeloid leukemia (CN-AML) adults; their prognostic impact in older (≥ 60 years) patients requires further investigation. We evaluated pretreatment expression of BAALC and ERG in 158 de novo patients treated on cytarabine/daunorubicin-based protocols. The patients were also characterized for other established molecular prognosticators. Low BAALC and ERG expression levels were associated with better outcome in univariable and multivariable analyses. Expression levels of both BAALC and ERG were the only factors significantly associated with overall survival upon multivariable analysis. To gain biological insights, we derived gene expression signatures associated with BAALC and ERG expression in older CN-AML patients. Furthermore, we derived the first microRNA expression signatures associated with the expression of these 2 genes. In low BAALC expressers, genes associated with undifferentiated hematopoietic precursors and unfavorable outcome predictors were down-regulated, whereas HOX genes and HOX-gene–embedded microRNAs were up-regulated. Low ERG expressers presented with down-regulation of genes involved in the DNA-methylation machinery, and up-regulation of miR-148a, which targets DNMT3B. We conclude that in older CN-AML patients, low BAALC and ERG expression associates with better outcome and distinct gene and microRNA expression signatures that could aid in identifying new targets and novel therapeutic strategies for older patients.

scholarly journals Prognostic Importance ofMN1Transcript Levels, and Biologic Insights FromMN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

2009 ◽  
Vol 27 (19) ◽  
pp. 3198-3204 ◽  
Author(s):  
Christian Langer ◽  
Guido Marcucci ◽  
Kelsi B. Holland ◽  
Michael D. Radmacher ◽  
Kati Maharry ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Microrna Expression ◽  
Wild Type ◽  
Prognostic Importance ◽  
Group B ◽  
Leukemia Group ◽  
Tandem Duplications ◽  
Acute Myeloid

PurposeTo determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene– and microRNA–expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML).Patients and MethodsMN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials.ResultsHigher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation.ConclusionMN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.

scholarly journals Age-Related Prognostic Impact of Different Types of DNMT3A Mutations in Adults With Primary Cytogenetically Normal Acute Myeloid Leukemia

2012 ◽  
Vol 30 (7) ◽  
pp. 742-750 ◽  
Author(s):  
Guido Marcucci ◽  
Klaus H. Metzeler ◽  
Sebastian Schwind ◽  
Heiko Becker ◽  
Kati Maharry ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Disease Free Survival ◽  
Microrna Expression ◽  
Molecular Characteristics ◽  
Prognostic Impact ◽  
Younger Patients ◽  
Acute Myeloid

Purpose To determine the frequency of DNMT3A mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in primary cytogenetically normal acute myeloid leukemia (CN-AML). Patients and Methods Four hundred fifteen previously untreated adults were analyzed for DNMT3A mutations and established prognostic gene mutations and expression markers. Gene- and microRNA-expression profiles were derived using microarrays. Results Younger (< 60 years; n = 181) and older (≥ 60 years; n = 234) patients had similar frequencies of DNMT3A mutations (35.3% v 33.3%). Missense mutations affecting arginine codon 882 (R882-DNMT3A) were more common (n = 92; 62%) than those affecting other codons (non–R882-DNMT3A). DNMT3A-mutated patients did not differ regarding complete remission rate, but had shorter disease-free survival (DFS; P = .03) and, by trend, overall survival (OS; P = .07) than DNMT3A–wild-type patients. In multivariable analyses, DNMT3A mutations remained associated with shorter DFS (P = .01), but not with shorter OS. When analyzed separately, the two DNMT3A mutation types had different significance by age group. Younger patients with non–R882-DNMT3A mutations had shorter DFS (P = .002) and OS (P = .02), whereas older patients with R882-DNMT3A mutations had shorter DFS (P = .005) and OS (P = .002) after adjustment for other clinical and molecular prognosticators. Gene- and microRNA-expression signatures did not accurately predict DNMT3A mutational status. Conclusion DNMT3A mutations are frequent in CN-AML, and their clinical significance seems to be age dependent. DNMT3A-R882 mutations are associated with adverse prognosis in older patients, and non–R882-DNMT3A mutations are associated with adverse prognosis in younger patients. Low accuracy of gene- and microRNA-expression signatures in predicting DNMT3A mutation status suggested that the role of these mutations in AML remains to be elucidated.

scholarly journals Mutations of the Wilms tumor 1 gene (WT1) in older patients with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study

Blood ◽  
2010 ◽  
Vol 116 (5) ◽  
pp. 788-792 ◽  
Author(s):  
Heiko Becker ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Age Groups ◽  
Gene Expression Signature ◽  
Specific Marker ◽  
Prognostic Impact ◽  
Wilms Tumor 1 ◽  
Group B ◽  
Acute Myeloid

We previously reported the adverse prognostic impact of Wilms tumor 1 gene (WT1) mutations in younger adult cytogenetically normal acute myeloid leukemia (CN-AML). Here, we investigated 243 older (≥ 60 years) primary CN-AML patients. WT1 mutated (WT1mut) patients (7%) had FLT3-ITD more frequently (P < .001), lower hemoglobin (P = .01), higher white blood cell count (P = .03) and percentage blood blasts (P = .03), and a shorter overall survival (P = .08) than WT1 wild-type (WT1wt) patients. Comparing older and younger WT1mut patients, they had similar pretreatment characteristics and outcome. By contrast, among WT1wt CN-AML, younger patients had a significantly better outcome. A WT1 mutation-associated gene-expression signature, reported here for the first time, included CD96, a leukemia stem cell-specific marker, and genes involved in gene regulation (eg, MLL, PML, and SNRPN) and in proliferative and metabolic processes (eg, INSR, IRS2, and PRKAA1), supporting the role of mutated WT1 in deregulating multiple homeostatic processes. Our results indicate that WT1mut CN-AML represents a distinct entity with poor treatment response across age groups. This study has been registered at www.clinicaltrials.gov as #NCT00900224.

BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1613-1618 ◽  
Author(s):  
Claudia D. Baldus ◽  
Stephan M. Tanner ◽  
Amy S. Ruppert ◽  
Susan P. Whitman ◽  
Kellie J. Archer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Free Survival ◽  
De Novo Aml ◽  
Normal Cytogenetics ◽  
Group B ◽  
Leukemia Group ◽  
Acute Myeloid

AbstractCytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). Of adults with de novo AML, 45% lack cytogenetic abnormalities, and identification of predictive molecular markers might improve therapy. We studied the prognostic impact of BAALC (Brain And Acute Leukemia, Cytoplasmic), a novel gene involved in leukemia, in 86 de novo AML patients with normal cytogenetics who were uniformly treated on Cancer and Leukemia Group B 9621. BAALC expression was determined by comparative real-time reverse transcriptase–polymerase chain reaction in pretreatment blood samples, and patients were dichotomized at BAALC's median expression into low and high expressers. Low expressers had higher white counts (P = .03) and more frequent French-American-British M5 morphology (P = .007). Compared to low expressers, high BAALC expressers showed significantly inferior overall survival (OS; median, 1.7 vs 5.8 years, P = .02), event-free survival (EFS; median, 0.8 vs 4.9 years, P = .03), and disease-free survival (DFS; median, 1.4 vs 7.3 years, P = .03). Multivariable analysis confirmed high BAALC expression as an independent risk factor. For high BAALC expressers the hazard ratio of an event for OS, EFS, and DFS was respectively 2.7, 2.6, and 2.2. We conclude that high BAALC expression predicts an adverse prognosis and may define an important risk factor in AML with normal cytogenetics.

Acute myeloid leukemia-type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndrome as defined by French-American-British criteria: a Cancer and Leukemia Group B Study.

1996 ◽  
Vol 14 (9) ◽  
pp. 2486-2494 ◽  
Author(s):  
S H Bernstein ◽  
V L Brunetto ◽  
F R Davey ◽  
D Wurster-Hill ◽  
R J Mayer ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Refractory Anemia ◽  
Newly Diagnosed ◽  
History Of ◽  
De Novo Aml ◽  
Group B ◽  
Leukemia Group ◽  
French American British ◽  
Acute Myeloid

PURPOSE To determine the treatment outcome of standard acute myeloid leukemia (AML)-type chemotherapy in a subset of patients with newly diagnosed myelodysplastic syndromes (MDS) compared with that of patients with de novo AML as defined using French-American-British (FAB) criteria. In addition, to determine the pretreatment variables having prognostic significance for treatment outcome in patients with MDS. PATIENTS AND METHODS Nine hundred seven newly diagnosed patients with no history of cytopenias having a local institutional de novo AML successfully karyotyped and treated on Cancer and Leukemia Group B (CALGB) protocols for AML from 1984 to 1992. Thirty-three of the 907 patients were reclassified as having MDS on central pathology review using FAB criteria and form the basis of this analysis. RESULTS The treatment outcomes for patients with MDS and AML were similar; the complete remission (CR) rate was 79% and 68%, respectively (P = .37); median CR duration was 11 and 15 months, respectively (P = .28); and median survival was 13 and 16 months, respectively (P = .72). For the MDS patients, there were no prognostic variables for CR rate identified. For CR duration, only the Sanz classification had prognostic value. The prognostic factors for survival in a univariate analysis included age, WBC count, Sanz classification, and percent blood blasts. In a proportional hazards analysis of survival, age greater than 60 years and WBC less than 2.6 x 10(9)/L were adverse prognostic factors. CONCLUSION In patients with no known history of cytopenias who are treated intensively at diagnosis, the FAB distinctions between MDS (refractory anemia with excess blasts and refractory anemia with excess blasts in transformation) and AML appear to have little therapeutic relevance.

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