FLT3 mutations have no prognostic impact in elderly patients with acute myeloid leukemia and normal karyotype

2009 ◽  
Vol 84 (8) ◽  
pp. 532-534 ◽  
Author(s):  
Felicetto Ferrara ◽  
Clelia Criscuolo ◽  
Cira Riccardi ◽  
Tiziana Izzo ◽  
Mariangela Pedata ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Flt3 Mutations ◽  
Acute Myeloid

Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3280-3288 ◽  
Author(s):  
Stefan Fröhling ◽  
Richard F. Schlenk ◽  
Sabine Kayser ◽  
Martina Morhardt ◽  
Axel Benner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Factors Affecting ◽  
Acute Myeloid

Abstract To assess the prognostic impact of cytogenetics in elderly patients with acute myeloid leukemia (AML) receiving intensive induction and consolidation treatment according to a single protocol specifically designed for patients above age 60, pretreatment samples from 361 patients registered for the AML HD98-B trial of the German-Austrian AML Study Group were analyzed by chromosome banding and fluorescence in situ hybridization, and cytogenetic findings were correlated with outcome. Using a proportional hazards model with backward selection, 3 prognostic subgroups were identified based on the influence of cytogenetic abnormalities on overall survival (OS): low-risk, t(15;17), and inv(16) in 25 of 361 patients (7%); standard-risk, normal karyotype, t(8;21), t(11q23), +8 within a noncomplex karyotype, and +11 within a noncomplex karyotype in 208 of 361 patients (58%); high-risk, all other aberrations in 128 of 361 patients (35%). On multivariate analysis, high-risk cytogenetics (hazard ratio [HR], 2.24) and age above 70 years (HR, 2.34) were independent prognostic factors affecting OS, and stratification according to these parameters demonstrated that a large subgroup of patients (55%), characterized by age 70 or older or high-risk cytogenetics, or both, had very unfavorable treatment results despite intensive chemotherapy. Thus, karyotype and age are major determinants of outcome in elderly patients with AML.

The Detection of Multilineage Dysplasia (MLD) Has No Influence on Prognosis in NPM1 Mutated Acute Myeloid Leukemia (AML) with Normal Karyotype

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2518-2518
Author(s):  
Ulrike Bacher ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
Tamara Weiss ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Biological Entity ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Cox Regression Analysis ◽  
Multilineage Dysplasia ◽  
Acute Myeloid

Abstract Acute myeloid leukemia with mutated nucleophosmin (AML NPM1mut) represents about one-third of all adult AML and shows distinctive biological and clinical features. For this reason, AML NPM1mut is planned to be included as a separate category in the revised WHO classification. A yet controversial issue, however, is whether AML NPM1mut with or without multilineage dysplasia (MLD) may differ biologically and clinically, as the presence of MLD might confer a negative prognostic impact. A further feature that was suggested to be typical for NPM1 mutated AML is “cup-like” morphology of blasts. We here analyzed 128 pts with AML NPM1mut and normal karyotype at first manifestation (59 females, 69 males; median age 60.5 years; 23.5–79.3 y). We investigated in parallel cytomorphology from bone marrow and/or peripheral blood, chromosome banding analysis, and molecular analyses. Presence of dysplasia was defined by dysplastic features in ≥50% of cells in the respective hematopoietic lineage as defined by the WHO. A 5% cut-off was taken for the presence of “cup-like” morphology of blasts. All cases were additionally analyzed for the FLT3-ITD, and in 122 pts for the FLT3-TKD. Statistical analysis was performed for overall survival (OS), and event-free survival (EFS) according to Kaplan-Meier using the 2-sided log-rank test. Cox regression analysis related OS and EFS with the analyzed parameters. We found a predominance of the FAB M1 (21.3% of all cases), M2 (33.9%), and M4 subtypes (28.3%). Cup-like morphology in ≥5% of all blasts was observed in 39 of 127 evaluable cases (31.3%) confirming previous observations of an association of the NPM1mut and this specific blast appearance. Molecular characterization detected NPM1 mutation subtype A (n=90/122; 73.8%), B (15/122; 12.3%), and D (7/122; 5.7%), which was in accordance to previous studies. In 56 cases (43.8%) there was a coincidence with an FLT3-ITD. Dysplasia of granulopoiesis was detected in 28/126 (22.2%), of erythropoiesis in 28/104 (26.9%), and of megakaryopoiesis in 57/87 (44.5%) cases in which the respective cell lineage could be analyzed. MLD (≥2 dysplastic hematopoietic lineages) was detected in 28 of 105 evaluable cases (21.9%). Clinical follow-up was available in 104 pts. (median follow-up 12,7 months). CR rate was 83.1% in 77 evaluable pts., and median EFS was 42.1 months in 104 evaluable pts (median OS not reached). An additional FLT3-ITD had a significantly inferior OS (p=0.003) and EFS (p=0.007), confirming the present series being representative. However, the presence of MLD was not significantly related to any endpoint such as CR rate, EFS, or OS. There was no association between MLD and the NPM1-subtype. Also, there was no significant correlation of MLD and the presence of a FLT3-ITD. In conclusion, the presence of MLD in AML NPM1mut with normal karyotype had no impact on CR rate and outcome, whereas coincidence of FLT3-ITD significantly worsened prognosis. These results give further evidence that AML with NPM1mut AML is a unique biological entity with clinical course mainly influenced by FLT3-ITD coincidence. These data do not support any additional prognostic influence of MLD in this AML subtype.

Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7052-7052
Author(s):  
B. C. Medeiros ◽  
J. R. Gotlib ◽  
S. E. Coutre ◽  
C. Jones ◽  
S. A. Khan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Elderly Patients ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Low Doses ◽  
Npm1 Mutation ◽  
Acute Myeloid

7052 Background: High treatment-related mortality and low response rates often discourage elderly patients with acute myeloid leukemia from receiving treatment. Previous data demonstrate that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Protracted exposure to low doses of temozolomide can significantly inhibit AGAT enzymatic activity. Methods: Phase II clinical trial of tailored temozolomide therapy to high-risk AML patients according to AGAT methylation promoter status. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200 mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) received protracted doses of temozolomide (100 mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Patients who achieved CR were given up to 5 consolidation treatments. Results: Fifteen patients have completed treatment to date. The median age was 78 (68–83) and nine were male. De novo AML was diagnosed in eight patients and five patients had s-AML. Nine patients had a normal karyotype and three patients had a complex karyotype. Two patients had only a NPM1 mutation and one had NPM1mut/FLT3-ITD. In 13 patients, the AGAT promoter was found to be unmethylated. AGAT protein was present in 5/11 patients. All patients had an intact mismatch repair pathway. Thirteen patients had HCT-CI scores of 0–2. Six patients (6/13) achieved a complete remission (CR) after 1 cycle of therapy (1/2 for patients with methylated and 5/11 for patients with unmethylated AGAT promoter). Nonhematologic toxicities were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Three patients remain in CR with a median duration of 22 weeks (14–36 weeks). Seven patients have died from disease progression, while two patients died of neutropenic sepsis (early deaths). With a median follow-up of 38 weeks (10–48), the median overall survival for the entire population is 12 weeks (3.5 - 38) weeks (responders 26.5 weeks). Conclusions: These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status. [Table: see text]

scholarly journals Effect of NPM1 and FLT3 Mutations on the Outcomes of Elderly Patients With Acute Myeloid Leukemia Receiving Standard Chemotherapy

2013 ◽  
Vol 13 (4) ◽  
pp. 435-440 ◽  
Author(s):  
Naval Daver ◽  
Theresa Liu Dumlao ◽  
Farhad Ravandi ◽  
Sherry Pierce ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Standard Chemotherapy ◽  
Flt3 Mutations ◽  
Acute Myeloid

A unique microRNA signature associated with nucleophosmin mutations in normal karyotype acute myeloid leukemia

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7015-7015
Author(s):  
R. Garzon ◽  
S. Volinia ◽  
B. Falini ◽  
C. M. Croce
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
Normal Karyotype ◽  
Microarray Platform ◽  
Housekeeping Genes ◽  
Mirna Signature ◽  
Flt3 Mutations ◽  
Novel Therapeutic Strategies ◽  
Acute Myeloid

7015 Background: Nucleophosmin (NPM) mutations are present in about 30 to 50 % of the patients with normal karyotype acute myeloid leukemia (NK-AML). The mutant NPM protein shows aberrant cytoplasmic location and is frequently associated with FLT3 mutations. Little is know, however how NPM mutants promote leukemia. To obtain insights about the biology of NPM+ AML we investigated the expression of microRNAs in NK-AML patients characterized for NPM mutations. Methods: We studied 85 adult NK-AML patients characterized for NPM, FLT3 ITD and FLT3 D835 mutations using a miRNA microarray platform containing 345 mature and precursors miRNAs. Mutation analysis for NPM, FLT3 ITD and FLT3 D835 were carried out in most of the patients as previously described (Falini, Blood 2006). The distribution of the mutations were as follows: NPMc+ (54 patients), NPMc- (31), FLT3 ITD+ (27), FLT3 ITD-(51) and FLT3 D835+ (21) and FLT3 D835-(26). Data were analyzed after background subtraction and normalization with a set of housekeeping genes using Significance Analysis of Microarrays and Predictive Analysis of microarrays. The results were validated using miRNA q-RT-PCR. Results: We identified a strong miRNA signature that distinguishes NPMc+ cases with high accuracy and includes the up-regulation of miR-10a, miR-10b and several let-7 family members. Many of the down-regulated miRNAs including miR-134, miR-194, miR-204, miR-526 and miR-28 are predicted to target many HOX genes suggesting that NPM mutants may induce HOX genes through the down-modulation of miRNA regulators of these genes. The signatures associated with FLT3 mutations were not accurate to predict this abnormality. However, when we analyzed the subgroup of NPMc+ FLT3 ITD + cases a distinctive signature was found with respect to other NPMc+ FLT3 negative cases. Conclusions: A unique miRNA signature is associated with NPMc+ mutations in AML. FLT3 ITD and FLT3 D835 are not clearly associated to any characteristic miRNA signature when analyzed individually. However the subgroup of NPMc+ FLT3 ITD has a distinctive miRNA signature. This data provide with new insights about the pathogenesis of NPMc+ AML that could be exploited to generate novel therapeutic strategies for one of the most common mutations in AML. No significant financial relationships to disclose.

The Amount of Mitochondrial Apoptosis Exerts Prognostic Impact on Normal Karyotype Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1481-1481
Author(s):  
Giovanni Del Poeta ◽  
Maria Ilaria Del Principe ◽  
Francesco Buccisano ◽  
Luca Maurillo ◽  
Benedetta Neri ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Mitochondrial Proteins ◽  
Prognostic Impact ◽  
Mitochondrial Apoptosis ◽  
P Glycoprotein ◽  
The Impact ◽  
Acute Myeloid

Abstract The unbalance between anti-apoptotic (bcl-2) and pro-apoptotic mitochondrial proteins (bax) represents a critical mechanism explaining the high rate of resistance and treatment failure in acute myeloid leukemia (AML) (Del Poeta, 2003). Moreover, the availability of novel and effective pro-apoptotic compounds such as bortezomib (Attar, 2008) and gemtuzumab (Del Poeta, 2008) moved us to widely investigate the impact of mitochondrial proteins such as bcl-2, bax and 7A6 on AML prognosis. 7A6 antigen has been found to be exposed on the mitochondrial membrane during the early stages of apoptosis and is recognized by monoclonal antibody APO2.7. For this purpose, a large series of 420 non M3 AML patients (pts), median age 63 years, treated with intensive chemotherapy regimens, were tested. The aims of our research were: to correlate bax/bcl-2 and APO2.7/bcl-2 ratios, as measures of mitochondrial apoptosis, with other well-known prognostic factors such as age, cytogenetics, FLT3-ITD, P-glycoprotein; to evaluate whether mitochondrial apoptosis was able to dissect normal karyotype AML with regard to prognosis, and finally to confirm that mitochondrial apoptosis is an independent prognostic factor. Bcl-2, bax and 7A6 proteins were assessed by multicolor flow cytometry and bax/bcl-2 or APO2.7/bcl-2 ratios were obtained by dividing mean fluorescence intensity (MFI) of bax/MFI bcl-2 or MFI of APO2.7/MFI bcl-2. The thresholds of positivity were set at the median values >0.35 and >0.60, respectively. Fifty-nine percent of pts were bax/bcl-2 positive and 50% were APO2.7/bcl-2 positive. There were strict correlations between higher bax/bcl-2 or higher APO2.7/bcl-2 and FAB M2 or M4/M5 AML subgroups (p<0.0001). Bax/bcl-2>0.35 or APO2.7/bcl-2>0.60 and CD34 negativity (p<0.0001) or normal karyotype (p<0.0001 and p=0.003) were closely associated. On the other hand, no significant relationships were found between bax/bcl-2 or APO2.7/bcl-2 and age, white blood cell count, P-glycoprotein or FLT3-ITD. A higher complete remission (CR) rate was found in pts either with higher bax/bcl-2 or higher APO2.7/bcl-2 (68% vs 32% and 60% vs 40%, p<0.0001). Moreover, a shorter time to relapse was observed in pts with bax/bcl-2 <0.35 (3.3 months vs 6 months, p=0.011). Overall survival (OS) and disease-free survival (DFS) were longer in pts with higher bax/bcl-2 (18% vs 0% at 3.5 years, p<0.0001 and 19 vs 0% at 2.7 years, p=0.00007) or higher APO2.7/bcl-2 (14% vs 2% at 4 years, p<0.0001 and 8% vs 0% at 4 years, p=0.02). Furthermore, in order to demonstrate the independent prognostic impact of the mitochondrial proteins, we investigated bax/bcl-2 and APO2.7/bcl-2 within the normal karyotype subgroup (243 pts). As a matter of fact, within this subset, higher bax/bcl-2 or higher APO2.7/bcl-2 were associated with higher CR rate (76% vs 24% and 64% vs 36%, p<0.0001) and longer OS (16% vs 0% at 3.5 years, p=0.00001 and 14% vs 4 at 4 years, p=0.002). The independent prognostic value of bax/bcl-2 and APO2.7/bcl-2 was confirmed in multivariate analysis with regard to CR (p=0.00007 and p=0.0005) and OS (p=0.0009 and p=0.03). Therefore, the significant and independent prognostic role of mitochondrial apoptosis implies that therapeutic strategies for improving outcome in AML should be focused on apoptosis-inducing compounds combined with conventional chemotherapy.

Activating FLT3 Mutations Display a Wide Range Of Transforming Potential and a Characteristic Pathway Profile Associated With Prognosis In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1312-1312
Author(s):  
Hanna Janke ◽  
Friederike Schneider ◽  
Daniela Schumacher ◽  
Tobias Herold ◽  
Hopfner Karl-Peter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Gene Expression Profile ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Wide Range ◽  
Flt3 Mutations ◽  
Acute Myeloid

Abstract Background Internal tandem duplication (ITD) and pointmutations in the tyrosine kinase domain (TKD) of the receptor tyrosine kinase FLT3 occur in about 30% of patients with acute myeloid leukemia (AML). In contrast to the negative prognostic impact of FLT3-ITD in normal karyotype AML, FLT3 pointmutations occurring in the TKD and juxtamembrane (JM) region are less frequent and of unclear clinical impact. Although TKD mutations can induce resistance to tyrosine kinase inhibitors the individual transforming potential of FLT3 pointmutations has not been analysed in detail. In this study we have performed a comprehensive analysis of various FLT3 mutants in a comparative setting in vitro and analyzed gene expression profiles, and clinical outcome with respect to FLT3mutation status. Material and Methods We analyzed relapse and survival in 672 cytogenetically normal AML patients and the FLT3 status at diagnosis and relapse in 156 patients. In the murine Ba/F3 cell model we analyzed the transforming potential, subcellular localization, phosphorylation status and signaling properties of eight different FLT3 mutants. The investigated FLT3 mutations include three ITD of different length and insertion site, V592A in the JM region, common FLT3-TKD mutations D835V and D835Y as well as D839G and I867S in the second TKD. FLT3-D839G and -I867S were recently found in AML patients by our group during routine diagnostics but have not been functionally characterized before. The corresponding remission samples did not express these mutations. Further a gene expression profile analysis with respect to FLT3-ITD and -TKD mutation status and evaluation of differences in activation of predefined STAT5 target gene set was performed. Results In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with an inferior relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a fully transformed phenotype in Ba/F3 cells, whereas FLT3 pointmutations showed a weaker but clearly transformed phenotype with gradual increase in proliferation and protection from apoptosis. The transforming capacity of the investigated mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD transformed cells, further gene expression profile analyses displayed differences in predefined STAT5 target genes between FLT3-ITD and FLT3-TKD mutations. In contrast, FLT3-non-ITD mutants had an enhanced signal of AKT and MAPK activation. Further differences were found on mRNA level presenting deregulation of SOCS2, ENPP2, PRUNE2 and ART3 expression between FLT3-ITD, FLT3-TKD and FLT3-WT. Conclusion Although apparently divergent in response to treatment all functionally characterized mutants showed a clear gain-of-function phenotype with a wide range of transforming activity associated with clinical prognosis and signaling. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Nucleophosmin mutation in Southeast Asian acute myeloid leukemia: eight novel variants, FLT3 coexistence and prognostic impact of NPM1/FLT3 mutations

Haematologica ◽  
2008 ◽  
Vol 93 (10) ◽  
pp. 1565-1569 ◽  
Author(s):  
C. Boonthimat ◽  
W. Thongnoppakhun ◽  
C. U. Auewarakul
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Southeast Asian ◽  
Prognostic Impact ◽  
Novel Variants ◽  
Flt3 Mutations ◽  
Acute Myeloid

Incidence and Prognostic Influence of DNMT3A Mutations in Acute Myeloid Leukemia

2011 ◽  
Vol 29 (21) ◽  
pp. 2889-2896 ◽  
Author(s):  
Felicitas Thol ◽  
Frederik Damm ◽  
Andrea Lüdeking ◽  
Claudia Winschel ◽  
Katharina Wagner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Direct Sequencing ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Entire Patient Cohort ◽  
Risk Patients ◽  
Acute Myeloid

Purpose To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. Patients and Methods A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1). Results DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients. Conclusion DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.

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