HighEVI1Expression Predicts Outcome in Younger Adult Patients With Acute Myeloid Leukemia and Is Associated With Distinct Cytogenetic Abnormalities

2010 ◽  
Vol 28 (12) ◽  
pp. 2101-2107 ◽  
Author(s):  
Stefan Gröschel ◽  
Sanne Lugthart ◽  
Richard F. Schlenk ◽  
Peter J.M. Valk ◽  
Karina Eiwen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Splice Variants ◽  
Quantitative Polymerase Chain Reaction ◽  
Prognostic Significance ◽  
Adult Patients ◽  
Prognostic Impact ◽  
Monosomy 7 ◽  
Free Survival ◽  
Acute Myeloid

PurposeThe purpose of this study was to investigate frequency and prognostic significance of high EVI1 expression in acute myeloid leukemia (AML).Patients and MethodsA diagnostic assay detecting multiple EVI1 splice variants was developed to determine the relative EVI1 expression by single real-time quantitative polymerase chain reaction in 1,382 newly diagnosed adult patients with AML younger than 60 years. Patients were treated on four Dutch-Belgian HOVON (n = 458) and two German-Austrian AML Study Group protocols (n = 924).ResultsThe EVI1 assay was tested in the HOVON cohort and validated in the AMLSG cohort. High EVI1 levels (EVI1+) were found with similar frequencies in both cohorts combined, with a 10.7% incidence (148 of 1,382). EVI1+independently predicted low complete remission (CR) rate (odds ratio, 0.54; P = .002), adverse relapse-free survival (RFS; hazard ratio [HR], 1.32; P = .05), and event-free survival (EFS; HR, 1.46; P < .001). This adverse prognostic impact was more pronounced in the intermediate cytogenetic risk group (EFS; HR, 1.64; P < .001; and RFS; HR, 1.55; P = .02), and was also apparent in cytogenetically normal AML (EFS; HR, 1.67; P = .008). Besides inv(3)/t(3;3), EVI1+was significantly associated with chromosome abnormalities monosomy 7 and t(11q23), conferring prognostic impact within these two cytogenetic subsets. EVI1+was virtually absent in favorable-risk AML and AML with NPM1 mutations. Patients with EVI1+AML (n = 28) who received allogeneic stem cell transplantation in first CR had significantly better 5-year RFS (33% ± 10% v 0%).ConclusionEVI1 expression in AML is unequally distributed in cytogenetic subtypes. It predicts poor outcome, particularly among intermediate cytogenetic risk AML. Patients with EVI1+AML may benefit from allogeneic transplantation in first CR. Pretreatment EVI1 screening should be included in risk stratification.

Clinical, Molecular, and Prognostic Significance of WHO Type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and Various Other 3q Abnormalities in Acute Myeloid Leukemia

2010 ◽  
Vol 28 (24) ◽  
pp. 3890-3898 ◽  
Author(s):  
Sanne Lugthart ◽  
Stefan Gröschel ◽  
H. Berna Beverloo ◽  
Sabine Kayser ◽  
Peter J.M. Valk ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Outcome Analysis ◽  
Prognostic Impact ◽  
Clinical Cancer Research ◽  
Monosomy 7 ◽  
Acute Myeloid

PurposeAcute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved.Patients and MethodsCytogenetics, molecular genetics, therapy response, and outcome analysis were performed in 6,515 newly diagnosed adult AML patients. Patients were treated on Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON/SAKK; n = 3,501) and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG; n = 3,014) protocols. EVI1 and MDS1/EVI1 expression was determined by real-time quantitative polymerase chain reaction.Results3q abnormalities were detected in 4.4% of AML patients (288 of 6,515). Four distinct groups were defined: A: inv(3)/t(3;3), 32%; B: balanced t(3q26), 18%; C: balanced t(3q21), 7%; and D: other 3q abnormalities, 43%. Monosomy 7 was the most common additional aberration in groups (A), 66%; (B), 31%; and (D), 37%. N-RAS mutations and dissociate EVI1 versus MDS1/EVI1 overexpression were associated with inv(3)/t(3;3). Patients with inv(3)/t(3;3) and balanced t(3q21) at diagnosis presented with higher WBC and platelet counts. In multivariable analysis, only inv(3)/t(3;3), but not t(3q26) and t(3q21), predicted reduced relapse-free survival (hazard ratio [HR], 1.99; P < .001) and overall survival (HR, 1.4; P = .006). This adverse prognostic impact of inv(3)/t(3;3) was enhanced by additional monosomy 7. Group D 3q aberrant AML also had a poor outcome related to the coexistence of complex and/or monosomal karyotypes and cryptic inv(3)/t(3;3).ConclusionVarious categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features. AML with inv(3)/t(3;3) represents a distinctive subgroup with unfavorable prognosis.

High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4329-4337 ◽  
Author(s):  
Sanne Lugthart ◽  
Ellen van Drunen ◽  
Yvette van Norden ◽  
Antoinette van Hoven ◽  
Claudia A. J. Erpelinck ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Splice Variants ◽  
Quantitative Polymerase Chain Reaction ◽  
Disease Free Survival ◽  
Molecular Diagnostic ◽  
Event Free Survival ◽  
Free Survival ◽  
Acute Myeloid

AbstractInappropriate expression of EVI1 (ecotropic virus integration-1), in particular splice form EVI1-1D, through chromosome 3q26 lesions or other mechanisms has been implicated in the development of high-risk acute myeloid leukemia (AML). To validate the clinical relevance of EVI1-1D, as well as of the other EVI1 splice forms and the related MDS1/EVI1 (ME) gene, real-time quantitative polymerase chain reaction was performed in 534 untreated adults with de novo AML. EVI1-1D was highly expressed in 6% of cases (n = 32), whereas 7.8% were EVI1+ (n = 41) when all splice variants were taken into account. High EVI1 predicted a distinctly worse event-free survival (HR = 1.9; P = .002) and disease-free survival (HR = 2.1, P = .006) following multivariate analysis. Importantly, we distinguished a subset of EVI1+ cases that lacked expression of ME (EVI1+ME−; n = 17) from cases that were ME+ (EVI1+ME+; n = 24). The atypical EVI1+ME− expression pattern exhibited cytogenetically detectable chromosomal 3q26 breakpoints in 8 cases. Fluorescence in situ hybridization revealed 7 more EVI1+ME− cases that carried cryptic 3q26 breakpoints, which were not found in the EVI1+ME+ group. EVI1+ME− expression predicts an extremely poor prognosis distinguishable from the general EVI1+ AML patients (overall survival [OS]: P < .001 and event-free survival [EFS]: P = .002). We argue that EVI1/ME quantitative expression analysis should be implemented in the molecular diagnostic procedures of AML.

Prognostic Significance of CEBPA Mutations in a Large Cohort of Younger Adult Patients With Acute Myeloid Leukemia: Impact of Double CEBPA Mutations and the Interaction With FLT3 and NPM1 Mutations

2010 ◽  
Vol 28 (16) ◽  
pp. 2739-2747 ◽  
Author(s):  
Claire L. Green ◽  
Kenneth K. Koo ◽  
Robert K. Hills ◽  
Alan K. Burnett ◽  
David C. Linch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Adult Patients ◽  
Prognostic Impact ◽  
Single Mutation ◽  
Npm1 Mutation ◽  
Double Mutation ◽  
Cebpa Mutations ◽  
Acute Myeloid

Purpose To determine the clinical relevance of mutations in the CCAAT/enhancer binding protein α (CEBPA) gene in acute myeloid leukemia (AML) and to examine factors that might modify prognostic impact. Patients and Methods The entire CEBPA coding sequence was screened in 1,427 young adult patients with AML, excluding acute promyelocytic leukemia, using denaturing high-performance liquid chromatography and direct sequencing. Results Of 107 patients (7%) with CEBPA mutations, 48 patients (45%) had one mutation (CEBPA-single), and 59 patients (55%) had two mutations (CEBPA-double). The incidence of CEBPA-double patients was similar in intermediate cytogenetic risk patients with and without a normal karyotype (6% and 5%, respectively). CEBPA-double patients had evidence of a lower coincidence with FLT3/ITDs (P = .04) and were highly unlikely to have an NPM1 mutation (P < .0001). CEBPA-double but not CEBPA-single patients had a significantly better overall survival (OS) at 8 years (34%, 31%, and 54% for CEBPA–wild-type [WT], CEBPA-single, and CEBPA-double, respectively, P = .004). This benefit was lost in the presence of a FLT3/ITD (OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-negative patients: 36%, 35%, 59%, respectively, P = .002; OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-positive patients: 26%, 21%, 14%, respectively, P = .05). There was no evidence of any additional favorable benefit for a CEBPA-single mutation in the presence of an NPM1 mutation (OS, 45%, 44%, and 56%, P = .2, for NPM1-positive/CEBPA-WT, NPM1-positive/CEBPA-single, and NPM1-negative/CEBPA-double patients, respectively). Conclusion Screening for CEBPA mutations can be restricted to patients with intermediate-risk cytogenetics lacking an FLT3/ITD or NPM1 mutation. Only the presence of a CEBPA-double mutation should be used for therapy risk stratification.

scholarly journals FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Naval Daver ◽  
Sangeetha Venugopal ◽  
Farhad Ravandi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Prognostic Significance ◽  
Treatment Algorithm ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

scholarly journals The Prognostic Significance of IRF8 Transcripts in Adult Patients with Acute Myeloid Leukemia

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e70812 ◽  
Author(s):  
Era L. Pogosova-Agadjanyan ◽  
Kenneth J. Kopecky ◽  
Fabiana Ostronoff ◽  
Frederick R. Appelbaum ◽  
John Godwin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Adult Patients ◽  
Acute Myeloid

Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4505-4511 ◽  
Author(s):  
Verena Ingeborg Gaidzik ◽  
Richard Friedrich Schlenk ◽  
Simone Moschny ◽  
Annegret Becker ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Negative Impact ◽  
Serum Lactate Dehydrogenase ◽  
Study Group ◽  
Prognostic Impact ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Acute Myeloid

AbstractTo evaluate the incidence and clinical impact of WT1 gene mutations in younger adult patients with cytogenetically normal acute myeloid leukemia (CN-AML), sequencing of the complete coding region was performed in diagnostic samples from 617 patients who were treated on 3 German-Austrian AML Study Group protocols. WT1 mutations were identified in 78 (12.6%) of the 617 patients; mutations clustered in exon 7 (54 of 78) and exon 9 (13 of 78), but also occurred in exons 1, 2, 3, and 8. WT1 mutations were significantly associated with younger age, higher serum lactate dehydrogenase levels, higher blood blast counts, and the additional presence of FLT3-ITD (P < .001) and CEBPA mutations (P = .004). There was no difference in relapse-free survival and overall survival between patients with (WT1mut) or without WT1 mutations. Subset analysis showed that patients with the genotype WT1mut/FLT3-ITDpos had a lower complete remission rate (P = .003) and an inferior relapse-free survival (P = .006) and overall survival (P < .001) compared with those with the genotype WT1mut/FLT3-ITDneg. In conclusion, in our large cohort of younger adults with CN-AML, WT1 mutation as a single molecular marker did not impact on outcome. However, our data suggest a negative impact of the genotype WT1mut/FLT3-ITDpos.

Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study

2006 ◽  
Vol 24 (24) ◽  
pp. 3904-3911 ◽  
Author(s):  
Peter Paschka ◽  
Guido Marcucci ◽  
Amy S. Ruppert ◽  
Krzysztof Mrózek ◽  
Hankui Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Core Binding Factor ◽  
Relapse Risk ◽  
Binding Factor ◽  
Acute Myeloid

Purpose To analyze the prognostic impact of mutated KIT (mutKIT) in core-binding factor acute myeloid leukemia (AML) with inv(16)(p13q22) and t(8;21)(q22;q22). Patients and Methods Sixty-one adults with inv(16) and 49 adults with t(8;21), assigned to postremission therapy with repetitive cycles of higher dose cytarabine were analyzed for mutKIT in exon 17 (mutKIT17) and 8 (mutKIT8) by denaturing high-performance liquid chromatography and direct sequencing at diagnosis. The median follow-up was 5.3 years. Results Among patients with inv(16), 29.5% had mutKIT (16% with mutKIT17 and 13% with sole mutKIT8). Among patients with t(8;21), 22% had mutKIT (18% with mutKIT17 and 4% with sole mutKIT8). Complete remission rates of patients with mutKIT and wild-type KIT (wtKIT) were similar in both cytogenetic groups. In inv(16), the cumulative incidence of relapse (CIR) was higher for patients with mutKIT (P = .05; 5-year CIR, 56% v 29%) and those with mutKIT17 (P = .002; 5-year CIR, 80% v 29%) compared with wtKIT patients. Once data were adjusted for sex, mutKIT predicted worse overall survival (OS). In t(8;21), mutKIT predicted higher CIR (P = .017; 5-year CIR, 70% v 36%), but did not influence OS. Conclusion We report for the first time that mutKIT, and particularly mutKIT17, confer higher relapse risk, and both mutKIT17 and mutKIT8 appear to adversely affect OS in AML with inv(16). We also confirm the adverse impact of mutKIT on relapse risk in t(8;21) AML. We suggest that patients with core-binding factor AML should be screened for mutKIT at diagnosis for both prognostic and therapeutic purposes, given that activated KIT potentially can be targeted with novel tyrosine kinase inhibitors.

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