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  • 1
    Keywords: SURVIVAL ; Germany ; MODEL ; HYBRIDIZATION ; PATIENT ; IMPACT ; INDUCTION ; treatment ; TRIAL ; IN-SITU ; cytogenetics ; AGE ; chemotherapy ; leukemia ; ABERRATIONS ; PROGNOSTIC-FACTORS ; HIGH-RISK ; PARAMETERS ; PROGNOSTIC-SIGNIFICANCE ; SELECTION ; ABNORMALITIES ; FLUORESCENCE ; ACUTE PROMYELOCYTIC LEUKEMIA ; POSTREMISSION THERAPY ; TRANS-RETINOIC ACID ; in situ hybridization ; PROGNOSTIC-FACTOR ; HIGH-DOSE CYTARABINE ; HISTONE ACETYLATION ; multivariate analysis ; SUBGROUPS ; COOPERATIVE-ONCOLOGY-GROUP ; CORE BINDING ; CUMULATIVE INCIDENCE ; GROUP-B
    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
    Type of Publication: Journal article published
    PubMed ID: 16840728
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  • 2
    Keywords: SURVIVAL ; CELL ; GENE ; PATIENT ; ACID ; MUTATIONS ; PROGNOSTIC-SIGNIFICANCE ; COLONY-STIMULATING FACTOR ; acute myeloid leukemia ; MYELODYSPLASTIC SYNDROME ; NORMAL CYTOGENETICS ; STUDY-GROUP ULM ; fludarabine ; all-trans retinoic acid ; CYTOSINE-ARABINOSIDE ; GENE MUTATION ; YOUNGER ADULTS ; OLDER ; predictive factor ; nucleophosmin-1 mutation ; T(5/17) VARIANT
    Abstract: Background In a previous randomized trial, AML HD98B, we showed that administration of all-trans retinoic acid in addition to intensive chemotherapy improved the outcome of older patients with acute myeloid leukemia. The objectives of this study were to evaluate the prognostic impact of gene mutations and to identify predictive genetic factors for the all-trans retinoic acid treatment effect. Design and Methods Data from mutation analyses of the NPM1, CEBPA, FLT3, and MLL genes were correlated with outcome in patients 61 years and older treated within the AML HD98B trial. Results The frequencies of mutations were: NPM1, 23%. CEBPA, 8.5% (analysis restricted to patients with a normal karyotype); FLT3 internal tandem duplications (ITD), 17%; FLT3 tyrosine kinase domain mutations, 5%; and MLL partial tandem duplications, 4.5%. T e genotype mutant NPM1 was positively and adverse cytogenetics as well as higher white blood cell count negatively correlated with achievement of complete remission. In Cox regression analysis, a significant interaction between the genotype mutant NPM1 without FLT3-ITD and treatment with all-trans retinoic acid was identified, in that the beneficial effect of all-trans retinoic acid on relapse-free and overall survival was restricted to this subgroup of patients. Other significant factors for survival were age, adverse cytogenetics, and logarithm of white cell count. Conclusions In elderly patients with acute myeloid leukemia, NPM1 mutations are associated with achievement of complete remission, and the genotype 'mutant NPM1 without FLT3-ITD' appears to be a predictive marker for response to all-trans retinoic acid given as an adjunct to intensive chemotherapy (ClinicalTrials.gov Identifier: NCT00151242)
    Type of Publication: Journal article published
    PubMed ID: 19059939
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  • 3
    Keywords: SURVIVAL ; Germany ; FOLLOW-UP ; RISK ; PATIENT ; IMPACT ; prognosis ; FREQUENCY ; TRIAL ; AGE ; MUTATION ; leukemia ; MUTATIONS ; diagnostics ; FREQUENT ; GLIOMAS ; acute myeloid leukemia ; ONCOLOGY ; ADULT ; ADULTS ; BRAIN-TUMORS ; overall survival ; MYELOID-LEUKEMIA ; PROGNOSTIC-FACTOR ; methods ; GENOTYPE ; RISK STRATIFICATION ; RECOMMENDATIONS ; CANCERS ; outcome ; IDH1 ; NADP(+)-DEPENDENT ISOCITRATE DEHYDROGENASE ; Genetic ; CODON 132 MUTATION ; GLIOBLASTOMAS ; RANGE ; ISOCITRATE DEHYDROGENASE ; GENETIC ALTERATIONS ; Follow up ; clinical oncology ; IDH1 mutation ; STRATIFICATION ; prognostic ; L-2-HYDROXYGLUTARIC ACIDURIA
    Abstract: Abstract PURPOSE: To analyze the frequency and prognostic impact of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations in acute myeloid leukemia (AML). PATIENTS AND METHODS: We studied 805 adults (age range, 16 to 60 years) with AML enrolled on German-Austrian AML Study Group (AMLSG) treatment trials AML HD98A and APL HD95 for mutations in exon 4 of IDH1 and IDH2. Patients were also studied for NPM1, FLT3, MLL, and CEBPA mutations. The median follow-up for survival was 6.3 years. RESULTS: IDH mutations were found in 129 patients (16.0%) -IDH1 in 61 patients (7.6%), and IDH2 in 70 patients (8.7%). Two patients had both IDH1 and IDH2 mutations. All but one IDH1 mutation caused substitutions of residue R132; IDH2 mutations caused changes of R140 (n = 48) or R172 (n = 22). IDH mutations were associated with older age (P 〈 .001; effect conferred by IDH2 only); lower WBC (P = .04); higher platelets (P 〈 .001); cytogenetically normal (CN) -AML (P〈 .001); and NPM1 mutations, in particular with the genotype of mutated NPM1 without FLT3 internal tandem duplication (ITD; P 〈 .001). In patients with CN-AML with the latter genotype, IDH mutations adversely impacted relapse-free survival (RFS; P = .02) and overall survival (P = .03), whereas outcome was not affected in patients with CN-AML who lacked this genotype. In CN-AML, multivariable analyses revealed a significant interaction between IDH mutation and the genotype of mutated NPM1 without FLT3-ITD (ie, the adverse impact of IDH mutation [RFS]; P = .046 was restricted to this patient subset). CONCLUSION: IDH1 and IDH2 mutations are recurring genetic changes in AML. They constitute a poor prognostic factor in CN-AML with mutated NPM1 without FLT3-ITD, which allows refined risk stratification of this AML subset.
    Type of Publication: Journal article published
    PubMed ID: 20567020
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  • 4
    Keywords: CANCER ; SURVIVAL ; TOXICITY ; DEATH ; RISK ; COMPLEX ; MUTATIONS ; ABNORMALITIES ; ACUTE PROMYELOCYTIC LEUKEMIA ; TOPOISOMERASE-II ; RECOMMENDATIONS ; CELL TRANSPLANTATION ; MYELODYSPLASTIC SYNDROMES ; MITOXANTRONE ; SECONDARY LEUKEMIAS
    Abstract: To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P 〈 .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with over-representation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P 〈 .0001); t-AML patients had NPM1 mutations (P 〈 .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P 〈 .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.
    Type of Publication: Journal article published
    PubMed ID: 21127174
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