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  • 1
    Keywords: EXPRESSION ; SURVIVAL ; COMBINATION ; Germany ; MODEL ; THERAPY ; RISK ; PATIENT ; IMPACT ; INDUCTION ; ACID ; NO ; DIFFERENCE ; AGE ; RATES ; chemotherapy ; leukemia ; MULTIVARIATE ; RISK GROUP ; COMPLETE REMISSION ; INITIATION ; COLONY-STIMULATING FACTOR ; Bcl-2 ; SOUTHWEST-ONCOLOGY-GROUP ; ACUTE MYELOGENOUS LEUKEMIA ; acute myeloid leukemia ; INDUCTION THERAPY ; ELDERLY-PATIENTS ; PHASE-III ; DEHYDROGENASE ; overall survival ; all-trans retinoic acid ; COUNCIL AML11 TRIAL ; CYTOSINE-ARABINOSIDE ; elderly patients ; IDARUBICIN
    Abstract: The purpose of our study was (i) to evaluate the impact of all-trans retinoic acid ( ATRA) given as adjunct to chemotherapy and (ii) to compare second consolidation vs maintenance therapy in elderly patients with acute myeloid leukemia (AML). A total of 242 patients aged greater than or equal to61 years (median, 66.6 years) with AML were randomly assigned to ATRA beginning on day +3 after the initiation of chemotherapy (ATRA-arm, n = 122) or no ATRA (standard-arm, n 120) in combination with induction and first consolidation therapy. A total of 61 patients in complete remission (CR) were randomly assigned to second intense consolidation (n = 31) or 1-year oral maintenance therapy ( n 30). After induction therapy the intention-to-treat analysis revealed a significant difference in CR rates between the ATRA- and the standard-arm (52 vs 39%; P = 0.05). Event-free (EFS) and overall survival ( OS) were significantly better in the ATRA- compared to the standard-arm (P = 0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy (P〈0.001). The multivariate model for survival revealed lactate dehydrogenase, cytogenetic risk group, age, and first and second randomization as prognostic variables. In conclusion, the addition of ATRA to induction and consolidation therapy may improve CR rate, EFS and OS in elderly patients with AML
    Type of Publication: Journal article published
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  • 2
    Keywords: SURVIVAL ; Germany ; THERAPY ; PATIENT ; IMPACT ; TRANSPLANTATION ; BINDING ; treatment ; chromosome ; NO ; TRIAL ; EXPERIENCE ; DIFFERENCE ; AGE ; meta-analysis ; chemotherapy ; leukemia ; PROGNOSTIC-FACTORS ; allogeneic ; PROGNOSTIC FACTORS ; ALLOGENEIC TRANSPLANTATION ; PROGNOSTIC FACTOR ; relapse ; COMPLETE REMISSION ; Y-CHROMOSOME ; acute myeloid leukemia ; INTENSIVE CHEMOTHERAPY ; POSTREMISSION THERAPY ; AUTOLOGOUS TRANSPLANTATION ; ONCOLOGY ; ADULT ; ADULTS ; overall survival ; REMISSION DURATION ; METAANALYSIS ; ACUTE MYELOBLASTIC-LEUKEMIA ; ADULT PATIENTS ; CHROMOSOME-ABNORMALITIES ; DE-NOVO AML ; HIGH-DOSE CYTARABINE ; REPETITIVE CYCLES ; STANDARD CYTOGENETICS
    Abstract: Purpose To evaluate prognostic factors for relapse-free survival (RFS) and overall survival (OS) and to assess the impact of different postremission therapies in adult patients with core binding factor (CBF) acute myeloid leukemias (AML). Patients and Methods Individual patient data-based meta-analysis was performed on 392 adults (median age, 42 years; range, 16 to 60 years) with CBF AML (t(8;21), n = 191; inv(1 6), n = 201) treated between 1993 and 2002 in prospective German AML treatment trials. Results RFS was 60% and 58% and OS was 65% and 74% in the t(8;21) and inv(16) groups after 3 years, respectively. For postremission therapy, intention-to-treat analysis revealed no difference between intensive chemotherapy and autologous transplantation in the t(8;21) group and between chemotherapy, autologous, and allogeneic transplantation in the inv(16) group. In the t(8;21) group, significant prognostic variables for longer RFS and OS were lower WBC and higher platelet counts; loss of the Y chromosome in male patients was prognostic for shorter OS. In the inv(16) group, trisomy 22 was a significant prognostic variable for longer RFS. For patients who experienced relapse, second complete remission rate was significantly lower in patients with t(8;21), resulting in a significantly inferior survival duration after relapse compared with patients with inv(16). Conclusion We provide novel prognostic factors for CBF AML and show that patients with t(8;21) who experience relapse have an inferior survival duration. (C) 2004 by American Society of Clinical Oncology
    Type of Publication: Journal article published
    PubMed ID: 15289486
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  • 3
    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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  • 4
    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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  • 5
    Keywords: SURVIVAL ; MYELODYSPLASTIC SYNDROME ; fludarabine ; HIGH-DOSE CYTARABINE ; CONDITIONING REGIMEN ; CUMULATIVE INCIDENCE ; 1ST COMPLETE REMISSION ; AML 10 TRIAL ; CONSOLIDATION THERAPY ; SUSTAINED REMISSIONS
    Abstract: PURPOSE: To assess the impact of allogeneic hematopoietic stem-cell transplantation (HSCT) from matched related donors (MRDs) and matched unrelated donors (MUDs) on outcome in high-risk patients with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. PATIENTS AND METHODS: Between 1998 and 2004, 844 patients (median age, 48 years; range, 16 to 62 years) with AML were enrolled onto protocol AMLHD98A that included a risk-adapted treatment strategy. High risk was defined by the presence of unfavorable cytogenetics and/or by no response to induction therapy. RESULTS: Two hundred sixty-seven (32%) of 844 patients were assigned to the high-risk group. Of these 267 patients, 51 patients (19%) achieved complete remission but had adverse cytogenetics, and 216 patients (81%) had no response to induction therapy. Allogeneic HSCT was actually performed in 162 (61%) of 267 high-risk patients, after a median time of 147 days after diagnosis. Graft sources were as follows: MRD (n = 62), MUD (n = 89), haploidentical donor (n = 10), and cord blood (n = 1). The 5-year overall survival rates were 6.5% (95% CI, 3.1% to 13.6%) for patients (n = 105) not proceeding to HSCT and 25.1% (95% CI, 19.1% to 33.0%; from date of transplantation) for patients (n = 162) receiving HSCT. Multivariable analysis including allogeneic HSCT as a time-dependent covariable revealed that allogeneic HSCT significantly improved outcome; there was no difference in outcome between allogeneic HSCT from MRD and MUD. CONCLUSION: Allogeneic HSCT in younger adults with high-risk AML has a significant beneficial impact on outcome, and allogeneic HSCT from MRD and MUD yields similar results.
    Type of Publication: Journal article published
    PubMed ID: 20805454
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  • 6
    Keywords: CELLS ; CELL ; Germany ; KINASE ; THERAPY ; DEATH ; RISK ; GENE ; GENES ; PROTEIN ; PATIENT ; TRANSPLANTATION ; BINDING ; ASSOCIATION ; ALPHA ; TRIAL ; TRIALS ; AGE ; MUTATION ; leukemia ; MUTATIONS ; HOMOLOG ; ONCOGENE ; OUTCOMES ; STEM-CELL TRANSPLANTATION ; Ras ; ACUTE MYELOGENOUS LEUKEMIA ; STUDY-GROUP ULM ; BINDING PROTEIN ; ADULT ; ADULTS ; THERAPIES ; INTERNAL TANDEM DUPLICATION ; methods ; USA ; normal karyotype ; GROUP-B ; viral ; MEDICINE ; CLINICAL-OUTCOMES ; NRAS ; YOUNGER ADULTS ; CEBPA MUTATIONS ; FAVORABLE PROGNOSTIC-SIGNIFICANCE ; KINASE DOMAIN MUTATIONS ; NUCLEOPHOSMIN NPM1
    Abstract: Background: Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein (alpha) gene (CEPBA), the myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these mutations with clinical outcomes in patients. Methods: We compared the mutational status of the NPM1, FLT3, CEBPA, MLL, and NRAS genes in leukemia cells with the clinical outcome in 872 adults younger than 60 years of age with cytogenetically normal AML. Patients had been entered into one of four trials of therapy for AML. In each study, patients with an HLA-matched related donor were assigned to undergo stem-cell transplantation. Results: A total of 53% of patients had NPM1 mutations, 31% had FLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosine kinase-domain mutations, 13% had CEBPA mutations, 7% had MLL partial tandem duplications (PTDs), and 13% had NRAS mutations. The overall complete-remission rate was 77%. The genotype of mutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, and younger age were each significantly associated with complete remission. Of the 663 patients who received postremission therapy, 150 underwent hematopoietic stem-cell transplantation from an HLA-matched related donor. Significant associations were found between the risk of relapse or the risk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD (hazard ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), the mutant CEBPA genotype (hazard ratio, 0.48; 95% CI, 0.30 to 0.75), and the MLL-PTD genotype (hazard ratio, 1.56; 95% CI, 1.00 to 2.43), as well as receipt of a transplant from an HLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44 to 0.82). The benefit of the transplant was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD. Conclusions: Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML
    Type of Publication: Journal article published
    PubMed ID: 18450602
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  • 7
    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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  • 8
    Keywords: CANCER ; EXPRESSION ; GENE ; ACUTE MYELOID-LEUKEMIA ; GENOMIC ABERRATIONS ; HIGH-DOSE CYTARABINE ; transcript ; GROUP-B ; AML1-ETO ; INSERTIONS
    Abstract: In acute myeloid leukemia (AML), nonrandom clonal chromosome aberrations are detectable in similar to 55% of adult cases. Translocation t(8;21)(q22;q22) resulting in the 50RUNX1/3'RUNX1T1 fusion gene occurs in similar to 8% of AML cases. Also, ins(8; 21) and ins(21; 8) have been described that show a broad heterogeneity at the molecular level with inserted fragment sizes ranging from 2.4 to 44 Mb. Microarray-based comparative genomic hybridization (arrayCGH) in 49 intermediate-risk AML and RT-PCR-based screening in 532 AML cases allowed the detection of ins(21;8)/ins(8;21) in three cases; arrayCGH and subsequent RT-PCR revealed an similar to 0.5 Mb sized inserted fragment generating the 5'RUNX1/3'RUNX1T1 fusion gene in one case with a submicroscopic ins(21;8)(q22;q22q22) whereas the other two cases were identified by banding analysis and RT-PCR, respectively. Gene expression profiling (GEP) and a detailed review of the literature highlighted similar biological features of AML cases with ins(21;8)/ins(8;21) and t(8;21)(q22;q22). Our study demonstrates the potential of high-resolution array-based analysis and GEP and provides further evidence that AML with insertions generating the 50RUNX1/3'RUNX1T1 fusion not only biologically resemble the t(8;21)(q22;q22) AML subgroup, but might also share its prognostically favorable clinical behavior. Thus, similar treatment options should be considered in these patients.
    Type of Publication: Journal article published
    PubMed ID: 20967878
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  • 9
    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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  • 10
    Keywords: CANCER ; TARGETS ; TUMOR-SUPPRESSOR ; GROUP-B ; AML ; MICRORNA ; CEBPA MUTATIONS ; SIGNATURES ; miR-34a ; MONOSOMAL KARYOTYPE
    Abstract: Recently, the p53-miR-34a network has been identified to have an important role in tumorigenesis. As in acute myeloid leukemia with complex karyotype (CK-AML) TP53 alterations are the most common known molecular lesion, we further analyzed the p53-nniR-34a axis in a large cohort of CK-AML with known TP53 status (TP53(altere)d, n = 57; Tp53(unaltered), n =31; altered indicates loss and/or mutation of TP53). Profiling microRNA (miRNA) expression delineated TP53 alteration-associated miRNA profiles, and identified miR-34a and nniR-100 as the most significantly down- and upregulated miRNA, respectively. Moreover, we found a distinct miR-34a expression-linked gene expression profile enriched for genes belonging to p53-associated pathways, and implicated in cell cycle progression or apoptosis. Clinically, low miR-34a expression and TP53 alterations predicted for chemotherapy resistance and inferior outcome. Notably, in TP53(unaltered) CK-AML, high miR-34a expression predicted for inferior overall survival (OS), whereas in TP53(biallelic altered) CK-AML, high miR-34a expression pointed to better OS. Thus, detailed molecular profiling links impaired p53 to decreased miR-34a expression, but also identifies p53-independent miR-34a induction mechanisms as shown in TP53(biallelic altered) cell lines treated with 15-deoxy-Delta(12,14)-prostaglandin. An improved understanding of this mechanism might provide novel therapeutic options to restore miR-34a function and thereby induce cell cycle arrest and apoptosis in Tp53(altered) CK-AML.
    Type of Publication: Journal article published
    PubMed ID: 22810507
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