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  • 1
    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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  • 2
    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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  • 3
    Keywords: THERAPY ; DIAGNOSIS ; TRIAL ; STEM-CELL TRANSPLANTATION ; CRITERIA ; RECOMMENDATIONS
    Abstract: To determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK+ patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK positive (MK+). MK+ patients were significantly older (p=0.0001), had lower white blood counts (p=0.0006) and lower percentages of bone marrow blasts (p=0.0004); MK was associated with the presence of -5/5q-, -7, 7q-, abnl(12p), abnl(17p), -18/18q-, -20/20q-, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)-related cytogenetic abnormalities (p〈0.0001, each); NPM1 mutations (p〈0.0001), FLT3 internal tandem duplications (p〈0.0001) and tyrosine kinase domain mutations (p=0.02) were less frequent in MK+. Response to induction therapy and overall survival in MK+ patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival. These trials are registered at www.clinicaltrials.gov as NCT00151255 and NCT00151242.
    Type of Publication: Journal article published
    PubMed ID: 22096250
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  • 4
    Keywords: THERAPY ; MICE ; DELETION ; AMPLIFICATION ; MALIGNANCIES ; p53 ; MUTATIONS ; POOR-PROGNOSIS ; TUMOR-SUPPRESSOR ; DISEASE PROGRESSION
    Abstract: To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P 〈 .0001) and by a higher frequency of specific copy number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13 similar to 25; among CK-AMLs, TP53altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.
    Type of Publication: Journal article published
    PubMed ID: 22186996
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