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1.
Ann Hematol ; 93(2): 193-202, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23978944

RESUMO

Few studies have evaluated granulocyte colony-stimulating factor (G-CSF) priming in elderly patients with intensively treated acute myeloid leukemia (AML), and no data are available for genetically defined AML subgroups. We provide long-term results (median follow-up 7.6 years) of a randomized trial in which 183 patients (median age 67 years) received G-CSF prior to (G-CSF priming) or after two cycles of induction chemotherapy. CR rates with G-CSF priming and G-CSF post-chemotherapy were comparable (57 vs. 67 %, p = 0.153), with overall survival (OS) probabilities of 14 vs. 17 % at 10 years. Induction mortality was significantly higher with G-CSF priming (23 vs. 10 %, p = 0.015), primarily in normal karyotype (NK) AML. In this subgroup, a trend for better relapse-free survival (RFS) was observed with G-CSF priming (44 vs. 22 % at 10 years, p = 0.074) but did not translate into an OS benefit. G-CSF priming had no impact on AML with FLT3-ITD and NPM mutations and did not improve outcome in patients with adverse cytogenetics. In a landmark analysis, late consolidation with autologous stem cell transplantation or a second consolidation cycle significantly improved RFS compared with one consolidation cycle (21.0 vs. 12.8 months, p = 0.046). Future studies on G-CSF priming should be restricted to NK AML and used only in post-remission therapy.


Assuntos
Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Quimioterapia de Indução/efeitos adversos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Idoso , Idoso de 80 Anos ou mais , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Taxa de Sobrevida , Fatores de Tempo , Tirosina Quinase 3 Semelhante a fms/genética
2.
Ann Hematol ; 92(5): 653-60, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23340738

RESUMO

Bendamustine demonstrated clinical activity in pre-treated hematological malignancies due to its unique mechanism of action distinct from standard alkylating agents. This study assessed its efficacy in patients with chronic lymphocytic leukemia pre-treated with an alkylator, in comparison to fludarabine. Patients with relapsed chronic lymphocytic leukemia requiring treatment after one previous systemic regimen (usually chlorambucil-based) were randomized to either receive bendamustine 100 mg/m(2) on days 1 and 2 of a 4-week cycle or standard fludarabine treatment consisting of 25 mg/m(2) on days 1 to 5 every 4 weeks. The primary objective was to achieve non-inferior progression-free survival (PFS) with bendamustine. Out of a total of 96 patients randomized, 92 were eligible, 49 allocated to bendamustine and 43 to fludarabine. About half of the patients received six or more cycles. Overall response rates were 76 % on bendamustine and 62 % on fludarabine, with clinical complete response rates of 27 and 9 %, respectively. Median PFS was 20.1 and 14.8 months (hazard ratio, 0.87; 90 % confidence interval, 0.60-1.27), median overall survival 43.8 and 41.0 months (hazard ratio, 0.82). Thrombocytopenia and gastrointestinal toxicities were marginally more frequent on bendamustine, albeit CTC grade 3/4 event incidence was similar. These data suggest at least comparable efficacy of bendamustine vs. fludarabine, pointing to an alternative treatment option in relapsing CLL patients after chlorambucil containing initial chemotherapy.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Compostos de Mostarda Nitrogenada/uso terapêutico , Vidarabina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Cloridrato de Bendamustina , Quimioterapia Adjuvante , Feminino , Alemanha , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos de Mostarda Nitrogenada/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/uso terapêutico
3.
Cancer Immunol Immunother ; 60(2): 161-71, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20963411

RESUMO

T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Leucemia Mieloide Aguda/terapia , Manitol/análogos & derivados , Mieloma Múltiplo/terapia , Ácidos Oleicos , Oligodesoxirribonucleotídeos , Peptídeos/uso terapêutico , Adolescente , Antígenos de Neoplasias/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Feminino , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Masculino , Manitol/efeitos adversos , Mucina-1/efeitos adversos , Mucina-1/química , Mucina-1/imunologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Mieloblastina/efeitos adversos , Mieloblastina/química , Mieloblastina/imunologia , Estadiamento de Neoplasias , Neoplasia Residual/imunologia , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Ácidos Oleicos/efeitos adversos , Oligodesoxirribonucleotídeos/efeitos adversos , Oligodesoxirribonucleotídeos/imunologia , Peptídeos/efeitos adversos , Peptídeos/imunologia , Projetos Piloto , Resultado do Tratamento , Proteínas WT1/efeitos adversos , Proteínas WT1/química , Proteínas WT1/imunologia
4.
Blood ; 116(4): 614-6, 2010 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-20421455

RESUMO

Mutations in the nicotinamide adenine dinucleotide phosphate(+)-dependent isocitrate dehydrogenase gene 2 (IDH2) have recently been found in patients with acute myeloid leukemia (AML) as well as in patients with leukemic transformation of myeloproliferative neoplasms. We analyzed 272 adult patients with cytogenetically normal AML (CN-AML) for the presence of IDH2 mutations in codons R140 and R172. IDH2 mutations of amino acid 140 or 172 could be identified in 12.1% of CN-AML patients, with the majority of mutations (90%) occurring at position R140. The incidence of IDH2 mutations in AML patients with aberrant karyotypes (n = 130) was significantly lower (3.8%, P = .006). IDH2 mutations were mutually exclusive with mutations in IDH1. IDH2 mutation status alone or in combination with IDH1 mutations had no impact on response to therapy, overall survival, and relapse-free survival in patients with CN-AML. In conclusion, IDH2 mutations are frequently found in CN-AML, but in our analysis these mutations did not influence treatment outcome. This study was registered at www.clinicaltrials.gov as #NCT00209833.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Adulto , Ensaios Clínicos como Assunto , Análise Citogenética , Análise Mutacional de DNA , Humanos , Isocitrato Desidrogenase/fisiologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Estudos Multicêntricos como Assunto , Mutação/fisiologia , Prognóstico , Recidiva , Análise de Sobrevida , Resultado do Tratamento
5.
J Clin Oncol ; 28(14): 2356-64, 2010 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-20368538

RESUMO

PURPOSE: We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism (SNP) located in the same exon of the IDH1 gene in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. PATIENTS AND METHODS: IDH1 exon four was directly sequenced in 275 CN-AML patients from two subsequent AML multicenter treatment trials and 120 healthy volunteers. Moreover, mutations in NPM1, FLT3, CEBPA, and WT1 were analyzed, and mRNA expression of IDH1 was quantified. RESULTS: IDH1 R132 mutations were found in 10.9% of CN-AML patients. IDH1 SNP rs11554137 was found in 12% of CN-AML patients and 11.7% of healthy volunteers. IDH1 R132 mutations had no impact on prognosis. In contrast, IDH1 SNP rs11554137 was an adverse prognostic factor for overall survival in univariate and multivariate analysis. Other significant factors were age, NPM1/FLT3 mutational status, WT1 SNP rs16754, and platelet count. The impact of IDH1 SNP rs11554137 was most pronounced in the NPM1/FLT3 high-risk patients (either NPM1 wild-type or FLT3-internal tandem duplication positive). Patients with IDH1 SNP rs11554137 had a higher expression of IDH1 mRNA than patients with two wild-type alleles. CONCLUSION: IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Mutação , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Distribuição de Qui-Quadrado , Análise Mutacional de DNA , Intervalo Livre de Doença , Éxons , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Genótipo , Alemanha , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Razão de Chances , Fenótipo , Modelos de Riscos Proporcionais , RNA Mensageiro/análise , Recidiva , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
6.
J Clin Oncol ; 28(4): 578-85, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20038731

RESUMO

PURPOSE: We assessed the prognostic impact of a known single nucleotide polymorphism (SNP) located in the mutational hotspot of WT1 in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. PATIENTS AND METHODS: WT1 exons 7 and 9 from 249 CN-AML patients from multicenter treatment trials AML-SHG Hannover 0199 (Clinical Trials Identifier NCT00209833) and 0295, and 50 healthy volunteers were analyzed by direct sequencing. NPM1, FLT3, CEBPA, and MLL were assessed for mutations and WT1 expression was quantified. RESULTS: The minor allele of SNP rs16754 (WT1(AG/GG)) was found in 25.7% of CN-AML patients' blasts and germline DNA and in 36% of healthy volunteers. Patient characteristics, frequencies of mutations, or WT1 expression levels were similarly distributed between patients homozygous for the major allele compared with patients heterozygous or homozygous for the minor allele. SNP rs16754 status was an independent predictor of relapse-free survival (RFS; hazard ratio [HR], 0.49; 95% CI, 0.3 to 0.81; P = .005) and overall survival (OS; HR, 0.44; 95% CI, 0.27 to 0.74; P = .002) in multivariate analysis. The favorable effect of SNP rs16754 was stronger in NPM1/FLT3-ITD (internal tandem duplication of the FLT3 gene) high-risk patients compared with NPM1/FLT3-ITD low-risk patients. Favorable prognosis could not be identified by any other known low-risk marker in half the patients with at least one minor allele (13% of all patients). No difference for complete remission rate, RFS, or OS was found between patients with or without acquired WT1 mutations. CONCLUSION: WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.


Assuntos
Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas WT1/genética , Adolescente , Adulto , Proteínas Estimuladoras de Ligação a CCAAT/genética , Feminino , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Histona-Lisina N-Metiltransferase , Humanos , Cariotipagem , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Nucleofosmina , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
7.
J Clin Oncol ; 21(23): 4413-22, 2003 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-14645432

RESUMO

PURPOSE: In patients with acute myeloblastic leukemia with t(8;21) or inv(16) aberrations (core binding factor [CBF] leukemias), minimal residual disease (MRD) can be sensitively detected during and after chemotherapy by use of molecular methods. However, the prognostic impact of qualitative MRD detection is still under debate. In this study, the prognostic value of MRD quantification in patients with CBF leukemias was assessed. PATIENTS AND METHODS: We quantified MRD at various time points during and after therapy by real-time reverse transcriptase polymerase chain reaction (RT-PCR) for AML1/MTG8 and CBFB/MYH11 in 37 patients with CBF leukemias treated within a multicenter trial. RESULTS: At initial diagnosis, the patients showed a heterogenous fusion gene expression relative to glyceraldehyde 3-phosphate dehydrogenase with a variation of more than two log steps. According to MRD status during/after therapy, two groups of patients were separated. Of the 26 patients who had MRD levels of less than 1% in relation to initial diagnosis at all time points tested after induction chemotherapy, only two experienced relapse after a median follow-up of 19 months. Of the 11 patients who had a sample with an MRD level >/= 1% at least at one time point after induction therapy, 10 experienced relapse, with a median remission duration of 10 months (P <.001). The median interval between the informative MRD sample and clinical relapse in these patients was 3 months. CONCLUSION: MRD quantification by real-time RT-PCR allows the identification of patients with a high risk of relapse among the CBF leukemias.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Inversão Cromossômica , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core , Primers do DNA/química , Feminino , Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/genética , Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/metabolismo , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Proteínas de Fusão Oncogênica/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/análise , Proteína 1 Parceira de Translocação de RUNX1 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Taxa de Sobrevida , Fatores de Transcrição/metabolismo , Translocação Genética
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