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1.
Leukemia ; 31(3): 555-564, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27686867

RESUMO

Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.


Assuntos
Biomarcadores Tumorais , Variações do Número de Cópias de DNA , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Feminino , Dosagem de Genes , Genes p53 , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento
2.
Bone Marrow Transplant ; 47(11): 1436-41, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22426749

RESUMO

To illustrate methodological issues, we compared donor vs no-donor to transplant vs no-transplant comparisons in a cohort of 107 patients aged 50 years with adverse karyotype AML in first CR. Adverse karyotypes were defined as -7, del(7q), -5, del(5q), t(9;22), 11q23, 3q26 or complex abnormalities. Mantel-Byar estimations and hematopoietic SCT (HSCT) as a time-dependent variable were used to compare transplant vs no-transplant cumulative incidence of relapse (CIR), relapse-free survival (RFS) and OS. In all, 52 patients had a sibling donor, but only 35 of them were transplanted in first CR, whereas 9 patients received HSCT from alternative stem cell sources. Donor-based analysis showed lower CIR in the donor group, not translating in prolonged RFS or OS. Conversely, transplant-based analysis showed that HSCT in the first CR improved the three CIR (multivariate hazard ratio (HR), 0.31; P<0.001), RFS (multivariate HR, 0.57; P=0.047) and OS (multivariate HR, 0.54; P=0.03) endpoints. At 5 years, OS was estimated at 33% in transplanted vs 18% in non-transplanted patients. The positive effect of HSCT was more pronounced in patients aged 35 years and/or in those transplanted in the more recent years. These results confirm that HSCT is likely the best curative option in younger patients with adverse karyotype AML.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/cirurgia , Adolescente , Adulto , Fatores Etários , Estudos de Coortes , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
3.
Leukemia ; 26(6): 1247-54, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22289988

RESUMO

Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French-American-British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P = 0.02) and overall survival (5-year OS: 23% vs 45%, P = 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.


Assuntos
Biomarcadores Tumorais/genética , Análise Citogenética , DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Mutação/genética , Adolescente , Adulto , DNA Metiltransferase 3A , DNA de Neoplasias/genética , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/classificação , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Reação em Cadeia da Polimerase , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
4.
Med Mal Infect ; 42(1): 10-4, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22153703

RESUMO

INTRODUCTION: Invasive aspergillosis is a serious disease, the lethality of which is important among hematology patients. Early diagnosis is crucial for treatment options and the prognosis. Detection of the antigen galactomannan is the most frequently used microbiological tools. But galactomannan detection may be falsely positive, and this false positivity has been associated with piperacillin-tazobactam treatment, the main antibiotic combination used in clinical hematology. OBJECTIVE: The purpose of our study, carried out from January 2009 to December 2010 at the Versailles hospital on in-patients with hematological disorders, was to evaluate the association between false galactomannan positivity and administration of piperacillin-tazobactam, and to study a possible variability of products issued by three manufacturers. PATIENTS AND METHOD: We noted that 207 patients were included (n=207), accounting for 69 false positive and 138 true negative results. The intrinsic galactomannan values in the study were sensitivity 100%, specificity 68%, positive and negative predictive values respectively 16%, 100%, and a likelihood positive and negative test at respectively 3.12, and 0. RESULTS: The statistical analysis did not determine any association between false positivity in galactomannan and piperacillin-tazobactam issued by two manufacturers (P=0.87 and P=0.94). But, there was a significant association between false galactomannan positivity and piperacillin-tazobactam issued by the third manufacturer (P=0.02). Four of the 25 batches issued by this manufacturer were tested and negative "in vitro" for galactomannan. DISCUSSION: This study results suggest that the association between false galactomannan positivity and piperacillin-tazobactam is not longer systematic, but can still prevail depending on the manufacturers. It also confirmed the positive contribution of testing piperacillin-tazobactam batches "in vitro" before using the antibiotic.


Assuntos
Antibacterianos/farmacologia , Antígenos de Fungos/sangue , Artefatos , Aspergilose/diagnóstico , Ensaio de Imunoadsorção Enzimática , Fungemia/diagnóstico , Mananas/sangue , Kit de Reagentes para Diagnóstico , Antibacterianos/uso terapêutico , Aspergilose/sangue , Biomarcadores , Reações Falso-Positivas , Fungemia/sangue , Fungemia/microbiologia , Galactose/análogos & derivados , Humanos , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Ácido Penicilânico/uso terapêutico , Piperacilina/farmacologia , Piperacilina/uso terapêutico , Combinação Piperacilina e Tazobactam , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
7.
Leukemia ; 21(3): 453-61, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17252021

RESUMO

In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Leucemia Mieloide/tratamento farmacológico , Pré-Medicação , Doença Aguda , Adolescente , Adulto , Amsacrina/administração & dosagem , Amsacrina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Divisão Celular/efeitos dos fármacos , Terapia Combinada , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Leucemia Mieloide/cirurgia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , Células-Tronco Neoplásicas/efeitos dos fármacos , Modelos de Riscos Proporcionais , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Risco , Terapia de Salvação , Estimulação Química , Transplante Homólogo , Resultado do Tratamento
8.
Leukemia ; 21(1): 66-71, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17051246

RESUMO

Pivotal phase II studies in acute myeloblastic leukemia (AML) patients in first relapse have used gemtuzumab ozogamicin (GO) (Mylotarg) at a dose of 9 mg/m(2) on days 1 and 14. These studies showed a 26% response rate (13% complete remission (CR) and 13% CRp (complete remission with incomplete platelet recovery)) but with high degree of hematological and liver toxicities. Based on in vitro studies showing a re-expression of CD33 antigenic sites on the cell surface of blasts cells after exposure to GO, we hypothesized that fractionated doses of GO may be efficient and better tolerated. Fifty-seven patients with AML in first relapse received GO at a dose of 3 mg/m(2) on days 1, 4 and 7 for one course. Fifteen patients (26%) achieved CR and four (7%) CRp. Remission rate correlated strongly with P-glycoprotein and MRP1 activities. The median relapse-free survival was 11 months, similar for CR or CRp patients. Median duration of neutropenia < 500/microl and thrombocytopenia < 50,000/microl were, respectively, 23 and 21 days. No grade 3 or 4 liver toxicity was observed. No veno-occlusive disease occurred after GO or after hematopoietic stem cell transplantation given after GO in seven patients. Mylotarg administered in fractionated doses demonstrated an excellent efficacy/safety profile.


Assuntos
Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoglicosídeos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Gemtuzumab , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/sangue , Recidiva , Indução de Remissão , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico
9.
Leukemia ; 20(9): 1526-32, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16838024

RESUMO

Acute lymphoblastic leukemia (ALL) in the elderly is characterized by its ominous prognosis. On the other hand, imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), which prompted us to assess the use of imatinib in previously untreated elderly patients. ALL patients aged 55 years or older were given steroids during 1 week. Ph+ve cases were then offered a chemotherapy-based induction followed by a consolidation phase with imatinib and steroids during 2 months. Patients in complete response (CR) after consolidation were given 10 maintenance blocks of alternating chemotherapy, including two additional 2-month blocks of imatinib. Thirty patients were included in this study and are compared with 21 historical controls. Out of 29 assessable patients, 21 (72%, confidence interval (CI): 53-87%) were in CR after induction chemotherapy vs 6/21 (29%, CI: 11-52%) in controls (P=0.003). Five additional CRs were obtained after salvage with imatinib and four after salvage with additional chemotherapy in the control group. Overall survival (OS) is 66% at 1 year vs 43% in the control group (P=0.005). The 1-year relapse-free survival is 58 vs 11% (P=0.0003). The use of imatinib in elderly patients with Ph+ ALL is very likely to improve outcome, including OS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Metilprednisolona/uso terapêutico , Cromossomo Filadélfia , Piperazinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Pirimidinas/uso terapêutico , Resultado do Tratamento , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Intervalo Livre de Doença , Humanos , Mesilato de Imatinib , Metilprednisolona/administração & dosagem , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Transplante de Células-Tronco
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