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1.
Haematologica ; 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30076173

RESUMO

The randomized, phase 3 ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival in adults with de novo acute myeloid leukemia. Here we report an independent review of event-free survival, final overall survival, and additional safety results from ALFA-0701. Patients (N=271) aged 50-70 years with de novo acute myeloid leukemia were randomized to receive conventional front-line induction chemotherapy (3+7 daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/2;/day on day 1) according to their initial randomization. The primary endpoint was investigator-assessed event-free survival. Secondary endpoints included overall survival and safety. A blinded independent review confirmed the investigator-assessed event-free survival results (August 1, 2011; hazard ratio, 0.66 [95% CI, 0.49-0.89]; 2-sided p=0.006), corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin versus control arm. Final overall survival (April 30, 2013) favored gemtuzumab ozogamicin but was not significant. No differences were observed between arms in early death rate. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated acute myeloid leukemia. (ClinicalTrials.gov identifier: NCT00927498).

3.
Haematologica ; 103(5): 822-829, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29472349

RESUMO

Assessment of minimal residual disease has emerged as a powerful prognostic factor in acute myeloid leukemia. In this study, we investigated the potential of IDH1/2 mutations as targets for minimal residual disease assessment in acute myeloid leukemia, since these mutations collectively occur in 15-20% of cases of acute myeloid leukemia and now represent druggable targets. We employed droplet digital polymerase chain reaction assays to quantify IDH1R132, IDH2R140, and IDH2R172 mutations on genomic DNA in 322 samples from 103 adult patients with primary IDH1/2 mutant acute myeloid leukemia and enrolled on Acute Leukemia French Association (ALFA) - 0701 or -0702 clinical trials. The median IDH1/2 mutant allele fraction in bone marrow samples was 42.3% (range, 8.2 - 49.9%) at diagnosis of acute myeloid leukemia, and below the detection limit of 0.2% (range, <0.2 - 39.3%) in complete remission after induction therapy. In univariate analysis, the presence of a normal karyotype, a NPM1 mutation, and an IDH1/2 mutant allele fraction <0.2% in bone marrow after induction therapy were statistically significant predictors of longer disease-free survival. In multivariate analysis, these three variables remained significantly predictive of disease-free survival. In 7/103 (7%) patients, IDH1/2 mutations persisted at high levels in complete remission, consistent with the presence of an IDH1/2 mutation in pre-leukemic hematopoietic stem cells. Five out of these seven patients subsequently relapsed or progressed toward myelodysplastic syndrome, suggesting that patients carrying the IDH1/2 mutation in a pre-leukemic clone may be at high risk of hematologic evolution.

5.
J Clin Oncol ; 35(11): 1223-1230, 2017 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-28221862

RESUMO

Purpose To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML). Patients and Methods Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term. Results At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles. Conclusion These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Clofarabina , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
6.
Infect Control Hosp Epidemiol ; 37(7): 845-51, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27340735

RESUMO

OBJECTIVE Invasive aspergillosis (IA) is a rare but severe infection caused by Aspergillus spp. that often develops in immunocompromised patients. Lethality remains high in this population. Therefore, preventive strategies are of key importance. The impact of a mobile air decontamination system (Plasmair, AirInSpace, Montigny-le-Bretonneux, France) on the incidence of IA in neutropenic patients was evaluated in this study. DESIGN Retrospective cohort study METHODS Patients with chemotherapy-induced neutropenia lasting 7 days or more were included over a 2-year period. Cases of IA were confirmed using the revised European Organization for Research and Treatment of Cancer (EORTC) criteria. We took advantage of a partial installation of Plasmair systems in the hematology intensive care unit during this period to compare patients treated in Plasmair-equipped versus non-equipped rooms. Patients were assigned to Plasmair-equipped or non-equipped rooms depending only on bed availability. Differences in IA incidence in both groups were compared using Fisher's exact test, and a multivariate analysis was performed to take into account potential confounding factors. RESULTS Data from 156 evaluable patients were available. Both groups were homogenous in terms of age, gender, hematological diagnosis, duration of neutropenia, and prophylaxis. A total of 11 cases of probable IA were diagnosed: 10 in patients in non-equipped rooms and only 1 patient in a Plasmair-equipped room. The odds of developing IA were much lower for patients hospitalized in Plasmair-equipped rooms than for patients in non-equipped rooms (P=.02; odds ratio [OR] =0.11; 95% confidence interval [CI], 0.00-0.84). CONCLUSION In this study, Plasmair demonstrated a major impact in reducing the incidence of IA in neutropenic patients with hematologic malignancies. Infect Control Hosp Epidemiol 2016;37:845-851.


Assuntos
Infecção Hospitalar/prevenção & controle , Descontaminação/métodos , Aspergilose Pulmonar Invasiva/prevenção & controle , Neutropenia/complicações , Idoso , Microbiologia do Ar , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/microbiologia , Estudos Retrospectivos
8.
Leuk Res ; 39(12): 1443-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26467814

RESUMO

EVI1 overexpression confers poor prognosis in acute myeloid leukemia (AML). Quantification of EVI1 expression has been mainly assessed by real-time quantitative PCR (RT-qPCR) based on relative quantification of EVI1-1D splice variant. In this study, we developed a RT-qPCR assay to perform quantification of EVI1 expression covering the different splice variants. A sequence localized in EVI1 exons 14 and 15 was cloned into plasmids that were used to establish RT-qPCR standard curves. Threshold values to define EVI1 overexpression were determined using 17 bone marrow (BM) and 31 peripheral blood (PB) control samples and were set at 1% in BM and 0.5% in PB. Samples from 64 AML patients overexpressing EVI1 included in the ALFA-0701 or -0702 trials were collected at diagnosis and during follow-up (n=152). Median EVI1 expression at AML diagnosis was 23.3% in BM and 3.6% in PB. EVI1 expression levels significantly decreased between diagnostic and post-induction samples, with an average variation from 21.6% to 3.56% in BM and from 4.0% to 0.22% in PB, but did not exceed 1 log10 reduction. Our study demonstrates that the magnitude of reduction in EVI1 expression levels between AML diagnosis and follow-up is not sufficient to allow sensitive detection of minimal residual disease.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/patologia , Proteínas de Neoplasias/biossíntese , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Reação em Cadeia da Polimerase em Tempo Real/métodos , Fatores de Transcrição/biossíntese , Adolescente , Adulto , Idoso , Células Sanguíneas/metabolismo , Células da Medula Óssea/metabolismo , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/genética , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteína do Locus do Complexo MDS1 e EVI1 , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Neoplasia Residual , Proto-Oncogenes/genética , RNA Mensageiro/sangue , RNA Neoplásico/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Sensibilidade e Especificidade , Fatores de Transcrição/sangue , Fatores de Transcrição/genética , Transcrição Genética , Adulto Jovem
9.
Oncotarget ; 6(39): 42345-53, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-26486081

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous disease. Even within the same NPM1-mutated genetic subgroup, some patients harbor additional mutations in FLT3, IDH1/2, DNMT3A or TET2. Recent studies have shown the prognostic significance of minimal residual disease (MRD) in AML but it remains to be determined which molecular markers are the most suitable for MRD monitoring. Recent advances in next-generation sequencing (NGS) have provided the opportunity to use multiple molecular markers. In this study, we used NGS technology to assess MRD in 31 AML patients enrolled in the ALFA-0701 trial and harboring NPM1 mutations associated to IDH1/2 or DNMT3A mutations. NPM1 mutation-based MRD monitoring was performed by RTqPCR. IDH1/2 and DNMT3A mutations were quantified by NGS using an Ion Torrent Proton instrument with high coverage (2 million reads per sample). The monitoringof IDH1/2 mutations showed that these mutations were reliable MRD markers that allowed the prediction of relapse in the majority of patients. Moreover, IDH1/2 mutation status predicted relapse or disease evolution in 100% of cases if we included the patient who developed myelodysplastic syndrome. In contrast, DNMT3A mutations were not correlated to the disease status, as we found that a preleukemic clone with DNMT3A mutation persisted in 40% of the patients who were in complete remission, reflecting the persistence of clonal hematopoiesis.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Isocitrato Desidrogenase/genética , Leucemia Mieloide/genética , Mutação , Neoplasia Residual/genética , Doença Aguda , Adulto , Idoso , Biomarcadores Tumorais/genética , França , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Leucemia Mieloide/diagnóstico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasia Residual/diagnóstico , Proteínas Nucleares/genética , Prognóstico , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Adulto Jovem
10.
Nature ; 525(7569): 380-3, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26331539

RESUMO

Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , PPAR gama/agonistas , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Tiazolidinedionas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , PPAR gama/metabolismo , Pioglitazona , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT5/metabolismo , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Transativadores/metabolismo
11.
J Immunol ; 195(6): 2580-90, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26246143

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous group of malignancies that may be sensitive to the NK cell antitumor response. However, NK cells are frequently defective in AML. In this study, we found in an exploratory cohort (n = 46) that NK cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK cell profile, including reduced expression of some activating NK receptors (e.g., DNAX accessory molecule-1, NKp46, and NKG2D) and decreased IFN-γ production, had a significantly higher risk of relapse (p = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g., IL15, IFNGR1, IFNGR2, and CXCR4), Ag processing (e.g., HLA-DRA, HLA-DRB1, and CD74) and adhesion molecule pathways (e.g., PVR and ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications.


Assuntos
Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Receptores de Células Matadoras Naturais/metabolismo , Evasão Tumoral/imunologia , Adulto , Idoso , Antígenos CD/imunologia , Moléculas de Adesão Celular/imunologia , Feminino , Cadeias alfa de HLA-DR/imunologia , Cadeias HLA-DRB1/imunologia , Humanos , Interferon gama/biossíntese , Interleucina-15/biossíntese , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Receptores CXCR4/biossíntese , Receptores de Interferon/biossíntese , Sialiltransferases/imunologia , Evasão Tumoral/genética , Adulto Jovem
12.
Oncotarget ; 6(26): 22812-21, 2015 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-26078355

RESUMO

Minimal Residual Disease (MRD) detection can be used for early intervention in relapse, risk stratification, and treatment guidance. FLT3 ITD is the most common mutation found in AML patients with normal karyotype. We evaluated the feasibility of NGS with high coverage (up to 2.4.10(6) PE fragments) for MRD monitoring on FLT3 ITD. We sequenced 37 adult patients at diagnosis and various times of their disease (64 samples) and compared the results with FLT3 ITD ratios measured by fragment analysis. We found that NGS could detect variable insertion sites and lengths in a single test for several patients. We also showed mutational shifts between diagnosis and relapse, with the outgrowth of a clone at relapse different from that dominant at diagnosis. Since NGS is scalable, we were able to adapt sensitivity by increasing the number of reads obtained for follow-up samples, compared to diagnosis samples. This technique could be applied to detect biological relapse before its clinical consequences and to better tailor treatments through the use of FLT3 inhibitors. Larger cohorts should be assessed in order to validate this approach.


Assuntos
Leucemia Mieloide Aguda/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Reação em Cadeia da Polimerase/métodos , Tirosina Quinase 3 Semelhante a fms/química
15.
Lancet Oncol ; 15(9): 986-96, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25008258

RESUMO

BACKGROUND: Gemtuzumab ozogamicin was the first example of antibody-directed chemotherapy in cancer, and was developed for acute myeloid leukaemia. However, randomised trials in which it was combined with standard induction chemotherapy in adults have produced conflicting results. We did a meta-analysis of individual patient data to assess the efficacy of adding gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia. METHODS: We searched PubMed for reports of randomised controlled trials published in any language up to May 1, 2013, that included an assessment of gemtuzumab ozogamicin given to adults (aged 15 years and older) in conjunction with the first course of intensive induction chemotherapy for acute myeloid leukaemia (excluding acute promyelocytic leukaemia) compared with chemotherapy alone. Published data were supplemented with additional data obtained by contacting individual trialists. The primary endpoint of interest was overall survival. We used standard meta-analytic techniques, with an assumption-free (or fixed-effect) method. We also did exploratory stratified analyses to investigate whether any baseline features predicted a greater or lesser benefit from gemtuzumab ozogamicin. FINDINGS: We obtained data from five randomised controlled trials (3325 patients); all trials were centrally randomised and open label, with overall survival as the primary endpoint. The addition of gemtuzumab ozogamicin did not increase the proportion of patients achieving complete remission with or without complete peripheral count recovery (odds ratio [OR] 0·91, 95% CI 0·77-1·07; p=0·3). However, the addition of gemtuzumab ozogamicin significantly reduced the risk of relapse (OR 0·81, 0·73-0·90; p=0·0001), and improved overall survival at 5 years (OR 0·90, 0·82-0·98; p=0·01). At 6 years, the absolute survival benefit was especially apparent in patients with favourable cytogenetic characteristics (20·7%; OR 0·47, 0·31-0·73; p=0·0006), but was also seen in those with intermediate characteristics (5·7%; OR 0·84, 0·75-0·95; p=0·005). Patients with adverse cytogenetic characteristics did not benefit (2·2%; OR 0·99, 0·83-1·18; p=0·9). Doses of 3 mg/m(2) were associated with fewer early deaths than doses of 6 mg/m(2), with equal efficacy. INTERPRETATION: Gemtuzumab ozogamicin can be safely added to conventional induction therapy and provides a significant survival benefit for patients without adverse cytogenetic characteristics. These data suggest that the use of gemtuzumab ozogamicin should be reassessed and its licence status might need to be reviewed. FUNDING: None.


Assuntos
Aminoglicosídeos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Adulto , Intervalos de Confiança , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão/métodos , Medição de Risco , Taxa de Sobrevida , Resultado do Tratamento
16.
Oncotarget ; 5(15): 6280-8, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25026287

RESUMO

We analysed the prognostic significance of minimal residual disease (MRD) level in adult patients with acute myeloid leukemia (AML) treated in the randomized gemtuzumab ozogamicin (GO) ALFA-0701 trial. Levels of WT1 and NPM1 gene transcripts were assessed using cDNA-based real-time quantitative PCR in 183 patients with WT1 overexpression and in 77 patients with NMP1 mutation (NPM1mut) at diagnosis. Positive WT1 MRD (defined as > 0.5% in the peripheral blood) after induction and at the end of treatment were both significantly associated with a higher risk of relapse and a shorter overall survival (OS). Positive NPM1mut MRD (defined as > 0.1% in the bone marrow) after induction and at the end of treatment also predicted a higher risk of relapse, but did not influence OS. Interestingly, the achievement of a negative NPM1mut MRD was significantly more frequent in patients treated in the GO arm compared to those treated in control arm (39 % versus 7% (p=0.006) after induction and 91% versus 61% (p=0.028) at the end of treatment). However, GO did not influence WT1 MRD levels. Our study supports the prognostic significance of MRD assessed by WT1 and NPM1mut transcript levels and show that NPM1 MRD is decreased by GO treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Proteínas WT1/genética , Idoso , Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Genes do Tumor de Wilms , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Proteínas Nucleares/biossíntese , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resultado do Tratamento , Proteínas WT1/biossíntese
17.
Blood ; 124(9): 1445-9, 2014 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-24973361

RESUMO

Acute myeloid leukemia (AML) with t(8;21) (q22;q22) is considered to have favorable risk; however, nearly half of t(8;21) patients are not cured, and recent studies have highlighted remarkable genetic heterogeneity in this subset of AML. Here we identify somatic mutations in additional sex combs-like 2 (ASXL2) in 22.7% (25/110) of patients with t(8;21), but not in patients with inv(16)/t(16;16) (0/60) or RUNX1-mutated AML (0/26). ASXL2 mutations were similarly frequent in adults and children t(8;21) and were mutually exclusive with ASXL1 mutations. Although overall survival was similar between ASXL1 and ASXL2 mutant t(8;21) AML patients and their wild-type counterparts, patients with ASXL1 or ASXL2 mutations had a cumulative incidence of relapse of 54.6% and 36.0%, respectively, compared with 25% in ASXL1/2 wild-type counterparts (P = .226). These results identify a high-frequency mutation in t(8;21) AML and identify the need for future studies to investigate the clinical and biological relevance of ASXL2 mutations in this unique subset of AML.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Feminino , Frequência do Gene , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/genética , Proteína 1 Parceira de Translocação de RUNX1 , Translocação Genética , Adulto Jovem
18.
Oncotarget ; 5(4): 916-32, 2014 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-24659740

RESUMO

We recently showed that the addition of fractionated doses of gemtuzumab ozogamicin (GO) to standard chemotherapy improves clinical outcome of acute myeloid leukemia (AML) patients. In the present study, we performed mutational analysis of 11 genes (FLT3, NPM1, CEBPA, MLL, WT1, IDH1/2, RUNX1, ASXL1, TET2, DNMT3A), EVI1 overexpression screening, and 6.0 single-nucleotide polymorphism array (SNP-A) analysis in diagnostic samples of the 278 AML patients enrolled in the ALFA-0701 trial. In cytogenetically normal (CN) AML (n=146), 38% of the patients had at least 1 SNP-A lesion and 89% of the patients had at least 1 molecular alteration. In multivariate analysis, the independent predictors of higher cumulative incidence of relapse were unfavorable karyotype (P = 0.013) and randomization in the control arm (P = 0.007) in the whole cohort, and MLL partial tandem duplications (P = 0.014) and DNMT3A mutations (P = 0.010) in CN-AML. The independent predictors of shorter overall survival (OS) were unfavorable karyotype (P <0.001) and SNP-A lesion(s) (P = 0.001) in the whole cohort, and SNP-A lesion(s) (P = 0.006), DNMT3A mutations (P = 0.042) and randomization in the control arm (P = 0.043) in CN-AML. Interestingly, CN-AML patients benefited preferentially more from GO treatment as compared to AML patients with abnormal cytogenetics (hazard ratio for death, 0.52 versus 1.14; test for interaction, P = 0.04). Although the interaction test was not statistically significant, the OS benefit associated with GO treatment appeared also more pronounced in FLT3 internal tandem duplication positive than in negative patients.


Assuntos
Aminoglicosídeos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Idoso , Estudos de Coortes , Citogenética , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento
19.
Am J Hematol ; 89(4): 399-403, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24375467

RESUMO

Gemtuzumab ozogamicin (fGO), a humanized anti-CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD33+ AML aged 55 years or more in first late relapse (≥ 6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m², days 1, 4, 7) with standard-dose cytarabine (200 mg/m² /day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty-four patients (median age 68 years) received fGO with cytarabine. Median follow-up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two-year overall survival (OS) was 51% (95% CI: 28-69) and 2 years relapse-free survival (RFS) was 51% (95%CI: 25-72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Salvação , Idoso , Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Ensaios de Uso Compassivo , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/genética , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Proteínas Recombinantes/uso terapêutico , Indução de Remissão , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente
20.
Genes Chromosomes Cancer ; 53(1): 106-16, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24249260

RESUMO

Mantle cell lymphoma (MCL) is usually an aggressive disease. However, a few patients do have an "indolent" evolution (iMCL) defined by a long survival time without intensive therapy. Many studies highlight the prognostic role of additional genetic abnormalities, but these abnormalities are not routinely tested for and do not yet influence the treatment decision. We aimed to evaluate the prognostic impact of these additional abnormalities detected by conventional cytogenetic testing, as well as their relationships with the clinical characteristics and their value in identifying iMCL. All consecutive MCL cases diagnosed between 1995 and 2011 at four institutions were retrospectively selected on the basis of an informative karyotype with a t(11;14) translocation at the time of diagnosis. A total of 125 patients were included and followed for an actual median time of 35 months. The median overall survival (OS) and survival without treatment (TFS) were 73.7 and 1.3 months, respectively. In multivariable Cox models, a high mantle cell lymphoma international prognostic index score, a complex karyotype, and blastoid morphology were independently associated with a shortened OS. Spleen enlargement, nodal presentation, extra-hematological involvement, and complex karyotypes were associated with shorter TFS. A score based on these factors allowed for the identification of "indolent" patients (median TFS 107 months) from other patients (median TFS: 1 month). In conclusion, in this multicentric cohort of MCL patients, a complex karyotype was associated with a shorter survival time and allowed for the identification of iMCL at the time of diagnosis.


Assuntos
Cromossomos Humanos/genética , Cariótipo , Linfoma de Célula do Manto/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Feminino , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
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