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1.
Haematologica ; 109(7): 2219-2228, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38356463

RESUMO

The treatment landscape for multiple myeloma has significantly evolved in the last decade. Notwithstanding, a large proportion of patients continue to relapse and novel combinations continue to be needed. In this phase II study, selinexor, a first-in-class inhibitor of exportin-1 was evaluated in combination with standard daratumumab-bortezomib-dexamethasone (DVd), for the treatment of relapsed and refractory multiple myeloma (RRMM). The aim of the trial was to assess the efficacy and safety of the combination of selinexor with DVd (S-DVd). A total of 57 patients were enrolled in the two parts of the study. Part 1 enrolled a heavily pretreated population with at least three prior lines (PL) of therapy and part 2 enrolled an early relapse population with at least one PL of therapy. The primary endpoint was complete response (CR) rate in part 2 and overall response rate (ORR) in part 1. In the latter, 24 patients were treated with a median of three PL. Overall response rate (ORR) was 50% with two CR. Median progression- free survival (PFS) was 7 months. In part 2, 33 patients were enrolled, with a median of one PL. ORR was 82% and CR or better was 33%. Median PFS was 24 months. In lenalidomide-refractory patients, a median PFS of 22.1 months was observed. Thrombocytopenia was the most common hematological adverse event (69%; grade 3-4: 34%) and nausea, the most frequent non-hematological adverse event (38%; grade 3-4: 6%). Sixty-two percent of the patients required dose modifications. In summary, although the primary endpoint of the study was not met, the combination of S-DVd showed encouraging clinical efficacy with a generally manageable safety profile representing a potential option for the treatment of RRMM patients.


Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Hidrazinas , Mieloma Múltiplo , Triazóis , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Triazóis/administração & dosagem , Triazóis/uso terapêutico , Triazóis/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Hidrazinas/administração & dosagem , Hidrazinas/uso terapêutico , Hidrazinas/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Idoso de 80 Anos ou mais , Adulto , Resultado do Tratamento , Resistencia a Medicamentos Antineoplásicos , Recidiva
2.
Haematologica ; 104(2): 288-296, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30093399

RESUMO

A high proportion of patients with acute myeloid leukemia who achieve minimal residual disease negative status ultimately relapse because a fraction of pathological clones remains undetected by standard methods. We designed and validated a high-throughput sequencing method for minimal residual disease assessment of cell clonotypes with mutations of NPM1, IDH1/2 and/or FLT3-single nucleotide variants. For clinical validation, 106 follow-up samples from 63 patients in complete remission were studied by sequencing, evaluating the level of mutations detected at diagnosis. The predictive value of minimal residual disease status by sequencing, multiparameter flow cytometry, or quantitative polymerase chain reaction analysis was determined by survival analysis. The sequencing method achieved a sensitivity of 10-4 for single nucleotide variants and 10-5 for insertions/deletions and could be used in acute myeloid leukemia patients who carry any mutation (86% in our diagnostic data set). Sequencing-determined minimal residual disease positive status was associated with lower disease-free survival (hazard ratio 3.4, P=0.005) and lower overall survival (hazard ratio 4.2, P<0.001). Multivariate analysis showed that minimal residual disease positive status determined by sequencing was an independent factor associated with risk of death (hazard ratio 4.54, P=0.005) and the only independent factor conferring risk of relapse (hazard ratio 3.76, P=0.012). This sequencing-based method simplifies and standardizes minimal residual disease evaluation, with high applicability in acute myeloid leukemia. It is also an improvement upon flow cytometry- and quantitative polymerase chain reaction-based prediction of outcomes of patients with acute myeloid leukemia and could be incorporated in clinical settings and clinical trials.


Assuntos
Biomarcadores Tumorais , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos Proporcionais , Fluxo de Trabalho
3.
Br J Haematol ; 181(3): 350-359, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29611196

RESUMO

Treatment with azacitidine (AZA) has been suggested to be of benefit for higher-risk myelodysplastic syndrome (HR-MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR-MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time-varying variable in multivariable analysis. A Cox Regression model with time-interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non-CK) and International Prognostic Scoring System risk (high versus intermediate-2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P < 0·001 at 1 year, 0·7 P = 0·019 at 2 years; 0·73 P = 0·029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non-CK patients, P < 0·05 for all). AZA also significantly improved progression-free survival (P < 0·01). This study confirms a time-dependent benefit of AZA on outcome in patients with HR-MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK.


Assuntos
Azacitidina/administração & dosagem , Cromossomos Humanos Par 7/genética , Síndromes Mielodisplásicas , Sistema de Registros , Idoso , Aberrações Cromossômicas , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
4.
Blood ; 126(7): 858-62, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26089396

RESUMO

Stringent complete response (sCR) criteria are used in multiple myeloma as a deeper response category compared with CR, but prospective validation is lacking, it is not always clear how evaluation of clonality is performed, and is it not known what the relative clinical influence is of the serum free light chain ratio (sFLCr) and bone marrow (BM) clonality to define more sCR. To clarify this controversy, we focused on 94 patients that reached CR, of which 69 (73%) also fulfilled the sCR criteria. Patients with sCR displayed slightly longer time to progression (median, 62 vs 53 months, respectively; P = .31). On analyzing this contribution to the prognosis of sFLCr or clonality, it was found that the sFLCr does not identify patients in CR at distinct risk; by contrast, low-sensitive multiparametric flow cytometry (MFC) immunophenotyping (2 colors), which is equivalent to immunohistochemistry, identifies a small number of patients (5 cases) with high residual tumor burden and dismal outcome; nevertheless, using traditional 4-color MFC, persistent clonal BM disease was detectable in 36% of patients, who, compared with minimal residual disease-negative cases, had a significantly inferior outcome. These results show that the current definition of sCR should be revised.


Assuntos
Medula Óssea/patologia , Cadeias Leves de Imunoglobulina/sangue , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Transplante de Medula Óssea , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Mieloma Múltiplo/terapia , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
5.
Blood ; 123(20): 3073-9, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24646471

RESUMO

We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma (MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD(-) by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P < .0001) and overall survival (median not reached vs 81 months; P = .02), compared with patients who were MRD(+). When stratifying patients by different levels of MRD, the respective TTP medians were: MRD ≥10(-3) 27 months, MRD 10(-3) to 10(-5) 48 months, and MRD <10(-5) 80 months (P = .003 to .0001). Ninety-two percent of VGPR patients were MRD(+). In complete response patients, the TTP remained significantly longer for MRD(-) compared with MRD(+) patients (131 vs 35 months; P = .0009).


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Medula Óssea/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Neoplasia Residual , Prognóstico
6.
Ann Hematol ; 94(4): 565-73, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25387664

RESUMO

Previous studies have shown the reproducibility of the 2008 World Health Organization (WHO) classification in myelodysplastic syndromes (MDS), especially when multilineage dysplasia or excess of blasts are present. However, there are few data regarding the reproducibility of MDS with unilineage dysplasia. The revised International Prognostic Scoring System R-IPSS described two new morphological categories, distinguishing bone marrow (BM) blast cell count between 0-2 % and >2- < 5 %. This distinction is critical for establishing prognosis, but the reproducibility of this threshold is still not demonstrated. The objectives of our study were to explore the reliability of the 2008 WHO classification, regarding unilineage vs. multilineage dysplasia, by reviewing 110 cases previously diagnosed with MDS, and to study whether the threshold of ≤2 % BM blasts is reproducible among different observers. We used the same methodology as in our previous paper [Font et al. (2013) Ann Hematol 92:19-24], by encouraging investigators to include patients with <5 % BM blasts. Samples were collected from 11 hospitals and were evaluated by 11 morphologists. Each observer evaluated 20 samples, and each sample was analyzed independently by two morphologists. Discordance was observed in 36/108 suitable cases (33 %, kappa test 0.503). Diagnosis of MDS with unilineage dysplasia (refractory cytopenia with unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts (RARS) or unclassifiable MDS) was assessed in 33 patients, by either of the two observers. We combined this series with the cases with RCUD or RARS included in our 2013 paper, thus obtaining 50 cases with unilineage dysplasia by at least one of the observers. The whole series showed very low agreement regarding RCUD (5/23, 21 %) and RARS (5/28, 18 %). Regarding BM blast count, the threshold of ≤2 % was not reproducible (discordance rate 32/108 cases, kappa test 0.277). Our study shows that among MDS WHO 2008 categories, interobserver discordance seems to be high in cases with unilineage dysplasia. We also illustrate that the threshold of ≤2 % BM blasts as settled by the R-IPSS may be not easy to reproduce by morphologists in real practice.


Assuntos
Crise Blástica/patologia , Medula Óssea/patologia , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Contagem de Células/estatística & dados numéricos , Linhagem da Célula , Citodiagnóstico/estatística & dados numéricos , Feminino , Humanos , Masculino , Variações Dependentes do Observador , Prognóstico , Reprodutibilidade dos Testes
7.
Eur J Haematol ; 93(4): 309-19, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24758317

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease. To date, many reviews and series have been described. We report the experience of our center by presenting a review of 56 PNH patient cases with an average age at diagnosis of 38 yr and follow-ups beginning at approximately 40 yr; the median survival rate was 11 yr. The average clonal size upon diagnosis was 48%, presenting a variable evolution. Thrombotic episodes and cancer were five each, and the main causes of death among our patients were equal at 8.9%. Radiological study by magnetic resonance imaging is presented as a fundamental technique for estimating the deposit of iron levels in the liver and kidney, as well as in some decisive cases at the start of eculizumab therapy. Sixteen patients have been treated with eculizumab so far in our series, and being a safe drug, it provides improvement in the patients' quality of life, and the disappearance of clinical symptoms, and avoids the emergence of new thrombosis.


Assuntos
Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Medula Óssea/patologia , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/mortalidade , Humanos , Imunofenotipagem , Transplante de Fígado , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Gravidez , Insuficiência Renal/etiologia , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
8.
BMC Gastroenterol ; 11: 130, 2011 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-22123067

RESUMO

BACKGROUND: Vascular complications, such as HAT, are an important cause of graft loss and recipient mortality. We aimed to characterize post-transplant thrombotic events in a cohort of liver transplant recipients, and identify independent risk factors for these complications. METHODS: We conducted a thrombophilic study of 293 orthotopic liver transplants performed in the Digestive Surgery Department of the 12 de Octubre Hospital (Madrid, Spain) between January 2001 and December 2006. RESULTS: The most frequent post-transplant thrombotic events were HAT (9%) and PVT (1.7%). The one variable associated with post-transplant thrombotic event was a high fibrinogen level in the global cohort of liver transplantation. But toxicity as event post-OLT has been associated with post-transplant thrombotic event in the retrospective group and high fibrinogen level and low protein C levels were associated post-transplant thrombotic event in the prospective group. Liver disease relapse (HR 6.609, p < 0.001), high levels of FVIII (HR 1.008, p = 0.019)) and low levels of antithrombin (HR 0.946, p < 0.001) were associated with poor overall survival (OS).In conclusion, high fibrinogen and decreased protein C levels were associated with allograft thrombosis. Further studies are required in order to assess the clinical relevance of these parameters in prospective studies and to study the effect of anticoagulation prophylaxis in this group of risk.


Assuntos
Sobrevivência de Enxerto , Artéria Hepática , Transplante de Fígado/efeitos adversos , Veia Porta , Trombofilia/complicações , Trombose/etiologia , Adolescente , Adulto , Antitrombinas/metabolismo , Criança , Pré-Escolar , Fator VIII/metabolismo , Feminino , Fibrinogênio/metabolismo , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Proteína C/metabolismo , Estudos Retrospectivos , Fatores de Risco , Trombofilia/sangue , Trombofilia/genética , Trombose/sangue , Adulto Jovem
9.
Antioxidants (Basel) ; 8(11)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652983

RESUMO

Control of oxidative stress in the bone marrow (BM) is key for maintaining the interplay between self-renewal, proliferation, and differentiation of hematopoietic cells. Breakdown of this regulation can lead to diseases characterized by BM failure such as the myelodysplastic syndromes (MDS). To better understand the role of oxidative stress in MDS development, we compared protein carbonylation as an indicator of oxidative stress in the BM of patients with MDS and control subjects, and also patients with MDS under treatment with the iron chelator deferasirox (DFX). As expected, differences in the pattern of protein carbonylation were observed in BM samples between MDS patients and controls, with an increase in protein carbonylation in the former. Strikingly, patients under DFX treatment had lower levels of protein carbonylation in BM with respect to untreated patients. Proteomic analysis identified four proteins with high carbonylation levels in MDS BM cells. Finally, as oxidative stress-related signaling pathways can modulate the cell cycle through p53, we analyzed the expression of the p53 target gene p21 in BM cells, finding that it was significantly upregulated in patients with MDS and was significantly downregulated after DFX treatment. Overall, our results suggest that the fine-tuning of oxidative stress levels in the BM of patients with MDS might control malignant progression.

11.
Leuk Res ; 38(3): 304-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24333115

RESUMO

Patients with isolated del(5q) and MDS are considered to have good prognosis as compared to other MDS subtypes. Most patients suffered of anemia and 50% of them required transfusions at diagnosis. It is known that for patients with MDS and del(5q) in transfusion dependence(TD), Lenalidomide is the first choice treatment. However, there are no data regarding natural evolution of anemia in patients diagnosed in MDS and del(5q) without TD, factors that may impact on the development of TD or disease outcome. In the present study we have performed a retrospective multicenter analysis on 83 patients with low-int 1 MDS and del(5q) without TD. During the study 61 patients became TD at a median of 1.7 years and only the Hb level 9 g/dL was associated with poorer TFS (p = 0.007) in the multivariate analysis. Among these 61 TD patients, 49 received treatment (19 Lenalidomide). Median follow up was 48 months, estimated OS at 2 and 5 year was 92% and 50% respectively. In the multivariate analysis for OS, platelets <100,000 mm(-3) and Lenalidomide treatment retained the statistical significant impact. LFS at 2 and 5 years was 86% and 73% respectively, and median time to sAML was 8.16 years (CI 95%: 6.05-10.27). In the multivariate analysis only thrombocytopenia retained statistical significance. In summary, this retrospective study show that level of Hb is an important parameter in order to determine the time until TD, it should be also stressed the importance of an early treatment in order to prevent TD development and shorter survival.


Assuntos
Anemia/diagnóstico , Transfusão de Sangue/estatística & dados numéricos , Deleção Cromossômica , Cromossomos Humanos Par 5 , Síndromes Mielodisplásicas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Anemia/mortalidade , Anemia/terapia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Progressão da Doença , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Fatores de Tempo
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