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1.
Blood ; 131(17): 1955-1959, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29437588

RESUMO

Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.


Assuntos
Aspergilose/induzido quimicamente , Aspergilose/epidemiologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/epidemiologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Adenina/análogos & derivados , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/microbiologia , Masculino , Piperidinas , Fatores de Tempo
2.
Br J Haematol ; 170(1): 40-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25825041

RESUMO

There are limited data on retreatment with monoclonal antibodies (mAb) in patients with chronic lymphocytic leukaemia (CLL). In a pivotal study, ofatumumab (human anti-CD20 mAb) monotherapy demonstrated a 47% objective response rate (ORR) in fludarabine refractory CLL patients. From this study, a subset of 29 patients who had at least stable disease and then progressed were retreated with eight weekly ofatumumab infusions (induction treatment period), followed by monthly infusions for up to 2 years (maintenance treatment period). The ORR after 8 weeks of induction retreatment was 45% and 24% had continued disease control after maintenance at 52 weeks. Efficacy and safety of the retreated patients were compared with their initial results in the pivotal study. Response duration was 24.1 months vs. 6.8 months; time to next therapy was 14.8 months vs. 12.3 months; and progression-free survival was 7.4 months vs. 7.9 months (medians). Upon retreatment, 72% had infusion reactions, mostly Grade 1-2. Three patients had fatal infections. In summary, ofatumumab retreatment and maintenance therapy was feasible in patients with heavily pretreated CLL and appeared to result in more durable disease control than initial ofatumumab treatment in this subset of patients who may have a more favourable disease profile.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Vidarabina/análogos & derivados , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Retratamento , Vidarabina/farmacologia
5.
Clin Nephrol ; 78(4): 316-21, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22981033

RESUMO

The association of Fanconi syndrome (FS) and chronic kidney disease (CKD) has been rarely described during the course of paroxysmal nocturnal hemoglobinuria (PNH). We report 2 patients with PNH and CKD associated with proximal tubule dysfunction, which manifested as full-blown FS in one case. In both patients, abnormal iron load within the kidneys was demonstrated by magnetic resonance imaging, which correlated with diffuse and numerous hemosiderin inclusions within proximal tubular cells. After 12 months, eculizumab treatment resulted in significant decrease in the kidney iron load in both cases. Glomerular filtration rate improved in one case and was stabilized in the other, in whom pretreatment kidney biopsy had shown severe extensive interstitial fibrosis. However, symptoms of proximal tubular dysfunction persisted in both patients. These data suggest that hemosiderin deposition in proximal tubules is probably an important mechanism involved in the development of FS, an under recognized and early manifestation of CKD in PNH. Prolonged treatment with eculizumab may improve long-term renal function in PNH patients with CKD.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome de Fanconi/etiologia , Hemoglobinúria Paroxística/complicações , Nefropatias/etiologia , Idoso , Doença Crônica , Feminino , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade
6.
Haematologica ; 95(6): 950-5, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20081058

RESUMO

BACKGROUND: Patients with poor-risk Waldenström's macroglobulinemia have suboptimal response and early post-treatment relapse with conventional therapies. Hence, new therapeutic approaches such as allogeneic stem cell transplantation should be evaluated in these patients. DESIGN AND METHODS: We examined the long-term outcome of allogeneic stem cell transplantation in Waldenström's macroglobulinemia by studying the records of 24 patients reported in the SFGM-TC database and one transplanted in the bone marrow unit in Hamburg. RESULTS: Median age at the time of transplant was 48 years (range, 24-64). The patients had previously received a median of 3 lines of therapy (range, 1-6) and 44% of them had refractory disease at time of transplant. Allogeneic stem cell transplantation after myeloablative (n=12) or reduced-intensity (n=13) conditioning yielded an overall response rate of 92% and immunofixation-negative complete remission in 50% of evaluable patients. With a median follow-up of 64 months among survivors (range, 11-149 months), 5-year overall survival and progression-free survival rates were respectively, 67% (95% CI: 46-81) and 58% (95% CI: 38-75). The 5-year estimated risk of progression was 25% (95% CI: 10-36%), with only one relapse among the 12 patients who entered complete remission, versus 5 in the 12 patients who did not. Only one of the 6 relapses occurred more than three years post-transplant. CONCLUSIONS: Allogeneic stem cell transplantation yields a high rate of complete remissions and is potentially curative in poor-risk Waldenström's macroglobulinemia.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Sociedades Médicas , Macroglobulinemia de Waldenstrom/cirurgia , Adulto , Intervalo Livre de Doença , Feminino , Seguimentos , França , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/mortalidade , Macroglobulinemia de Waldenstrom/patologia , Adulto Jovem
7.
Leukemia ; 34(8): 2038-2050, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32071431

RESUMO

We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0-99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p < 0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W&W, p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care "watch and wait" for these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Estudos Prospectivos , Rituximab/administração & dosagem , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
8.
Ann Hematol ; 88(12): 1215-21, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19340428

RESUMO

Several prognostic factors can predict the rapid progression in chronic lymphocytic leukaemia (CLL), including IGHV mutational status, cytogenetic abnormalities and, more recently, LPL/ADAM29 expression. In contrast, few studies have been devoted to the influence of these factors on clinical outcome in responding patients after therapy. We here propose to analyse the impact of IGHV gene status, LPL and ADAM29 gene expression on disease-free survival (DFS) and overall survival (OS) in 41 stage B or C CLL patients in remission after oral fludarabine plus cyclophosphamide. The median follow-up was of 64 (16-74) months. Sequencing of IGHV showed mutated (M) VH genes in 16 of 41 cases and unmutated (UM) in 25 cases. Analysis of LPL and ADAM29 expression in 35 of 41 cases showed overexpression of ADAM29 in 17 cases (14 M and three UM) and LPL in 18 cases (all UM). Patients expressing UM IGHV and LPL had shorter DFS and OS when compared to patients expressing M IGHV and/or ADAM29. Furthermore, blood minimal residual disease (MRD) evaluation using four-colour flow cytometry was performed in 33 out the 41 patients. We showed that patients who achieved phenotypic remission displayed longer DFS than those with MRD(+). Our results support the use of LPL and ADAM29 gene expression associated to IGHV mutational status for predicting the clinical outcome of patients treated by oral fludarabine + cyclophosphamide and could be considered for treatment strategies.


Assuntos
Proteínas ADAM/genética , Antineoplásicos/uso terapêutico , Ciclofosfamida/uso terapêutico , Genes de Cadeia Pesada de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B , Lipase Lipoproteica/genética , Vidarabina/análogos & derivados , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Indução de Remissão , Resultado do Tratamento , Vidarabina/uso terapêutico
9.
Ann Biol Clin (Paris) ; 77(4): 439-445, 2019 08 01.
Artigo em Francês | MEDLINE | ID: mdl-31418706

RESUMO

A 67 years old woman with a Waldenström disease was admitted in the intensive care unit for dyspnea and fever. During hospitalization, episodes of undetectable glycemia were observed without any hypoglycemia symptoms. Plasma glucose was determined with the hexokinase method (recommended). From this observation, a literature review on PubMed was performed to investigate similar cases. In patients with protides in excess (e.g. immunoproliferative syndrome), absorption measurements could be disrupted by the precipitation of excess protein (IgM in most cases). Other parameters could be affected: bilirubin, phosphate, HDL cholesterol, GGT, CRP and calcemia. In our case, the main difficulty was to identify the cause of the interference and then correct it. Using a series of dilution, we prevented protide precipitation allowing correct glucose determination. Those interferences are rare, but present a real analytical difficulty. Biologists should be aware of those interferences because of dramatics consequences.


Assuntos
Análise Química do Sangue/métodos , Glicemia/análise , Hexoquinase/metabolismo , Hipoglicemia/diagnóstico , Paraproteínas/efeitos adversos , Macroglobulinemia de Waldenstrom/sangue , Idoso , Artefatos , Análise Química do Sangue/normas , Glicemia/metabolismo , Diagnóstico Diferencial , Dispneia/sangue , Dispneia/diagnóstico , Dispneia/etiologia , Reações Falso-Positivas , Feminino , Febre/sangue , Febre/diagnóstico , Febre/etiologia , Hexoquinase/química , Humanos , Hipoglicemia/sangue , Paraproteínas/metabolismo , Hemorragia Retiniana/sangue , Hemorragia Retiniana/diagnóstico , Hemorragia Retiniana/etiologia , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/diagnóstico
10.
Br J Haematol ; 143(1): 54-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18710390

RESUMO

A multicentre single-arm study testing the efficacy and toxicity of the oral combination of fludarabine and cyclophosphamide (FC) over 5 d in 75 patients with untreated B cell-chronic lymphocytic leukaemia. Oral FC demonstrated high efficacy with overall (OR) and complete response (CR) rates of 80% and 53%, respectively. Out of the 30 CR patients studied for Minimal Residual Disease (MRD) using 4-colour flow-cytometry and the 22 using Clonospecific polymerase chain reaction, 22 (66%) and 16 (68%), respectively, were MRD negative. Median survival and median treatment-free interval had not been reached at 7 years of follow-up. Median progression-free survival (PFS) was 5 years. Toxicity was acceptable, with 52% and 16% of National Cancer Institute grade 3/4 neutropenia and infections, respectively. Gastrointestinal toxicity was mild. Oral FC demonstrated a high efficacy and an acceptable safety profile and may be considered as the standard first line treatment in chronic lymphocytic leukaemia.


Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Fosfato de Vidarabina/análogos & derivados , Adulto , Idoso , Biomarcadores/urina , Creatinina/urina , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento , Fosfato de Vidarabina/efeitos adversos , Fosfato de Vidarabina/uso terapêutico
11.
Leuk Lymphoma ; 58(6): 1366-1375, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28271952

RESUMO

This prospective non-interventional study assessed the management of relapsed/refractory CLL after one or two treatments with rituximab, and retreatment with a rituximab-based regimen. An interim analysis was performed at the end of the induction period in 192 evaluable patients. Median age was 72 years [35-89], first relapse (55%), and second relapse (45%). Rituximab administered during first (68%), second (92%), or both treatment lines (20%). R-bendamustine administered in 56% of patients, R-purine analogs (21%), and R-alkylating agents (19%). The overall response rate (ORR) was 74.6%, in favor of R-purine analogs (90%), R-bendamustine (75%), and R-alkylating agents (69%). Lower ORR in Del 17p patients (43%) and third time rituximab (31%). Most frequent adverse events were hematological (23% patients) including neutropenia (11%) and infections (12%); grade 3/4 AEs (23% patients), mainly hematological (18%); death during induction treatment (7%). This first large study focusing on relapsed/refractory CLL patients retreated with rituximab-based regimens is still ongoing.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , França/epidemiologia , Humanos , Leucemia Linfocítica Crônica de Células B/epidemiologia , Masculino , Pessoa de Meia-Idade , Recidiva , Retratamento , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Resultado do Tratamento
12.
Leuk Lymphoma ; 58(11): 2615-2623, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28395585

RESUMO

In patients with advanced Waldenström macroglobulinemia (WM), overall response rate (ORR) and median progression-free survival (PFS) achieved with bortezomib alone and bortezomib rituximab combination were 27-85% and 7.9 months, and 81% and 16.4 months, respectively. We checked the role of dexamethasone in combination with bortezomib by enrolling in a phase II trial 34 patients with relapsed/refractory WM. Bortezomib (1.3 mg/m2 IV D1, 4, 8, and 11 every 21 days) was used for six cycles. In non-responding patients, dexamethasone (20 mg daily for two days) was added to each infusion after the second cycle. After two cycles, the Bayes estimated ORR was 43.2 (95% Credible Interval: 28.0-59.1%) using the informative prior. Two-year survival rate was 84.0% and the median PFS 15.3 months without difference between patients treated with or without dexamethasone. We conclude that dexamethasone must be associated to bortezomib-based regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Teorema de Bayes , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Macroglobulinemia de Waldenstrom/patologia
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