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2.
Future Oncol ; 15(11): 1197-1205, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30730219

RESUMO

The decisive factor in selecting a treatment regimen for a frail patient with aggressive non-Hodgkin's lymphoma is identifying whether a patient is fit enough to tolerate curative-intent anthracycline-containing regimens or too frail and therefore at risk of being undertreated. As cardiac comorbidities are an important contributor to both the health status and the selection of treatment, cardiovascular profiling and baseline risk stratification prior to treatment should be considered. Comprehensive geriatric assessment is an efficient means of identifying elderly patients with non-Hodgkin's lymphoma who may benefit from a curative treatment approach. If anthracycline-based therapy is not suitable, alternative treatment options are available in frail patients with cardiac comorbidities, but these must be adjusted to the patient's health status to achieve a maximal benefit-risk ratio.


Assuntos
Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Comorbidade , Gerenciamento Clínico , Idoso Fragilizado , Humanos , Linfoma não Hodgkin/epidemiologia , Gradação de Tumores
3.
J Clin Neurosci ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30472338

RESUMO

We present the unique case of an 67-year-old female patient with primary intraspinal B-cell non-Hodgkin's lymphoma without cerebral manifestation mimicking myelitis in clinical presentation and neuroradiological diagnostic. It illustrates the broad spectrum of differential diagnoses for paraplegia and the importance of rapid interdisciplinary diagnostic work-up since the neurologic status after treatment mainly depends on the delay of treatment. Review of existing literature suggests combined radio- and chemotherapy as well as high-dose intravenous methotrexate or rituximab. The rising incidence of spinal lymphomas especially in patients with acquired immunodeficiency underlines the importance of fast diagnosis and initiation of treatment of this rare entity.

4.
Haematologica ; 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237266

RESUMO

Despite significantly improved survival and response rates in patients diagnosed with multiple myeloma, it still remains an incurable disease with a poor outcome especially in high-risk groups. Allogeneic stem cell transplantation offers a potentially curative option but is discussed controversially due to considerable treatment related toxicity. We analyzed 109 consecutive myeloma patients who received reduced-intensity conditioning allogeneic transplantation at the Freiburg University Medical Center between 2000 and 2017. Although most patients were heavily pretreated in high-risk constellations, the overall response rate was high with 70%, the median overall survival 39.2 and the median progression free survival 14.2 months, with a median follow-up of 71.5 months. Survival was significantly better in patients with response to previous therapies than in those with progressive disease (median OS 65 vs. 11.5 months, p=0.003; median PFS 18.4 vs. 5.1 months, p=0.001). Moreover, survival of patients transplanted in first-line was significantly prolonged compared to relapsed/refractory disease (median OS not reached vs. 21.6 months, p<0.001; median PFS 47.7 vs. 9.6 months, p<0.001). The non-relapse mortality was relatively low with a cumulative incidence of 12.4% at 10 years. Acute graft-versus-host disease II-IV occurred in 25%, moderate or severe chronic graft-versus-host disease in 24%. Quality of life assessed with the revised Myeloma Comorbidity Index before and after transplantation remained unchanged. Our data suggest that allogeneic transplantation in the context of novel immunotherapeutic approaches may enable long-term survival and even potential cure in a carefully selected subgroup of high-risk multiple myeloma patients with acceptable toxicity and preserved quality of life.

5.
Leuk Res ; 72: 20-26, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30064039

RESUMO

The combination of 5-azacytidine (AZA) with donor lymphocyte infusions (DLIs) can induce remissions in patients with relapsed myeloid malignancies after allo-HCT. As decitabine (DAC) is known to be effective also in AML/MDS with leukocytosis, we investigated the combination of DAC with DLIs for relapse after allo-HCT. Between 2006 and 2016, 26 patients (median age 59 years) with AML (n = 18), MDS (n = 6), or MPN (n = 2) and overt hematological relapse after allo-HCT were treated. Median duration from allo-HCT to relapse was 306 days (range, 76-4943). Eighteen patients received DAC + DLIs, 8 DAC-only (median number cycles of DAC: 2, range 1-13, median number of DLIs: 2, range 1-10). The incidence of acute and chronic GvHD in patients receiving DLI was 17% (3/18) and 6% (1/18), respectively. CR/CRi was achieved in 15% (4/26), PR in 4% (1/26), and stable disease in 58% (15/26) of patients. Eight patients received a second allo-HCT. Median overall survival was 4.7 months. Elevated PD-L1 protein expression in bone marrow cells was detected in 4/8 patients with >20% blast infiltration prior to DAC, without a clear association with response. In conclusion, the DAC + DLI regimen proved feasible and effective in relapsed myeloid malignancies after allo-HCT, with efficacy not restricted to patients with low leukemic burden.

6.
Biol Blood Marrow Transplant ; 24(11): 2277-2284, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29964193

RESUMO

Lung function deterioration contributes to treatment-related morbidity and mortality in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Better understanding of impaired lung function including bronchiolitis obliterans syndrome (BOS) as chronic manifestation of graft-versus-host disease (GVHD) might improve outcomes of patients after allo-HCT. To detect early pulmonary function test abnormalities associated with BOS incidence and outcome after allo-HCT, we performed a retrospective analysis of homogenous-treated 445 patients (median age, 61.9 years; range, 19 to 76 years) with a reduced intensity/toxicity conditioning protocol. The cumulative incidence of BOS was 4.1% (95% confidence interval [CI], 2.6 to 6.4) at 1 year and 8.6% (95% CI, 6.3 to 11.6) at 5 years after allo-HCT with a median follow-up of 43.2 months (range, 3.3 to 209 months). In multivariate analysis, pre-existence of moderate small airway disease reflected by decreased midexpiratory flows before allo-HCT was associated with increased risk for BOS development. In addition, severe small airway disease before allo-HCT and combined restrictive/obstructive lung disease at day +100 after allo-HCT were associated with higher risk for nonrelapse mortality (NRM) due mainly to pulmonary cause of death. In summary, we identified novel pulmonary function test abnormalities prior and after allo-HCT associated with BOS development and NRM. These findings might help to identify a risk population and result in personalized GVHD prophylaxis and preventive or early therapeutic interventions.

8.
Br J Haematol ; 178(6): 927-935, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28643323

RESUMO

The optimal therapeutic approach for young diffuse large B-cell lymphoma (DLBCL) patients with high-intermediate and high-risk age-adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10-year single-centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R-CHOP-21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first-line high-dose chemotherapy with autologous stem-cell support (HDCT-ASCT), resulting in 2-year progression-free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP-14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose-dense rituximab and high-dose methotrexate resulting in promising overall response- (93·3%) and complete remission (90%) rates and sustained survival (2-year PFS and OS: 93·3%). In an intention-to-treat analysis, 2-year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox-regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83-35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28-26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor-prognosis DLBCL patients appears superior after early therapy intensification.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Transplante de Células-Tronco/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/terapia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prednisona/administração & dosagem , Prognóstico , Rituximab/administração & dosagem , Resultado do Tratamento , Vincristina/administração & dosagem
9.
Lancet Oncol ; 17(3): 319-31, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26899778

RESUMO

BACKGROUND: Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma. METHODS: The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0-2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1-21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov, number NCT00875667. FINDINGS: Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 [67%] were randomly assigned to receive lenalidomide, 84 [33%] to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6-31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months [95% CI 5·5-12·1] vs 5·2 months [95% CI 3·7-6·9]) with a hazard ratio of 0·61 (95% CI 0·44-0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3-4 adverse events included neutropenia (73 [44%] of 167 vs 28 [34%] of 83) without increased risk of infection, thrombocytopenia (30 [18%] vs 23 [28%]), leucopenia (13 [8%] vs nine [11%]), and anaemia (14 [8%] vs six [7%]). INTERPRETATION: Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options. FUNDING: Celgene Corporation.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos/farmacologia , Intervalos de Confiança , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Lenalidomida , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Sobrevida , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Resultado do Tratamento
10.
Leuk Lymphoma ; 57(9): 2150-60, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26757600

RESUMO

The immune cell composition of the follicular lymphoma (FL) tumor microenvironment is increasingly recognized as an important determinant for clinical outcome. Here, we explored frequency and distribution of dendritic cell (DC) subtypes in relation to regulatory T cells (Treg) by immunohistochemistry in lymph node biopsies from patients with de novo FL. We found that neoplastic follicles contained lower DC and higher Treg frequencies than hyperplastic follicles in control lymph nodes. Treg numbers particularly correlated with the subset of conventional CD11c(+ )DCs. Additionally, both a high intra- to interfollicular ratio of CD11c(+ )DCs and increased intrafollicular Treg frequencies were associated with decreased overall survival. This suggests that functional interactions between these cells may be relevant for FL progression/recurrence. The presence of CD11c(+ )DCs in the tumor microenvironment may assist tumor infiltration by Tregs, thus contributing to the suppression of an otherwise beneficial T-cell-dominated FL microenvironment.


Assuntos
Células Dendríticas/imunologia , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Progressão da Doença , Feminino , Expressão Gênica , Antígenos HLA-DR/genética , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfonodos/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Linfoma Folicular/mortalidade , Linfoma Folicular/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
12.
Blood ; 126(24): 2578-84, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26480933

RESUMO

This long-term follow-up analysis evaluated overall survival (OS) and relapse-free survival (RFS) in a phase 2 study of the bispecific T-cell engager antibody construct blinatumomab in 36 adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). In the primary analysis, 25 (69%) patients with relapsed/refractory ALL achieved complete remission with full (CR) or partial (CRh) hematologic recovery of peripheral blood counts within the first 2 cycles. Twenty-five patients (69%) had a minimal residual disease (MRD) response (<10(-4) blasts), including 22 CR/CRh responders, 2 patients with hypocellular bone marrow, and 1 patient with normocellular bone marrow but low peripheral counts. Ten of the 36 patients (28%) were long-term survivors (OS ≥30 months). Median OS was 13.0 months (median follow-up, 32.6 months). MRD response was associated with significantly longer OS (Mantel-Byar P = .009). All 10 long-term survivors had an MRD response. Median RFS was 8.8 months (median follow-up, 28.9 months). A plateau for RFS was reached after ∼18 months. Six of the 10 long-term survivors remained relapse-free, including 4 who received allogeneic stem cell transplantation (allo-SCT) as consolidation for blinatumomab and 2 who received 3 additional cycles of blinatumomab instead of allo-SCT. Three long-term survivors had neurologic events or cytokine release syndrome, resulting in temporary blinatumomab discontinuation; all restarted blinatumomab successfully. Long-term survivors had more pronounced T-cell expansion than patients with OS <30 months.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Imunossupressores/uso terapêutico , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Terapia de Salvação , Subpopulações de Linfócitos T/patologia , Adolescente , Adulto , Idoso , Aloenxertos , Anticorpos Biespecíficos/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Citocinas/metabolismo , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/efeitos adversos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Recidiva , Indução de Remissão , Subpopulações de Linfócitos T/efeitos dos fármacos , Adulto Jovem
13.
Biomark Insights ; 10(Suppl 3): 15-23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26327780

RESUMO

Targeting tyrosine kinases represents a highly specific treatment approach for different malignancies. This also includes non-Hodgkin lymphoma since it is well known that these enzymes are frequently involved in the lymphomagenesis. Hereby, tyrosine kinases might either be dysregulated intrinsically or be activated within signal transduction pathways leading to tumor survival and growth. Among others, Bruton's tyrosine kinase (Btk) is of particular interest as a potential therapeutic target. Btk is stimulated by B-cell receptor signaling and activates different transcription factors such as nuclear factor κB. The Btk inhibitor ibrutinib has been approved for the treatment of chronic lymphocytic leukemia and mantle-cell lymphoma recently. Numerous clinical trials evaluating this agent in different combinations (eg, with rituximab or classical chemotherapeutic agents) as a treatment option for aggressive and indolent lymphoma are under way. Here, we summarize the role of tyrosine kinase inhibitors in the treatment of indolent and other non-Hodgkin lymphomas (eg, mantle-cell lymphoma).

14.
J Allergy Clin Immunol ; 135(4): 988-97.e6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25595268

RESUMO

BACKGROUND: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted. OBJECTIVE: We sought to define the outcomes of HSCT for patients with CVID. METHODS: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. RESULTS: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. CONCLUSION: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.


Assuntos
Imunodeficiência de Variável Comum/terapia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Adolescente , Adulto , Causas de Morte , Criança , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/mortalidade , Feminino , Seguimentos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento , Adulto Jovem
15.
J Clin Oncol ; 32(36): 4134-40, 2014 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-25385737

RESUMO

PURPOSE: Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell-engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort. PATIENTS AND METHODS: Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs). RESULTS: Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically. CONCLUSION: The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Biespecíficos/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Recidiva , Indução de Remissão
16.
PLoS One ; 9(11): e112831, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25397617

RESUMO

Constitutive Ras signaling has been shown to augment IL-2 production, reverse anergy, and functionally replace many aspects of CD28 co-stimulation in CD4+ T cells. These data raise the possibility that introduction of active Ras into primary T cells might result in improved functionality in pathologic situations of T cell dysfunction, such as cancer or chronic viral infection. To test the biologic effects of active Ras in primary T cells, CD4+ T cells from Coxsackie-Adenovirus Receptor Transgenic mice were transduced with an adenovirus encoding active Ras. As expected, active Ras augmented IL-2 production in naive CD4+ T cells. However, when cells were cultured for 4 days under conditions to promote effector cell differentiation, active Ras inhibited the ability of CD4+ T cells to acquire a Th1 or Th2 effector cytokine profile. This differentiation defect was not due to deficient STAT4 or STAT6 activation by IL-12 or IL-4, respectively, nor was it associated with deficient induction of T-bet and GATA-3 expression. Impaired effector cytokine production in active Ras-transduced cells was associated with deficient demethylation of the IL-4 gene locus. Our results indicate that, despite augmenting acute activation of naïve T cells, constitutive Ras signaling inhibits the ability of CD4+ T cells to properly differentiate into Th1/Th2 effector cytokine-producing cells, in part by interfering with epigenetic modification of effector gene loci. Alternative strategies to potentiate Ras pathway signaling in T cells in a more regulated fashion should be considered as a therapeutic approach to improve immune responses in vivo.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Citocinas/biossíntese , Proteínas ras/metabolismo , Animais , Western Blotting , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/genética , Ativação Enzimática/fisiologia , Ensaio de Imunoadsorção Enzimática , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real
17.
Haematologica ; 98(1): 31-40, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22801964

RESUMO

Despite advances in immunosuppressive regimens, acute graft-versus-host disease remains a frequent complication of allogeneic hematopoietic cell transplantation. Pathogenic donor T cells are dependent on correct attachment of small GTPases to the cell membrane, mediated by farnesyl- or geranylgeranyl residues, which, therefore, constitute potential targets for graft-versus-host disease prophylaxis. A mouse model was used to study the impact of a farnesyl-transferase inhibitor and a geranylgeranyl-transferase inhibitor on acute graft-versus-host disease, anti-cytomegalovirus T-cell responses and graft-versus-leukemia activity. Treatment of mice undergoing allogeneic hematopoietic cell transplantation with farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor reduced the histological severity of graft-versus-host disease and prolonged survival significantly. Mechanistically, farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor treatment resulted in reduced alloantigen-driven expansion of CD4 T cells. In vivo treatment led to increased thymic cellularity and polyclonality of the T-cell receptor repertoire by reducing thymic graft-versus-host disease. These effects were absent when squalene production was blocked. The farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor did not compromise CD8 function against leukemia cells or reconstitution of T cells that were subsequently responsible for anti-murine cytomegalovirus responses. In summary, we observed an immunomodulatory effect of inhibitors of farnesyl-transferase and geranylgeranyl-transferase on graft-versus-host disease, with enhanced functional immune reconstitution. In the light of the modest toxicity of farnesyl-transferase inhibitors such as tipifarnib in patients and the potent reduction of graft-versus-host disease in mice, farnesyl-transferase and geranylgeranyl-transferase inhibitors could help to reduce graft-versus-host disease significantly without having a negative impact on immune reconstitution.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Prenilação/fisiologia , Prenilação de Proteína/fisiologia , Animais , Transplante de Medula Óssea/efeitos adversos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Leucemia/efeitos dos fármacos , Efeito Enxerto vs Leucemia/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Prenilação/efeitos dos fármacos , Prenilação de Proteína/efeitos dos fármacos , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Resultado do Tratamento
18.
Ann Hematol ; 91(12): 1929-35, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22847152

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) is a curative approach for several diseases predominantly affecting elderly patients. Overall survival is compromised by treatment-related mortality (TRM), GvHD, and relapse. Pretransplant clinical risk indicators in elderly patients qualifying for HCT are highly desirable. Pro-BNP is known as a predictor of death in patients with an increasing variety of clinical conditions and frequently used as a routine parameter for organ complications in the allogeneic transplant setting without well-established scientific evidence. Our hypothesis was that pre-HCT NT-pro-BNP could aid in identifying elderly patients at risk for early mortality. We retrospectively evaluated NT-pro-BNP values in 177 consecutive patients of ≥60 years HCT (2005-2010). In 29.4 % of cases, NT-pro-BNP values were within our institute's normal range (<125 pg/ml). Analysis of different NT-pro-BNP cutoff points by receiver operating characteristics curve for mortality at day +100 revealed no single cutoff value with satisfying specificity and sensitivity. The individual outcome of patients with extremely high NT-pro-BNP values was not associated with an increase in mortality or cardiovascular morbidity. NT-pro-BNP values of patients succumbing to TRM did not differ significantly from those alive or having died of relapse-median 276 vs. 217 pg/ml. In conclusion, pre-HCT NT-pro-BNP was of no convincing prognostic relevance for day 100 mortality.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/sangue , Transtornos Linfoproliferativos/sangue , Síndromes Mielodisplásicas/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Centros Médicos Acadêmicos , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/fisiopatologia , Leucemia Mieloide Aguda/terapia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/fisiopatologia , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/fisiopatologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Curva ROC , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo
19.
Cell Immunol ; 276(1-2): 187-95, 2012 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22695258

RESUMO

Rap1, which is closely related to ras, plays a key role in T-cell receptor (TCR)-signaling. TCR-stimulation without costimulation leads to constitutively activated rap1, which may mediate T-cell anergy via inhibition of ras-dependent induction of extracellular signal-regulated kinases (ERK). This activation is mediated by a second protein kinase b-Raf. Rap1-GTP is thought to activate ERK in a ras-independent manner by binding b-raf. Generally, T cells do not express b-raf while they express the adaptor protein raf-1, which is usually sequestered by rap1 leading to inhibition of ras-mediated ERK activation. In this study, we demonstrate that in rap1-deficient T cells, signaling by the ERK and p38 kinases is increased following activation by different stimuli leading to increased intracellular accumulation and secretion of cytokines. In addition, in a hypersensitivity model rap1-deficient mice demonstrated reduced contact dermatitis compared to wildtype mice, demonstrating the impact of rap1-deficiency on the inflammatory response in vivo.


Assuntos
Citocinas/imunologia , Sistema de Sinalização das MAP Quinases , Proteínas rap1 de Ligação ao GTP/imunologia , Animais , Ativação Enzimática , Inflamação/imunologia , Camundongos , Camundongos Knockout , Fenótipo , Proteínas rap1 de Ligação ao GTP/deficiência
20.
Biol Blood Marrow Transplant ; 18(9): 1430-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22430085

RESUMO

Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use. For less-fit patients with acute lymphoblastic leukemia and other hematologic malignancies frequently affecting the central nervous system, we designed a radiation-free regimen with fludarabine (25 mg/m2/day on days -6 to -4), carmustine (400 mg/m2 on day -6), and thiotepa (5 mg/kg twice daily on days -5 and -4), all of which readily penetrate the blood-brain barrier and have potent antileukemic and lymphotoxic activity. Here we present a series of 30 consecutive patients with high-risk or relapsed disease who underwent allogeneic hematopoietic cell transplantation with this protocol. The median patient age was 60 years (range, 42-70 years), and the median follow-up was 968 days (range, 58-1989 days). Graft-versus-host disease prophylaxis consisted of cyclosporine A and alemtuzumab (10-20 mg). At 2 years, overall survival was 52% (95% confidence interval [CI], 34%-71%), event-free survival was 39% (95% CI, 22%-57%), cumulative incidence of relapse/progression was 30% (95% CI, 17%-52%), and treatment-related mortality was 31% (95% CI, 18%-53%). Neurologic toxicity is a concern, especially in older and heavily pretreated patients. Our experience indicates the feasibility of this regimen as an alternative to total body irradiation and a potentially curative option for less-fit patients who need a highly central nervous system-active conditioning.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Alemtuzumab , Anticorpos Monoclonais Humanizados/uso terapêutico , Carmustina/uso terapêutico , Sistema Nervoso Central/fisiopatologia , Ciclosporina/uso terapêutico , Esquema de Medicação , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Tiotepa/uso terapêutico , Transplante Homólogo , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
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