RESUMO
BACKGROUND: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. RESULTS: Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58). CONCLUSION: BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.
Assuntos
Índice de Massa Corporal , Doença de Hodgkin/mortalidade , Linfoma Folicular/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Obesidade/mortalidade , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/tratamento farmacológico , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Prospectivos , Rituximab , Resultado do Tratamento , Estados Unidos , Vincristina/uso terapêuticoRESUMO
BACKGROUND: We previously reported results of the phase 2, multicenter PINNACLE study, which confirmed the substantial single-agent activity of bortezomib in patients with relapsed or refractory mantle cell lymphoma (MCL). MATERIALS AND METHODS: We report updated time-to-event data, in all patients and by response to treatment, after extended follow-up (median 26.4 months). RESULTS: Median time to progression (TTP) was 6.7 months. Median time to next therapy (TTNT) was 7.4 months. Median overall survival (OS) was 23.5 months. In responding patients, median TTP was 12.4 months, median duration of response (DOR) was 9.2 months, median TTNT was 14.3 months, and median OS was 35.4 months. Patients achieving complete response had heterogeneous disease characteristics; among these patients, median TTP and DOR were not reached, and median OS was 36.0 months. One-year survival rate was 69% overall and 91% in responding patients. Median OS from diagnosis was 61.1 months, after median follow-up of 63.7 months. Activity was seen in patients with refractory disease and patients relapsing following high-intensity treatment. Toxicity was generally manageable. CONCLUSIONS: Single-agent bortezomib is associated with lengthy responses and notable survival in patients with relapsed or refractory MCL, with considerable TTP and TTNT in responding patients, suggesting substantial clinical benefit.
Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Bortezomib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazinas/efeitos adversos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Arsenic trioxide (As(2)O(3)) has established clinical activity in acute promyelocytic leukaemia and has pre-clinical data suggesting activity in lymphoid malignancies. Cell death from As(2)O(3) may be the result of oxidative stress. Agents which deplete intracellular glutathione, such as ascorbic acid (AA), may potentiate arsenic-mediated apoptosis. This multi-institution phase II study investigated a novel dosing schedule of As(2)O(3) and AA in patients with relapsed or refractory lymphoid malignancies. Patients received As(2)O(3) 0.25 mg/kg iv and AA 1000 mg iv for five consecutive days during the first week of each cycle followed by twice weekly infusions during weeks 2-6. Cycles were repeated every 8 weeks. The primary end point was objective response. In a subset of patients, sequential levels of intracellular glutathione and measures of Bcl-2 and Bax gene expression were evaluated in peripheral blood mononuclear cells during treatment. Seventeen patients were enrolled between March 2002 and February 2004. The median age was 71, and the majority of enrolled patients had non-Hodgkin's lymphoma (12/17). Sixteen patients were evaluable, and one patient with mantle cell lymphoma achieved an unconfirmed complete response after five cycles of therapy for an overall response rate of 6%. The trial, which had been designed as a two-stage study, was closed after the first stage analysis due to lack of activity. Haematologic toxicities were the most commonly reported events in this heavily pre-treated population, and comprised the majority of grade 3 and 4 toxicities. Intracellular depletion of glutathione was not consistently observed during treatment. As(2)O(3) and AA in this novel dosing strategy was generally well tolerated but had limited activity in patients with relapsed and refractory lymphoid malignancies.
Assuntos
Arsenicais/uso terapêutico , Ácido Ascórbico/uso terapêutico , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Óxidos/toxicidade , Óxidos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Trióxido de Arsênio , Ácido Ascórbico/toxicidade , Feminino , Glutationa/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , SegurançaRESUMO
Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.
Assuntos
Proteínas F-Box/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Tirosina Quinase da Agamaglobulinemia , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Análise por Conglomerados , Perfilação da Expressão Gênica , Humanos , Linfoma de Célula do Manto/patologia , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Sulfonamidas/farmacologiaRESUMO
Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin's lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11-target genes. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.
Assuntos
Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Fatores de Transcrição SOXC/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Sítios de Ligação , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Imunoprecipitação da Cromatina , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Motivos de Nucleotídeos , Prognóstico , Ligação Proteica , Fatores de Transcrição SOXC/genética , Transdução de Sinais , Transcrição Gênica , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
The purpose of this study was to evaluate the efficacy and toxicity of the preparative regimen of thiotepa and etoposide in patients undergoing autologous transplantation for relapsed non-Hodgkin's lymphoma. The study involved 65 consecutive patients who underwent autologous transplantation using the thiotepa/etoposide regimen for relapsed intermediate-grade NHL at the University of Wisconsin Hospital and Clinics (UWHC) between 1987 and 2001. The regimen consisted of thiotepa 300 mg/m(2)/day and etoposide 700 mg/m(2)/day on days -6, -5, and -4. The median age at the time of transplant was 49 years. A total of 50 patients (76%) had diffuse large-cell lymphoma. A total of 50 (77%) patients had chemosensitive disease, and 15 (23%) were chemoresistant. With a median follow-up of 34 months (range, 3-163), 28 patients (43%) remain in CR and 33 (51%) have developed recurrent or progressive disease. The overall survival and event-free survival at 3 years are 40% (95% CI 26-53%) and 32% (95% CI 20-45%), respectively. There was one death attributed to regimen-related toxicity (RRT). Reversible gastrointestinal toxicity was the major RRT, and there was minimal pulmonary and cardiac toxicity. We conclude that the combination of thiotepa and etoposide is an effective preparative regimen with acceptable RRT.
Assuntos
Etoposídeo/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma não Hodgkin/terapia , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Resistencia a Medicamentos Antineoplásicos , Feminino , Gastroenteropatias/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Terapia de Salvação/métodos , Análise de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo , Resultado do TratamentoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Seguimentos , Humanos , Linfoma de Célula do Manto/radioterapia , Prednisona/uso terapêutico , Radioimunoterapia/métodos , Rituximab , Vincristina/uso terapêuticoRESUMO
Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.
Assuntos
Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Anticorpos Monoclonais Murinos/administração & dosagem , Biomarcadores Tumorais/metabolismo , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Técnicas Imunoenzimáticas , Imunofenotipagem , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prednisona/administração & dosagem , Prognóstico , Rituximab , Taxa de Sobrevida , Análise Serial de Tecidos , Vincristina/administração & dosagemRESUMO
BACKGROUND: There is no standard first line treatment for mantle cell lymphoma. PATIENTS AND METHODS: This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide, vincristine doxorubicin, dexamethasone (modified R-hyperCVAD) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years. Unlike traditional hyperCVAD regimens, no methotrexate or cytarabine was administered. RESULTS: Of 22 patients, the overall response rate was 77% and the complete response rate was 64%. With a median follow-up time of 37 months in surviving patients, the median PFS was 37 months and the median OS was not reached. The achievement of a molecular remission did not correlate with improved outcome. The major toxicity was expected myelosuppression. Two patients died during induction treatment. There were no major adverse effects during maintenance therapy. CONCLUSION: In a multicenter trial, modified R-hyperCVAD was tolerable and effective induction therapy for untreated MCL. Maintenance rituximab appeared to prolong PFS without increasing toxicity.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunossupressores/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/análogos & derivados , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Indução de Remissão , Rituximab , Análise de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
In the spring of 1993 an outbreak of a new illness caused by a new pathogen was identified in the southwestern United States. This infection struck relatively young, healthy individuals, was characterized by fever, myalgias, respiratory failure, and a high mortality rate. This illness was caused by a new hantavirus and has been termed hantavirus pulmonary syndrome (HPS). The virus is carried by rodents, shed in saliva, urine, and feces. Human infection occurs through inhalation of aerosolized virus. The clinical syndrome has many non-specific signs and symptoms, but does follow a typical course with characteristic laboratory and radiographic findings. Early recognition of this infection is important so maximal supportive care can be initiated. We report the first documented case of hantavirus pulmonary syndrome in Wisconsin and Illinois.