RESUMO
In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated patients with advanced-stage, indolent non-Hodgkin lymphoma (iNHL). After a median patient follow-up of more than 108 months, we performed an intent-to-treat analysis of our 83 participants. Progression-free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten-year PFS rates for those with beta-2-microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10-year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long-term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10-year follow-up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Doenças da Medula Óssea/mortalidade , Ciclofosfamida/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/mortalidade , Pentostatina/administração & dosagem , Rituximab/administração & dosagem , Resultado do TratamentoRESUMO
Histone methylation and demethylation regulate B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting cure rates. Since histone methylation status correlates with disease aggressiveness and relapse, we investigated the therapeutic potential of inhibiting histone 3 Lys27 demethylase KDM6B, in vitro, using the small molecule inhibitor GSK-J4. KDM6B is overexpressed in the germinal center B-cell subtype of diffuse large B-cell lymphoma, and higher KDM6B levels are associated with worse survival in patients with diffuse large B-cell lymphoma treated with R-CHOP. GSK-J4-induced apoptosis was observed in five (SU-DHL-6, OCI-Ly1, Toledo, OCI-Ly8, SU-DHL-8) out of nine germinal center B-cell diffuse large B-cell lymphoma cell lines. Treatment with GSK-J4 predominantly resulted in downregulation of B-cell receptor signaling and BCL6. Cell lines expressing high BCL6 levels or CREBBP/EP300 mutations were sensitive to GSK-J4. Our results suggest that B-cell receptor-dependent downregulation of BCL6 is responsible for GSK-J4-induced cytotoxicity. Furthermore, GSK-J4-mediated inhibition of KDM6B sensitizes germinal center B-cell diffuse large B-cell lymphoma cells to chemotherapy agents that are currently utilized in treatment regimens for diffuse large B-cell lymphoma.
Assuntos
Antineoplásicos/farmacologia , Benzazepinas/farmacologia , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/metabolismo , Pirimidinas/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Prognóstico , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Mantle cell lymphoma (MCL) is considered an aggressive subtype of non-Hodgkin's lymphoma with variable treatment responses. There is an urgent need to identify novel markers with prognostic and therapeutic value for MCL. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancers, including MCL. Metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a lncRNA located at pathognomonic translocation site of t (11; 14) of MCL. MALAT1 is known to be overexpressed in solid tumors and hematologic malignancies. However, the pathological role and clinical relevance of MALAT1 in MCL are not completely understood. METHODS: We quantified MALAT1 in MCL samples (40) and CD19+ B cells by quantitative real time polymerase chain reaction (qRT-PCR) and correlated levels with clinical outcome. We silenced MALAT1 in MCL cell lines and analyzed cells in tumorigenic assays and formation of transcription complexes. RESULTS: We found that the expression of MALAT1 was elevated in human MCL tumors and cell lines as compared to normal controls, and the elevated levels of MALAT1 correlated with higher MCL international prognostic index (MIPI) and reduced overall survival. MCL with knockdown of MALAT1 showed impaired cell proliferation, facilitated apoptosis and produced fewer clonogenic foci. The increased expression of p21 and p27 upon MALAT1 knockdown was regulated by enhancer of zeste homolog 2 (EZH2). Moreover, decreased phosphorylation of EZH2 at T350 attenuated the binding to MALAT1. CONCLUSIONS: Our findings illuminate the oncogenic role of MALAT1, which may serve as a novel biomarker and as a therapeutic target in MCL.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , RNA Longo não Codificante/metabolismo , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Modelos Biológicos , Fosforilação , Complexo Repressor Polycomb 2/metabolismo , Ligação Proteica , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Análise de SobrevidaRESUMO
We conducted a prospective phase II trial of pentostatin, cyclophosphamide and rituximab as initial therapy for patients with previously untreated advanced stage low-grade or indolent B-cell lymphomas (iNHLs). Of 83 evaluable patients, 91·6% attained an overall response and 86·8% a complete or unconfirmed complete response. The 3-year progression-free survival (PFS) and overall survival rates were 73% and 93%, respectively. The 3-year PFS rate was significantly different for different diagnoses (P = 0·01): 83% [95% confidence interval (CI): 0·72, 0·96] for follicular lymphomas, 73% (95% CI: 0·54, 1·0) for marginal zone lymphomas and 61% (95% CI: 0·46, 0·81) for small lymphocytic lymphomas. The most common adverse events were haematological. Of 509 cycles of chemotherapy administered, grade 3 or 4 neutropenia was reported in 68 cycles (13% of cycles administered) and most frequently occurred during cycles 4-6. This is the first report demonstrating the effectiveness of pentostatin, cyclophosphamide and rituximab in patients with previously untreated iNHLs, including those over 60 years of age.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Pentostatina/administração & dosagem , Indução de Remissão , Rituximab , Resultado do TratamentoRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse after a complete response or are refractory to therapy. To survive, the activated B-cell (ABC) subtype of DLBCL relies upon B-cell receptor signaling, which can be modulated by the activity of Bruton tyrosine kinase (BTK). Targeting BTK with ibrutinib, an inhibitor, provides a therapeutic approach for this subtype of DLBCL. However, non-Hodgkin lymphoma is often resistant to ibrutinib or acquires resistance soon after exposure. We explored how this resistance develops. We generated 3 isogenic ibrutinib-resistant DLBCL cell lines and investigated the deregulated pathways known to be associated with tumorigenic properties. Reduced levels of BTK and enhanced phosphatidylinositol 3-kinase (PI3K)/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of PI3K-ß expression was demonstrated to drive resistance in ibrutinib-resistant cells, and resistance was reversed by the blocking activity of PI3K-ß/δ. Treatment with the selective PI3K-ß/δ dual inhibitor KA2237 reduced both tumorigenic properties and survival-based PI3K/AKT/mTOR signaling of these ibrutinib-resistant cells. In addition, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited metabolic growth. This study elucidates the compensatory upregulated PI3K/AKT axis that emerges in ibrutinib-resistant cells.
Assuntos
Linfoma Difuso de Grandes Células B , Fosfatidilinositol 3-Quinase , Tirosina Quinase da Agamaglobulinemia , Linhagem Celular Tumoral , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Recidiva Local de Neoplasia , Fosfatidilinositol 3-Quinases/genéticaRESUMO
The new capability to generate mimicking chemical analogues and perform mass screenings of candidate drugs has been tested on B-cell receptor signalling, a driver of B-cell malignancies. These efforts have identified ibrutinib as a potent inhibitor of Bruton's tyrosine kinase. As the clinical use of ibrutinib increases, continued vigilant monitoring for rare adverse events is prudent, including the development of secondary malignancies. To date, the most common reported secondary malignancy is non-melanoma skin cancer; however, we present a case of secondary primary lung adenocarcinoma becoming clinically apparent shortly after initiating therapy with ibrutinib. Our patient had a sudden regression of the tumour with discontinuance of ibrutinib, and based on our understanding of paradoxical tumour growth caused by tyrosine kinase inhibitors it is our hypothesis that the complex multikinase activity of ibrutinib may stimulate tumour growth by targeting a subset of protein kinases critical for growth in some cancer cells.
Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma de Pulmão , Idoso , Humanos , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Piperidinas , Tomografia Computadorizada por Raios XRESUMO
Interdigitating dendritic cell sarcoma (IDCS) is a rare tumour; only seven cases of IDCS associated with chronic lymphocytic leucaemia/small lymphocytic lymphoma (CLL/SLL) have been reported. We present the case of a 60-year-old man who presented with fevers, night sweats and significant unintentional weight loss. Investigations led to a diagnosis of synchronous SLL and IDCS. Subsequent fluorodeoxyglucose (FDG) positron emission tomography CT (PET-CT) imaging revealed an unusual clinical course with spontaneously resolving highly metabolic lesions. After 42 months of follow-up, the patient remains free of clinical symptoms and evidence of IDCS.
Assuntos
Sarcoma de Células Dendríticas Interdigitantes/diagnóstico , Leucemia Linfocítica Crônica de Células B/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Tomografia por Emissão de Pósitrons , Remissão Espontânea , Transformação Celular Neoplásica , Sarcoma de Células Dendríticas Interdigitantes/metabolismo , Sarcoma de Células Dendríticas Interdigitantes/patologia , Febre/etiologia , Fluordesoxiglucose F18/administração & dosagem , Fluordesoxiglucose F18/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/metabolismo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Redução de PesoRESUMO
UNLABELLED: Hepatocellular carcinomas (HCC) show resistance to chemotherapy and have blunt response to apoptotic stimuli. HCC cell lines express low levels of the Fas death receptor and are resistant to FasL stimulation, whereas immortalized hepatocytes are sensitive. The variable Fas transcript levels and consistently low Fas protein in HCC cells suggest posttranscriptional regulation of Fas expression. The 3'-untranslated region (UTR) of Fas mRNA was found to interact with the ribonucleoprotein Human Antigen R (HuR) to block mRNA translation. Silencing of HuR in HCC cells increased the levels of cell surface Fas and sensitized HCC cells to FasL. Two AU-rich domains within the 3'-UTR of Fas mRNA were identified as putative HuR-binding sites and were found to mediate the translational regulation in reporter assay. Hydrodynamic transfection of HuR plasmid into mice induced downregulation of Fas expression in livers and established functional resistance to the killing effects of Fas agonist. Human HCC tumor tissues showed significantly higher overall and cytoplasmic HuR staining compared with normal liver tissues, and the high HuR staining score correlated with worse survival of patients with early-stage HCC. Combined, the protumorigenic ribonucleoprotein HuR blocks the translation of Fas mRNA and effectively prevents Fas-mediated apoptosis in HCC, suggesting that targeting HuR would sensitize cells to apoptotic stimuli and reverse tumorigenic properties. IMPLICATIONS: Demonstrating how death receptor signaling pathways are altered during progression of HCC will enable the development of better methods to restore this potent apoptosis mechanism.