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1.
Blood Adv ; 7(16): 4576-4585, 2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37307169

RESUMO

Time to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton's tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Célula do Manto , Adulto , Humanos , Linfoma de Célula do Manto/patologia , Antígeno Ki-67 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico
2.
Lancet ; 397(10277): 892-901, 2021 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676628

RESUMO

BACKGROUND: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients. METHODS: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529. FINDINGS: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date. INTERPRETATION: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients. FUNDING: Loxo Oncology.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma de Células B/patologia , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do Tratamento
3.
Ann Pharmacother ; 54(9): 879-898, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32079411

RESUMO

Objectives: To discuss (1) recent and emerging data for pharmacological management of untreated and relapsed/refractory (R/R) mantle cell lymphoma (MCL) with agents approved in the United States, (2) important considerations for toxicity monitoring and management, and (3) preliminary data and ongoing studies for agents in MCL-specific clinical trials. Data Sources: PubMed/MEDLINE, EMBASE, Google Scholar, product labeling, National Comprehensive Cancer Network, American Cancer Society, and ClinicalTrials.gov were searched for studies published between January 1, 2017, and January 31, 2020, and key historical trials. Study Selection and Data Extraction: Relevant studies conducted in humans and selected supporting preclinical data were reviewed. Data Synthesis: MCL is a rare but usually aggressive non-Hodgkin lymphoma that most commonly affects the older population. Traditionally, the treatment of MCL has been determined based on transplant eligibility. Newer data suggest that more tolerable frontline therapy may produce outcomes similar to intensive historical induction regimens, possibly precluding fewer patients from autologous stem cell transplant and producing better long-term outcomes in transplant-ineligible patients. In the R/R setting, novel regimens are improving outcomes and changing the landscape of treatment. Relevance to Patient Care and Clinical Practice: This review summarizes and discusses recent and emerging data for management of newly diagnosed and R/R MCL; key supportive care considerations for agents are also discussed. Conclusions: Recent study results are changing management of MCL. Although these data have complicated the picture of regimen selection, increasingly effective and tolerable therapy and additional anticipated data point to a brighter future for patients with MCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Linfoma de Célula do Manto/tratamento farmacológico , Administração Oral , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
4.
Comb Chem High Throughput Screen ; 22(7): 483-495, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31526347

RESUMO

AIM AND OBJECTIVE: Mantle Cell Lymphoma (MCL) is typically an aggressive and rare disease with poor prognosis, therefore new effective therapeutics are urgently needed. Drug repurposing for cancer treatment is becoming increasingly more attractive as an alternative approach to discover clinically approved drugs that demonstrate antineoplastic effect. The objective of this study was to screen an approved drug library and identify candidate compounds with an antineoplastic effect in MCL cells using High-Throughput Screening (HTS) technique. MATERIALS AND METHODS: Using the HTS technique, nearly 3,800 clinically approved drugs and drug candidates were screened in Jeko and Mino MCL cell lines. We also demonstrated the selectivity window of the candidate compounds in six normal cell lines. Further validations were performed in caspase-3/7 apoptosis assay and three-dimensional (3D) multicellular aggregates model using Z138 cell line. RESULTS: We identified 98 compounds showing >50% inhibition in either MCL cell line screened, they were distributed across eight unique therapeutic categories and have different mechanisms of action (MOA). We selected alisertib, carfilzomib, pracinostat and YM155 for further validation based on their antiproliferative activity in two MCL cell lines, selectivity to normal cell lines, and drug developing stages in terms of clinical research. Alisertib and carfilzomib showed antiproliferative effect on MCL cell with EC50 = 6 nM and >100-fold selectivity to normal cell lines, especially for alisertib which demonstrated >1000-fold selectivity to 5 out of 6 normal cell lines. Pracinostat and YM155 had potency of 11 and 12 nM in MCL cell with >20-fold selectivity to normal cell lines. All four compounds had been tested in caspase-dependent apoptosis assay. We further validated and demonstrated their anti-MCL effect on cell proliferation and (3D) multicellular aggregates model using Z138 cell line. CONCLUSION: This is the first study to examine such a large library of clinically approved compounds for the identification of novel drug candidates for MCL treatment, the results could be rapidly translated into clinical practice in patients with MCL.


Assuntos
Antineoplásicos/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios de Triagem em Larga Escala , Humanos , Linfoma de Célula do Manto/patologia , Bibliotecas de Moléculas Pequenas/química
5.
Clin Cancer Res ; 23(23): 7158-7164, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28733439

RESUMO

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. Clin Cancer Res; 23(23); 7158-64. ©2017 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Projetos de Pesquisa , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Modelos Teóricos , Piperidinas , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento
6.
J Clin Oncol ; 34(11): 1256-69, 2016 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-26755518

RESUMO

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma previously considered to have a poor prognosis. Large gains were made in the first decade of the new century when clinical trials established the importance of high-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients and the benefits of maintenance rituximab and bendamustine in older patients. In particular, greater depth of understanding of the molecular pathophysiology of MCL has resulted in an explosion of specifically targeted new efficacious agents. In particular, agents recently approved by the Food and Drug Administration include the proteasome inhibitor bortezomib, immunomodulator lenalidomide, and Bruton's tyrosine kinase inhibitor ibrutinib. We review recent advances in the understanding of MCL biology and outline our recommended approach to therapy, including choice of chemoimmunotherapy, the role of stem-cell transplantation, and mechanism-based targeted therapies, on the basis of a synthesis of the data from published clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/administração & dosagem , Bortezomib/farmacologia , Citarabina/administração & dosagem , Esquema de Medicação , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Quimioterapia de Indução , Lenalidomida , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/cirurgia , Quimioterapia de Manutenção , Estadiamento de Neoplasias , Piperidinas , Prognóstico , Pirazóis/farmacologia , Pirimidinas/farmacologia , Fatores de Risco , Rituximab/administração & dosagem , Talidomida/análogos & derivados , Talidomida/farmacologia , Transplante Autólogo
7.
Future Oncol ; 12(4): 477-91, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26759179

RESUMO

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase which acts by downstream inhibition of the B-cell receptor. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile in relapsed/refractory MCL. Although the majority of disease responses are partial, efficacy data are impressive with more than two-thirds of patients demonstrating a durable response. This article focuses on all aspects of ibrutinib in the context of MCL, including a summary of the basic pharmacology and pharmacokinetics; a review of the safety and efficacy data published to date and a discussion of the future implications in MCL.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Piperidinas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/metabolismo , Recidiva , Resultado do Tratamento
8.
Cancer ; 120(13): 1993-9, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24706502

RESUMO

BACKGROUND: T-cell lymphomas (TCLs) are uncommon in the United States. The accurate diagnosis of TCL is challenging and requires morphologic interpretation, immunophenotyping, and molecular techniques. The authors compared pathologic diagnoses at referring centers with diagnoses from expert hematopathology review to determine concordance rates and to characterize the usefulness of second-opinion pathology review for TCL. METHODS: Patients in the National Comprehensive Cancer Network non-Hodgkin lymphoma database with peripheral TCL, not otherwise specified (PTCL-NOS), angioimmunoblastic TCL (AITL), and anaplastic lymphoma kinase (ALK)-positive and ALK-negative anaplastic large cell lymphoma (ALCL) were eligible if they had prior tissue specimens examined at a referring institution. Pathologic concordance was evaluated using available pathology and diagnostic testing reports and provider progress notes. The etiology of discordance and the potential impact on treatment were examined. RESULTS: Among 131 eligible patients, 57 (44%) had concordant results, totaling 64% of the 89 patients who were referred with a final diagnosis. Thirty-two patients (24%) had discordant results, representing 36% of those who were referred with a final diagnosis. The rates of discordance among patients with of PTCL-NOS, AITL, ALK-negative ALCL, and ALK-positive ALCL were 19%, 33%, 34%, and 6%, respectively. In 14 patients (44% of discordant results), pathologic reclassification could have resulted in a different therapeutic strategy. Forty-two patients (32%) were referred for classification with a provisional diagnosis. CONCLUSIONS: In a large cohort of patients with TCL who were referred to National Comprehensive Cancer Network centers, the likelihood of a concordant final diagnosis at a referring institution was low. As current and future therapies target TCL subsets, these data suggest that patients with suspected TCLs would benefit from evaluation by an expert hematopathologist.


Assuntos
Biomarcadores Tumorais/análise , Linfoma de Células T/patologia , Receptores Proteína Tirosina Quinases/análise , Encaminhamento e Consulta , Atenção Secundária à Saúde , Adulto , Idoso , Quinase do Linfoma Anaplásico , Estudos de Coortes , Diagnóstico Diferencial , Linfoma de Células T Associado a Enteropatia/patologia , Feminino , Citometria de Fluxo , Humanos , Linfadenopatia Imunoblástica/patologia , Imuno-Histoquímica , Imunofenotipagem , Linfoma Difuso de Grandes Células B/patologia , Linfoma Anaplásico de Células Grandes/patologia , Linfoma de Célula do Manto/patologia , Linfoma de Células T/terapia , Masculino , Pessoa de Meia-Idade , Encaminhamento e Consulta/estatística & dados numéricos , Atenção Secundária à Saúde/estatística & dados numéricos , Estados Unidos
9.
Leuk Res ; 36(7): 912-20, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22560334

RESUMO

Mantle cell lymphoma (MCL) is one of the most difficult B-cell lymphomas to be treated. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is constitutively activated in MCL and plays a critical role in tumor growth and survival. However, single targeted agent mTOR has limited efficacy in treating MCL. Here, we investigate for the first time potential efficacy of NVP-BEZ235 (BEZ235) in treating MCL by simultaneously targeting Akt and mTOR. In this study, phosphorylated Akt and mTOR level were elevated in tissue samples from MCL patients and in MCL cell lines. We also generated bortezomib-resistant MCL cell lines and found increased phosphorylation of Akt and mTOR. Individual inhibition of PI3K or mTOR had limited anti-proliferative effects, whereas dual inhibition with BEZ235 effectively inhibited cell growth. The effect of BEZ235 was synergistic and sensitized the cells to the cytotoxic effects of conventional agents. Furthermore, BEZ235 could overcome acquired resistance to bortezomib in MCL cells and suppress the activated Akt/mTOR pathway. Therefore, these data suggest that the Akt/mTOR pathway plays a key role in the growth and survival of MCL cells and that these proteins may need to be simultaneously targeted for effective treatment of the disease. Our findings suggest that BEZ235 may be an effective agent for the treatment of MCL.


Assuntos
Ácidos Borônicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imidazóis/farmacologia , Linfoma de Célula do Manto/patologia , Pirazinas/farmacologia , Quinolinas/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Ácidos Borônicos/administração & dosagem , Bortezomib , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/administração & dosagem , Quinolinas/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores
10.
Leuk Lymphoma ; 52(3): 394-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21323520

RESUMO

Bortezomib and gemcitabine have each shown activity as single agents in mantle cell lymphoma (MCL), which is incurable. The purpose of this phase II study was to determine the efficacy and safety of the previously unstudied combination of bortezomib and gemcitabine in patients with relapsed or refractory MCL. Patients were eligible if they had relapsed MCL with 1-3 prior therapies. Patients were treated with gemcitabine 1000 mg/m(2) on days 1 and 8 and bortezomib 1.0 mg/m(2) IV on days 1, 4, 8, and 11, on a 21-day schedule. Twenty-six patients were evaluable for toxicity and 25 for response. The overall response rate was 60% and the median progression free survival was 11.4 months. The main adverse effects were hematological, with 40% and 48% of patients experiencing grade 3/4 thrombocytopenia and granulocytopenia, respectively. Bortezomib and gemcitabine is an active combination in relapsed and refractory MCL with clinically meaningful results. It offers a chemotherapy backbone to which other agents, less myelosuppressive, may be added.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Desoxicitidina/análogos & derivados , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/efeitos adversos , Bortezomib , Canadá , Ensaios Clínicos como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Oncologia/organização & administração , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Pirazinas/efeitos adversos , Recidiva , Sociedades Médicas , Gencitabina
11.
Cancer ; 117(11): 2442-51, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24048792

RESUMO

BACKGROUND: In vitro studies in mantle cell lymphoma (MCL) cell lines and patient-derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R-bortezomib) compared with single-agent bortezomib. Therefore, the authors of this report evaluated R-bortezomib in a preclinical model and in a phase 2 clinical trial. METHODS: A Hu-MCL-severe combined immunodeficiency (SCID) model engrafted with the Jeko cell line was treated with R-bortezomib, bortezomib, or rituximab. Twenty-five patients with relapsed follicular lymphoma (n = 11) and MCL (n = 14) received 375 mg/m(2) rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m(2) bortezomib on Days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1-5 cycles). RESULTS: R-bortezomib resulted in a statistically significant improvement in overall survival in Hu-MCL-SCID mice. In the clinical trial, the overall response rate was 40% in all 25 patients, 55% in patients with follicular lymphoma, and 29% in patients with MCL. The estimated 2-year progression-free survival (PFS) rate was 24% (95% confidence interval [CI], 10%-53%) in all patients and 60% (95% CI, 20%-85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity, which consisted of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients who were heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (P = .009) after R-bortezomib compared with HH and RR homozygotes. CONCLUSIONS: R-bortezomib had significant activity in patients with relapsed or refractory follicular lymphoma and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity was a potential limiting factor with this combination.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/uso terapêutico , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Receptores de IgG/genética , Recidiva , Rituximab , Resultado do Tratamento
12.
PLoS One ; 5(6): e10941, 2010 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-20532179

RESUMO

BACKGROUND: While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies. PRINCIPAL FINDINGS: In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC(50) (50% growth inhibitory concentration) of AR-42 is 0.61 microM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC(50) (concentration lethal to 50%) of AR-42 is 0.76 microM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity. CONCLUSIONS/SIGNIFICANCE: Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies.


Assuntos
Linfoma de Burkitt/patologia , Inibidores de Histona Desacetilases/farmacologia , Linfoma de Célula do Manto/patologia , Fenilbutiratos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Apoptose , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos
13.
Br J Haematol ; 150(2): 158-69, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20507312

RESUMO

Mantle cell lymphoma (MCL) is characterized by translocation t(11;14)(q13;q32), aggressive clinical behaviour, and poor patient outcomes following conventional chemotherapy. New treatment approaches are needed that target novel biological pathways. All trans retinoic acid (ATRA) is a key retinoid that acts through nuclear receptors that function as ligand-inducible transcription factors. The present study evaluated cell killing effects of ATRA-enriched nanoscale delivery particles, termed nanodisks (ND), on MCL cell lines. Results show that ATRA-ND induced cell death more effectively than naked ATRA (dimethyl sulphoxide) or empty ND. ATRA-ND induced reactive oxygen species (ROS) generation to a greater extent than naked ATRA. The antioxidant, N-acetylcysteine, inhibited ATRA-ND induced apoptosis. Compared to naked ATRA, ATRA-ND enhanced G1 growth arrest, up-regulated p21and p27, and down regulated cyclin D1. At ATRA concentrations that induced apoptosis, expression levels of retinoic acid receptor-alpha (RARalpha) and retinoid X receptor-gamma (RXRgamma) were increased. Compared to naked ATRA, ATRA-ND significantly stimulated transcriptional activity of RARA in a model carcinoma cell line. Furthermore, the RAR antagonist, Ro 41-5253, inhibited ATRA-ND induced ROS generation and prevented ATRA-ND induced cell growth arrest and apoptosis. In summary, incorporation of ATRA into ND enhanced the biological activity of this retinoid in cell culture models of MCL.


Assuntos
Antineoplásicos/farmacologia , Linfoma de Célula do Manto/patologia , Receptores do Ácido Retinoico/efeitos dos fármacos , Tretinoína/farmacologia , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Benzoatos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/efeitos dos fármacos , Cromanos/farmacologia , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Fatores de Troca do Nucleotídeo Guanina/biossíntese , Fatores de Troca do Nucleotídeo Guanina/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/metabolismo , Nanopartículas , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/efeitos dos fármacos , Proteínas Nucleares/biossíntese , Proteínas Nucleares/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores do Ácido Retinoico/antagonistas & inibidores , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides/efeitos dos fármacos , Receptores X de Retinoides/metabolismo , Transcrição Gênica/efeitos dos fármacos , Tretinoína/administração & dosagem , Células Tumorais Cultivadas
14.
Br J Haematol ; 147(3): 297-307, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19709085

RESUMO

8-Chloroadenosine (8-Cl-Ado), an RNA-directed nucleoside analogue, is currently under evaluation in phase I clinical trials for treatment of chronic lymphocytic leukaemia. In the current study, the efficacy of 8-Cl-Ado was evaluated using mantle cell lymphoma (MCL) cell lines: Granta 519, JeKo, Mino, and SP-53. After continuous exposure to 10 mumol/l 8-Cl-Ado for 24 h, loss of mitochondrial transmembrane potential and poly [adenosine diphosphate (ADP)-ribose] polymerase (PARP) cleavage were detected in three of four cell lines. Reduced ATP levels (30-60% reduction) and concurrent 8-Cl-ATP accumulation were highly associated with cell death (P < 0.01). The intracellular 8-Cl-ATP concentrations were also highly correlated with inhibition of global transcription (50-90%, r(2) = 0.90, P < 0.01). However, the inhibition of transcription only accounted for 30-40% of cell death as determined by equivalent inhibition with actinomycin D. Likewise, short-lived mRNAs, those encoding cyclin D1 and Mcl-1, were not consistently reduced after treatment. Unique to MCL as compared to other haematological malignancies, 8-Cl-Ado inhibited the rates of DNA synthesis and selectively depleted dATP pools (50-80%). We conclude that the DNA and RNA directed actions of 8-Cl-Ado in combination with depleted energetics may promote cell death and inhibit growth of MCL cell lines.


Assuntos
2-Cloroadenosina/análogos & derivados , Antineoplásicos/farmacologia , Linfoma de Célula do Manto/patologia , 2-Cloroadenosina/farmacocinética , 2-Cloroadenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Antineoplásicos/farmacocinética , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/biossíntese , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Linfoma de Célula do Manto/metabolismo , Transcrição Gênica/efeitos dos fármacos , Células Tumorais Cultivadas
15.
Clin Cancer Res ; 14(17): 5416-25, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18765533

RESUMO

PURPOSE: The ubiquitin-proteasome pathway has been validated as a target in non-Hodgkin's lymphoma through demonstration of the activity of the proteasome inhibitor bortezomib. EXPERIMENTAL DESIGN: Another potentially attractive target is the human homologue of the murine double minute-2 protein, HDM-2, which serves as the major p53 E3 ubiquitin ligase; we therefore evaluated the activity of a novel agent, MI-63, which disrupts the HDM-2/p53 interaction. RESULTS: Treatment of wild-type p53 mantle cell lymphoma (MCL) cell lines with MI-63 resulted in a dose- and time-dependent inhibition of proliferation, with an IC(50) in the 0.5 to 5.0 micromol/L range. MI-63 induced p53 and HDM-2 accumulation, as well as other downstream p53 targets such as p53 up-regulated modulator of apoptosis and p21(Cip1). This was associated with cell cycle arrest at G(1)-S; activation of caspase-3, caspase-8, and caspase-9; cleavage of poly-(ADP-ribose) polymerase; and loss of E2F1. HDM-2 inhibition caused phosphorylation of p53 at multiple serine residues, including 15, 37, and 392, which coincided with low levels of DNA strand breaks. DNA damage occurred in a small percentage of cells and did not induce phosphorylation of the DNA damage marker H2A.X(Ser139). Combinations of MI-63 with the molecularly targeted agents bortezomib and rapamycin showed synergistic, sequence-dependent antiproliferative effects. Treatment of primary MCL patient samples resulted in apoptosis and induction of p53 and p21, which was not seen in normal controls. CONCLUSIONS: These findings support the hypothesis that inhibition of the HDM-2/p53 interaction may be a promising approach both by itself and in combination with currently used chemotherapeutics against lymphoid malignancies.


Assuntos
Linfoma de Célula do Manto/genética , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Avaliação Pré-Clínica de Medicamentos , Humanos , Linfoma de Célula do Manto/patologia , Fosforilação , Ubiquitina-Proteína Ligases/antagonistas & inibidores
16.
Blood ; 109(12): 5455-62, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17317853

RESUMO

Atiprimod is a novel cationic amphiphilic compound and has been shown to exert antimyeloma effects both in vitro and in mouse experiments. This study was undertaken to evaluate the therapeutic efficacy of atiprimod on mantle cell lymphoma (MCL) and elucidate the mechanism by which it induces cell apoptosis. Atiprimod inhibited the growth and induced apoptosis of MCL cell lines and freshly isolated primary tumor cells in vitro. More importantly, atiprimod significantly inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice. However, atiprimod also exhibited lower cytotoxicity toward normal lymphocytes. Atiprimod activated c-Jun N-terminal protein kinases (JNK) and up-regulated the level of Bax, Bad, and phosphorylated Bcl-2, resulting in release of apoptosis-inducing factor (AIF) and cytochrome c from mitochondria and activation and cleavage of caspase-9, caspase-3, and PARP. However, AIF, but not activation of caspases or PARP, was responsible for apoptosis in MCL cells because an AIF inhibitor, but not pan-caspase or paspase-9 inhibitors, completely abrogated atiprimod-induced apoptosis. Taken together, our results demonstrate that atiprimod displays a strong anti-MCL activity. Cell apoptosis was induced mainly via activation of the AIF pathway. These results support the use of atiprimod as a potential agent in MCL chemotherapy.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linfoma de Célula do Manto/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Linfoma de Célula do Manto/patologia , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/efeitos dos fármacos
17.
Br J Haematol ; 135(1): 68-71, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16925576

RESUMO

Mantle cell lymphoma (MCL), a distinct type of non-Hodgkin lymphoma, is characterised by the overexpression of cyclin D1. Heat shock protein 90 (HSP90) is a molecular chaperon to proteins that regulate cell cycle and survival. 17-allylamino-17-demethoxy-geldanamycin (17-AAG), a HSP90 small molecule inhibitor, induced G(0/1) cell cycle arrest and cell death in a dose- and time-dependent manner in MCL cell lines. This effect was associated with the downregulation of cyclin D1, cdk4 and Akt, depletion of Bid, and activation of the intrinsic/mitochondrial caspase pathway. These data suggest that 17-AAG may have a potential therapeutic value in patients with MCL.


Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Linfoma de Célula do Manto/patologia , Proteínas de Neoplasias/metabolismo , Apoptose/efeitos dos fármacos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Caspase 9 , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Tumorais Cultivadas
18.
Eur J Haematol ; 76(1): 42-50, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16343270

RESUMO

OBJECTIVES: Mantle cell lymphoma (MCL) is an incurable disease with an aggressive course and novel treatment strategies are urgently needed. The purpose of this study was to evaluate the effects of histone deacetylase (HDAC) inhibitors, a new group of antiproliferative agents, on human MCL cells. METHODS: Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) for 8-72 h. Their effects on cell viability, apoptosis induction and cell cycle proliferation were studied. Moreover, the influence of SAHA on the expression of cyclin D1, the cell cycle regulators p21 and p27 and the production of vascular endothelial growth factor (VEGF) were analyzed. RESULTS: The HDAC inhibitors induced accumulation of acetylated histones in MCL cells. MTT assays and Annexin-V staining showed that they potently inhibited viability in a dose-dependent manner and induced apoptosis in all cell lines tested. Cell cycle analysis indicated that their exposure to SAHA or NaB decreased the proportion of cells in S phase and increased the proportion of cells in the G0/G1 and/or G2/M phases. Incubation with the two HDAC inhibitors resulted in downregulation of cyclin D1. SAHA lead to an upregulation of p21 in all cell lines and an upregulation of p27 in JeKo-1 and Granta-519 cells, while expression of p27 in Hbl-2 was not altered. In addition, SAHA inhibited the production of the angiogenic cytokine VEGF. Treatment with NaB increased the expression of p21 in JeKo-1 and Hbl-2 cells, while in Granta 519 cells no effect was noted. The expression of p27 remained constant in all three cell lines after exposure to NaB. CONCLUSION: Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in MCL and may represent a promising therapeutic approach.


Assuntos
Apoptose/efeitos dos fármacos , Butiratos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/farmacologia , Linfoma de Célula do Manto/enzimologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Linfoma de Célula do Manto/patologia , Antígeno Nuclear de Célula em Proliferação/biossíntese , Vorinostat
19.
Exp Hematol ; 33(11): 1337-47, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16263418

RESUMO

Mantle cell lymphoma (MCL) is a distinct form of non-Hodgkin's lymphoma (NHL) derived from CD5+ B cells. MCL cells overexpress cyclin D1 as a consequence of translocation of the gene into the immunoglobulin heavy-chain gene locus. MCL is an aggressive form of NHL with frequent relapses after standard-dose chemotherapy. In this context, a variety of novel therapies for patients with MCL have been investigated. In this study, we use an expanded panel of attenuated adenoviruses to study adenovirus-mediated cytotoxicity of MCL cells. Our results demonstrate: 1) adenovirus infection of MCL cells despite the absence of receptor/coreceptor molecules known to be important for adenovirus infection of other cells types; 2) cytotoxicity of MCL cells after infection with specific adenovirus mutants; 3) a high degree of cytotoxicity after infection of some patient samples with viruses lacking the E1B 19k "antiapoptotic" gene; and 4) cytotoxicity after infection with viruses containing mutations in E1A pRb or p300 binding. The extent of cytotoxicity with the panel of viruses demonstrated interpatient variability, but 100% cytotoxicity, as determined by molecular analysis, was detected in some samples. These studies provide the foundation for: 1) the development of adenoviruses as cytotoxic agents for MCL and 2) analyses of key regulatory pathways operative in MCL cells.


Assuntos
Infecções por Adenoviridae , Adenoviridae/patogenicidade , Terapia Biológica/métodos , Linfoma de Célula do Manto/terapia , Adenoviridae/genética , Proteínas E1A de Adenovirus/genética , Proteínas E1B de Adenovirus/deficiência , Proteínas E1B de Adenovirus/genética , Morte Celular , Humanos , Linfoma de Célula do Manto/patologia , Mutação , Vacinas Atenuadas/farmacologia , Virulência/genética
20.
Sao Paulo Med J ; 122(3): 131-3, 2004 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-15448813

RESUMO

CONTEXT: Gastrointestinal multiple lymphomatous polyposis is a rare type of malignant lymphoma that has aggressive biological behavior, early systemic dissemination and poor prognosis. It is considered to be a manifestation of non-Hodgkin lymphoma and represents the gastrointestinal counterpart of mantle cell nodal lymphoma. OBJECTIVE: A case of gastrointestinal multiple lymphomatous polyposis is presented and the anatomopathological, clinical, diagnostic and treatment aspects of this unusual neoplasia are discussed. CASE REPORT: The patient was a 59-year-old white male with a complaint of asthenia, night sweating, alteration in intestinal habit and weight loss over the preceding two months. The physical examination showed pallid mucosa and a palpable mass in the epigastrium and mesogastrium. Endoscopy of the upper digestive tract showed the presence of gastric and duodenal polyps. An opaque enema showed multiple polypoid lesions, especially in the cecum. A rectal biopsy revealed infiltration of the mucosa and submucosa by diffuse lymphoma consisting of small cleaved cells. Immunohistochemical study showed lymphocytes that expressed the antibody CD20 (L-26) and light-chain kappa (k) immunoglobulin, but not light-chain lambda (l) immunoglobulin. The patient presented a condition of acute intestinal obstruction with the presence of a mesenteric mass formed by agglutinated lymph nodes that surrounded the proximal ileum, thereby obstructing its lumen. He was submitted to a segmental enterectomy and gastrotomy with excisional biopsies of the gastric polypoid lesions. After two cycles of chemotherapy there was a worsening of the general state, with an increase in the dimensions of the abdominal masses and sepsis, accompanied by progressive respiratory insufficiency, leading to death.


Assuntos
Neoplasias Gastrointestinais/patologia , Polipose Intestinal/patologia , Linfoma de Célula do Manto/patologia , Diagnóstico Diferencial , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade
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