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1.
J Oncol Pharm Pract ; 26(1): 99-104, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30924740

RESUMO

OBJECTIVE: This study was conducted with the aim of making the contribution to a decision for treatment and determination of the modalities in patients diagnosed with non-Hodgkin lymphoma which increasingly become widespread in the geriatric population. MATERIALS AND METHODS: Ninety-one patients aged over 65 years diagnosed with lymphoma and treated in Bezmialem Vakif University Medical Faculty Hospital and Haseki Training and Research Hospital between 2008 and 2013 were retrospectively evaluated. Finally, 63 patients for whom data could be reached were included in the study. RESULTS: Examining the results, histological diagnoses of our patients were as follows: diffuse large B-cell lymphoma (50.8%), follicular lymphoma (23.8%), marginal zone lymphoma (12.7%), mantle cell lymphoma (4.8%), T-cell lymphoma (4.8%), lymphoplasmacytic lymphoma (1.6%) and small lymphocytic lymphoma (1.6%). Stages at the time of diagnosis were early stage by 33.3% and late stage by 66.7%. Of the patients, 36.5% had a low-intermediate and 63.5% a high-intermediate International Prognostic Index score. According to the Eastern Cooperative Oncology Group scoring, 34.9% of the patients have an Eastern Cooperative Oncology Group score of 2-4. Activities of daily living score of 33.3% patients was under 5. Looking at the responses to treatment, the complete response was found in 50.8%, partial response in 4.8%, stable disease in 1.6% and progressive disease in 9.5% of the patients. The mean follow-up duration of patients was found as 25.2 months and disease-free survival after remission as 20.2 months. CONCLUSION: We found that we have achieved a complete remission in more than half of our patients (50.8%). Based on this, treatment should aim remission in elderly patients.


Assuntos
Atividades Cotidianas , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Indução de Remissão/métodos , Estudos Retrospectivos
2.
Rinsho Ketsueki ; 60(8): 929-931, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31484892

RESUMO

A 51-year-old man was diagnosed with stage IV mantle cell lymphoma based on terminal ileum biopsy and treated with the R-CHOP regimen. Abdominal CT to assess continuous fever after three courses of R-CHOP revealed three low-density areas in the liver. PCR of the fluid obtained by percutaneous drainage revealed Entamoeba histolytica positivity, although the cultures were negative. Metronidazole treatment achieved cure. The patient was not a homosexual but had an 8-month stay in Lesotho 21 years ago, leading to the possibility that E. histolytica infection at the time continued as an asymptomatic colonization until the initiation of corticosteroid-containing chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Entamoeba histolytica , Abscesso Hepático Amebiano , Linfoma de Célula do Manto , Anticorpos Monoclonais Murinos/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Humanos , Abscesso Hepático Amebiano/induzido quimicamente , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Rituximab , Vincristina/efeitos adversos
3.
Expert Opin Pharmacother ; 20(15): 1893-1905, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31373238

RESUMO

Introduction: Mantle cell lymphoma (MCL) is a disease with an indolent histology, but mostly aggressive clinical course. While treatment can yield more promising results in younger patients, the disease is most diagnosed at a median age of approximately 70 years, and treatment in this group still presents a major challenge for oncohematologists. Unfortunately, due to comorbidities and poorer general status, the implementation of intensive treatment approaches with the cytarabine-based regimens and autologous stem cell transplantation is generally not possible, and the disease remains incurable, especially in elderly patients. Areas covered: In this paper, the authors discuss the therapeutic options available for older patients with MCL in the first line and relapsed/refractory settings, indicating new therapeutic options, which may achieve longer remissions and overall survival. Expert opinion: Although great progress has been made in the treatment of MCL in recent years, there remains a need for new treatment lines which can allow improved patient outcomes. Novel agents targeting altered the signal transduction pathways in MCL cells may offer more promise than traditional chemotherapy or immunochemotherapy and are currently being tested in clinical trials.


Assuntos
Linfoma de Célula do Manto/tratamento farmacológico , Idoso , Humanos
4.
Anticancer Res ; 39(8): 4179-4184, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366503

RESUMO

BACKGROUND/AIM: Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), possesses histone N-methyltransferase (HMT) activity and plays an essential role in cancer initiation and development. The aim of the present study was to investigate the potential of Wedelolactone (WL) to inhibit the methylation activity of EZH2. MATERIALS AND METHODS: The mantle cell lymphoma (MCL) cell line, Mino, was treated with WL, while untreated cells were used as control. HMT activity and EZH2 amount were measured in nuclear extracts from WL-treated and control Mino cells. RESULTS: WL was found to target EZH2-mediated histone H3K27 methylation. Along with the inhibition of H3K27 methylation in vitro (IC50=0.3 µM), WL suppressed HMT activity in Mino cells with an IC50 value of 3.2 µM. We detected a reduced amount of EZH2 in Mino cells treated with WL, compared to untreated control cells. CONCLUSION: This is the first study to show that WL induces inhibition of H3K27 methylation via EZH2 modulation and decreases cell proliferation in MCL, in vitro. WL is proposed as a promising agent and a novel epigenetic approach in MCL investigation and treatment.


Assuntos
Cumarínicos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Código das Histonas/genética , Linfoma de Célula do Manto/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Metilação/efeitos dos fármacos , Complexo Repressor Polycomb 2/genética
5.
Clin Adv Hematol Oncol ; 17(4): 223-233, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31188814

RESUMO

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Antígenos CD20/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Ensaios Clínicos como Assunto , Previsões , Neoplasias Gastrointestinais/induzido quimicamente , Hemorragia/induzido quimicamente , Humanos , Fatores Imunológicos/administração & dosagem , Linfocitose/induzido quimicamente , Linfoma de Célula do Manto/enzimologia , Terapia de Alvo Molecular/efeitos adversos , Infecções Oportunistas/induzido quimicamente , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Terapia de Salvação
6.
Medicine (Baltimore) ; 98(22): e15811, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31145313

RESUMO

Immunoglobulin heavy chain variable region (IGHV) gene mutation status is a biomarker for the prognosis of chronic lymphocytic leukemia, whether it is associated with the diagnosis, staging, and prognosis of patients with mantle cell lymphoma (MCL) remains to be determined.The IGHV gene mutations of 52 MCL patients were determined by DNA sequencing and compared with published IGHV germline sequences.DNA sequence alignment of IGHV variable regions with published IGHV germline sequences showed that the coincidence rate was 94% to 100%. Ten cases (21%) were significantly mutated with the rate of 96.9% to 94.0%. The overall survival time of patients was negatively correlated with the degree of IGHV gene mutation. Further survival analysis with log-rank test demonstrated that the patients with significant IGHV gene mutations showed a trend towards poor survival.The mutation rate of the IGHV variant region may be determined to assess the prognosis and overall survival time of MCL patients.


Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/mortalidade , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Análise de Sobrevida
7.
J Clin Pharm Ther ; 44(5): 800-804, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31111511

RESUMO

WHAT IS KNOWN AND OBJECTIVE: High-dose methotrexate (HD-MTX) is associated with a plethora of adverse drug reactions and potential drug interactions (DIs). But there is a paucity of information regarding the safety of co-administering primaquine with HD-MTX. CASE SUMMARY: A 65-year-old male patient was diagnosed with mantle cell lymphoma (MCL) with CNS involvement and treated with three cycles of IV HD-MTX. His case was further complicated by fungal pneumonia treated with primaquine during cycle-2. Serial blood sampling and subsequent population pharmacokinetics (PK) modelling suggests a possible distribution-mediated DI between the two drugs. WHAT IS NEW AND CONCLUSION: This is the first case report to highlight the safe co-administration of MTX and primaquine, despite a possible PK interaction.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Metotrexato/uso terapêutico , Primaquina/uso terapêutico , Idoso , Humanos , Masculino
8.
Int J Hematol ; 110(1): 77-85, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31127456

RESUMO

This multicenter phase II study (UMIN000008145) aims to investigate the efficacy and safety of six cycles of combination therapy (RBD) comprising rituximab, bendamustine, and dexamethasone (DEX) for relapsed or refractory (RR) indolent B-cell non-Hodgkin lymphoma (B-NHL) and mantle cell lymphoma (MCL). Although the initial study protocol comprised 20 mg/body DEX on days 1 and 2, and 10 mg/body on days 3-5 [high-dose (HD-) DEX group], the dose of DEX was later decreased to 8 mg/body on days 1 and 2 [low-dose (LD-) DEX group] due to frequent cytomegalovirus (CMV) antigenemia and recurrent retinitis. We enrolled 33 patients, and LD-DEX and HD-DEX were administered in 15 and 18 patients, respectively. The overall response and the 3-year progression-free survival rates were 88% and 75.5%, respectively. The leading adverse event was myelosuppression. Incidence of grade 3-4 leukocytopenia, neutropenia, and lymphocytopenia was 55%, 67%, and 91%, respectively. The most frequent nonhematological adverse events were CMV antigenemia and rash (33% and 30%, respectively). Incidence of CMV antigenemia over 10/100,000 white blood cells was significantly lower with LD-DEX than that with HD-DEX (P = 0.0127). In conclusion, RBD showed significant effectiveness for RR indolent B-NHL and MCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Terapia de Salvação/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Infecções por Citomegalovirus/etiologia , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Leucopenia/etiologia , Linfoma de Células B/complicações , Linfoma de Célula do Manto/complicações , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Rituximab/administração & dosagem , Terapia de Salvação/efeitos adversos , Adulto Jovem
9.
Blood ; 133(24): 2570-2574, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-30967367

RESUMO

Mantle cell lymphoma (MCL) is a unique type of non-Hodgkin lymphoma characterized by the overexpression of cyclin D1. MCL patients typically live for years but experience multiple relapses. Acalabrutinib is a novel second-generation oral Bruton tyrosine kinase inhibitor approved by the US Food and Drug Administration for relapsed MCL based on a clinical trial demonstrating an overall response rate of 81%. It provides a valuable new treatment option for MCL patients and is now being tested upfront.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/uso terapêutico , Humanos , Inibidores de Proteínas Quinases/uso terapêutico
10.
Acta Haematol ; 141(4): 209-213, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943468

RESUMO

A 37-year-old male was admitted with an atypical presentation of central nervous system (CNS) aspergillosis while on ibrutinib therapy for a CNS relapse of mantle cell lymphoma. This case highlights the importance of a high clinical suspicion of opportunistic infections in patients receiving small-molecule kinase inhibitors. This report includes a review of reported cases of Aspergillus infections in patients receiving ibrutinib and the shared features of these cases.


Assuntos
Linfoma de Célula do Manto/tratamento farmacológico , Neuroaspergilose/induzido quimicamente , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Adulto , Humanos , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/metabolismo , Masculino , Neuroaspergilose/diagnóstico por imagem , Neuroaspergilose/metabolismo , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Recidiva
11.
Am J Hematol ; 94(6): 710-725, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30963600

RESUMO

Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL-indolent vs aggressive-is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX-11 expression. Cyclin-D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki-67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long-term follow-up on chemo-immunotherapy studies has demonstrated durable remissions in some patients; however, long-term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy-free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine-microenvironmental milieu, incorporation of positron emission tomography-computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next-generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto , Proteínas de Neoplasias/genética , Intervalo Livre de Doença , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/mortalidade , Taxa de Sobrevida
12.
Rev Med Chil ; 147(1): 9-17, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-30848759

RESUMO

BACKGROUND: Mantle cell lymphoma (MCL) has high relapse and mortality rates. There is a survival benefit when treatment is intensified with cytarabine (AraC), hematopoietic cell transplantation (HCT) and maintenance with rituximab. AIM: To assess the outcomes of patients with MCL treated in a university hospital. MATERIAL AND METHODS: Review of an oncology center database and medical records identifying patients with MCL treated between 2006 and 2017. Death dates were obtained from the death certificate database of the National Identification Service. We analyzed the response rate, overall survival (OS) and progression-free survival (PFS). As a secondary objective, the survival impact of AraC, HCT and maintenance with rituximab, was also analyzed. RESULTS: Information on 20 patients aged 62 ± 11 years, followed for a median of 45 months was retrieved. Eighty-five percent were diagnosed at an advanced stage. The most used first-line regime was R-CHOP in 11 patients, followed by R-HyperCVAD in five. Only 47% achieved complete response. 4-year PFS and OS were of 30 and 77% respectively. Mantle Cell Lymphoma International Prognostic Index (MIPI) significantly predicted PFS and OS. Maintenance with rituximab or HCT was associated with better PFS (48 vs 21 months, p < 0.01). The exposure to AraC or HCT, in refractory or relapsed disease, was associated with an increase in PFS from 9 to 28 months (p = 0,02) and 4-year OS from 40 to 100% (p = 0.05). OS increased even more, from 25 to 100% in those with high-risk MIPI (p = 0.04). CONCLUSIONS: The incorporation of AraC, HCT and maintenance with rituximab in the therapeutic backbone of MCL, especially for high-risk cases, was associated with improved survival.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Citarabina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/cirurgia , Rituximab/uso terapêutico , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento
14.
PLoS One ; 14(2): e0211228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785921

RESUMO

INTRODUCTION: Ibrutinib is an oral covalent inhibitor of Bruton's tyrosine kinase approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma and WaldenstrÓ§m's macroglobulinemia. Ibrutinib has an increased risk of atrial fibrillation but the mechanism is unknown, and hypertension may play a role in the pathogenesis of this adverse drug reaction. METHODS: We aimed to review the risk of hypertension and atrial fibrillation as adverse events associated with ibrutinib through a systematic review with meta-analysis of randomized controlled trials (RCTs) retrieved in December 2018 on MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. The data were pooled using random-effects meta-analyses using the risk ratio (RR) with the 95% confidence interval (95%CI). The confidence on the pooled estimates was ascertained through the grading of recommendations assessment, development, and evaluation (GRADE) approach. RESULTS: There were 8 eligible RCTs (2580 patients), all reporting safety data of interest. Ibrutinib was associated with a significant increase in the risk of hypertension with a RR of 2.82 (95%CI 1.52-5.23) with moderate quality evidence. Ibrutinib increased significantly the risk of atrial fibrillation with a RR of 4.69 (95%CI 2.17-7.64) with high quality evidence. CONCLUSIONS: Ibrutinib was associated with significantly increased risks of both hypertension and atrial fibrillation.


Assuntos
Fibrilação Atrial/etiologia , Hipertensão/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Bases de Dados Factuais , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco
15.
Blood ; 133(11): 1201-1204, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30692121

RESUMO

Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton's tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Piperazinas/administração & dosagem , Prognóstico , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Taxa de Sobrevida
16.
Leukemia ; 33(7): 1675-1686, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30664664

RESUMO

p97 is an ATPase that works in concert with histone deacetylase 6 (HDAC6), to facilitate the degradation of misfolded proteins by autophagosomes. p97 has also been implicated in DNA repair and maintaining genomic stability. In this study, we determined the effect of combined inhibition of p97 and HDAC6 activities in mantle cell lymphoma (MCL) cells. We report that treatment with p97 inhibitors induces dose-dependent apoptosis in MCL cells. The p97 inhibitor CB-5083 induces ER stress markers GRP78 and CHOP and results in the accumulation of polyubiquitylated proteins. Co-treatment with CB-5083 and the HDAC6 inhibitor ACY-1215 result in marked downregulation of CDK4, Cyclin D1, and BRCA1 levels without inhibiting autophagic flux. Consequently, treatment with CB-5083 accentuates DNA damage in response to treatment with ACY-1215 resulting in enhanced accumulation of H2AX-γ and synergistic apoptosis. Furthermore, ATM loss severely impairs phosphorylation of 53BP1 following co-treatment with CB-5083 and ACY-1215 in response to gamma irradiation. Finally, co-treatment CB-5083 and ACY-1215 results in reduced tumor volumes and improves survival in Z138C and Jeko-1 xenografts in NSG mice. These observations suggest that combined inhibition of p97 and HDAC6 abrogates resolution of proteotoxic stress and impairs DNA repair mechanisms in MCL cells.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Reparo do DNA/efeitos dos fármacos , Sinergismo Farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Proteínas Nucleares/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Apoptose , Autofagia , Proliferação de Células , Dano ao DNA/efeitos dos fármacos , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Humanos , Linfoma de Célula do Manto/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Medicine (Baltimore) ; 98(1): e13741, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30608386

RESUMO

Mantle cell lymphoma (MCL) is an invasive B-cell lymphoma with significant individual differences. Currently, MCL international prognostic index (MIPI) score and tumor cell proliferation index Ki-67 have been proved to be the most important prognostic factors. But the prognostic effect of these factors in Asian population is uncertain. This study aimed to analyze the disease characteristics and prognostic factors of Chinese MCL patients.A total of 83 cases of newly-diagnosed MCL patients diagnosed by the Department of Pathology of our hospital between January 1, 2011, and May 31, 2016, were enrolled. The disease characteristics, treatment effects, and outcomes of the patients were collected and analyzed.According to our analysis, MCL cases accounted for 6.2% of non-Hodgkin lymphoma (NHL) cases and mainly occurred in elderly males. But the proportion of patients at stage IV by Ann Arbor staging system and high-risk group by simplified-MIPI (s-MIPI) were significantly lower than that among European patients. Immunochemotherapy containing rituximab was significantly more effective than chemotherapy (overall response rate, [ORR]: 88.5% vs 65.2%, P = .021) and significantly prolonged patient survival (progression free survival [PFS]: 45.5 m vs 16.2 m, P = .001; overall survival [OS]: 58.3 m vs 22.8 m, P = .001). The multivariate analysis showed that the B symptoms, s-MIPI and administration of immunochemotherapy were independent prognostic factors that affected PFS and OS of the patients. s-MIPI and B symptom make up s-MIPI-B stratification method, by which patients in low-risk group of s-MIPI without B symptom were classified as low-risk, patients in high-risk group of s-MIPI and patients in low-risk group of s-MIPI with B symptom as high-risk, the rest as middle-risk. 3-year PFS of the 3 groups were 74.9%, 43.4% and 16.1%, respectively (P = .001). 3-year OS were 84.4%, 62.2%, 27.6% (P <.001).Chinese MCL was male predominance. We have a minor proportion of late-stage and high-risk patients compared to European patients. Immunochemotherapy was proved to significantly improve the prognosis of MCL patients. B symptoms, s-MIPI, and administration of rituximab independently influenced the outcome. s-MIPI-B prognostic stratification method may better predict the prognosis of Asian MCL patients. Still, further confirmation in larger populations is needed.


Assuntos
Linfoma de Célula do Manto/diagnóstico , Medição de Risco/métodos , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Criança , China , Feminino , Humanos , Antígeno Ki-67/análise , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Rituximab/uso terapêutico , Adulto Jovem
18.
Expert Opin Pharmacother ; 20(5): 487-494, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30608891

RESUMO

INTRODUCTION: Although a variety of therapeutic schemes for Mantle Cell Lymphoma (MCL) have been attempted, the clinical outcome of patients continues to be unsatisfactory especially among patients with a very high-risk profile and in the relapsed/refractory setting. For this reason, recent clinical trials have explored novel approaches, either by the use of biological agents in chemotherapy-free schedules or by integrating them with chemoimmunotherapy regimens. Areas covered: The efficacy of lenalidomide monotherapy and combination therapy established in clinical studies mainly involving relapsed/refractory MCL is reviewed. The mechanism of action of lenalidomide is also discussed. Furthermore, the current position of lenalidomide in the MCL treatment algorithm is debated. Expert opinion: Lenalidomide demonstrated high efficacy and tolerability in several clinical trials as well as in retrospective real-world reports, even in patients who relapsed or were resistant to bortezomib and ibrutinib. In 2013, lenalidomide was approved by the Food and Drug Administration (FDA) for relapsed/refractory MCL after two prior therapies including at least one prior treatment with bortezomib. However, the potential synergistic anti-neoplastic effects of lenalidomide in combination with other biological agents, i.e. ibrutinib and venetoclax, especially in the management of p53-mutated cases, still remain an open issue.


Assuntos
Antineoplásicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Humanos , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Resultado do Tratamento
20.
Expert Rev Clin Pharmacol ; 12(3): 179-187, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30638402

RESUMO

INTRODUCTION: Although advances in mantle cell lymphoma (MCL) therapy have improved overall survival (OS), managing relapsed/refractory (R/R) cases remains a great challenge. Bruton tyrosine kinase (BTK) inhibitors have broadened therapeutic options in MCL and became the backbone of second-line strategies. Areas covered: Ibrutinib, the first-in-class BTK inhibitor registered for MCL therapy, is efficient, with clear benefits of its use. However, ibrutinib-related adverse events due to off-target inhibition of other kinases led to the development of more selective molecules with comparable efficacy and better safety profiles. Expert commentary: Acalabrutinib, a new BTK inhibitor, currently being evaluated in numerous clinical studies is approved by FDA in relapsing/refractory MCL. Its role will evolve over the next few years. Efficacy and good tolerability of acalabrutinib gives even greater opportunity for potential upfront use and new therapeutic combinations, including monoclonal antibodies, antibody-drug conjugates, immune checkpoint inhibitors, bcl-2 (B-cell lymphoma-2) or IP3K (phosphoinositide 3-kinase) inhibitors.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/administração & dosagem , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/administração & dosagem , Adulto , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Humanos , Linfoma de Célula do Manto/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Taxa de Sobrevida
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