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1.
Drugs Today (Barc) ; 57(4): 277-289, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33851691

RESUMO

Bruton tyrosine kinase (BTK) plays an important role in the B-cell receptor (BCR) signaling pathway by mediating proliferation, migration and adhesion in B-cell malignancies. Therefore, the components of BCR signaling, especially BTK, are considered to be attractive therapeutic targets. Ibrutinib, a first-in-class BTK inhibitor, has been approved for the treatment of several types of B-cell malignancies worldwide. However, ibrutinib has off-target activities on non-BTK kinase that are related to adverse effects or might translate into clinical limitations. To overcome these limitations, more specific BTK inhibitors are needed. Tirabrutinib hydrochloride (tirabrutinib) is a potent, highly selective, irreversible oral inhibitor of BTK. Tirabrutinib irreversibly and covalently binds to BTK in B cells and has demonstrated effective in vitro cytotoxicity in many types of B-cell malignancies and in vivo antitumor activity in mouse models. Here, we provide a comprehensive review of the preclinical and clinical activity of tirabrutinib, a drug approved in Japan for relapsed or refractory primary central nervous system lymphoma and all lines of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma.


Assuntos
Linfoma de Células B , Inibidores de Proteínas Quinases , Animais , Imidazóis , Japão , Linfoma de Células B/tratamento farmacológico , Camundongos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos
2.
Lancet Haematol ; 8(4): e267-e277, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33667420

RESUMO

BACKGROUND: R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEP trial. METHODS: In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18-60 years with newly diagnosed, high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, using Pocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide, doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14) or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT (R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPI factors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre. The primary endpoint was event-free survival, analysed here 10 years after randomisation. 10-year overall survival, progression-free survival, conditional survival, relapse patterns, secondary malignancies, and molecular characteristics were also analysed. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00129090. FINDINGS: Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14 (n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patients in the R-MegaCHOEP group were included in the intention-to-treat population. After a median follow-up of 9·3 years (IQR 5·1-11·1), 10-year event-free survival was 51% (95% CI 42-61) in the R-MegaCHOEP group and 57% (47-67) in the R-CHOEP-14 group (adjusted hazard ratio [HR] 1·3 [95% CI 0·9-1·8], p=0·23). 10-year progression-free survival was 59% (50-68) in the R-MegaCHOEP group and 60% (51-70) in the R-CHOEP-14 group (adjusted HR 1·1 [0·7-1·7], p=0·64). 10-year overall survival was 66% (57-76) in the R-MegaCHOEP group and 72% (63-81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8-2·1], p=0·26). Relapse occurred in 30 (16% [95% CI 11-22]) of 190 patients who had complete remission or unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 group and 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients had low-grade histology at relapse and had better outcomes compared with patients who relapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64 patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treat population; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126 patients in the R-MegaCHOEP group. INTERPRETATION: Event-free survival and overall survival were similar between groups after 10 years of follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a high incidence of CNS involvement and poor prognosis. For these patients, novel therapies are greatly warranted. FUNDING: Deutsche Krebshilfe (German Cancer Aid).


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Células B/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Doenças do Sistema Nervoso Central/epidemiologia , Doenças do Sistema Nervoso Central/patologia , Etoposídeo/uso terapêutico , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Análise de Intenção de Tratamento/métodos , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Intervalo Livre de Progressão , Segurança , Inibidores da Topoisomerase II/uso terapêutico , Transplante Autólogo/métodos , Resultado do Tratamento , Vincristina/uso terapêutico
5.
J Med Chem ; 64(3): 1725-1732, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33529029

RESUMO

A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures in vivo.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Linfoma de Células B/tratamento farmacológico , Camundongos , Modelos Moleculares , Pró-Fármacos/farmacocinética , Piridonas/farmacocinética , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Rinsho Ketsueki ; 62(1): 55-57, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33551427

RESUMO

A 68-year-old male presented with appetite loss and abdominal distention. The whole-body computed tomography scan revealed an ileocecal mass with a large amount of ascites, which was consistent with malignant lymphoma. Due to the worsening of his general condition following admission, he was intubated and admitted to the intensive care unit (ICU). In the ICU, we performed a core-needle biopsy (CNB) on the left peritoneal mass, the findings of which showed a pathological diffuse infiltration of CD20+ middle-sized lymphoid cells. After chemotherapy was initiated, the patient showed complete response, suggesting that CNB can be performed immediately and safely even on a critically ill patient.


Assuntos
Linfoma de Células B , Idoso , Biópsia com Agulha de Grande Calibre , Humanos , Unidades de Terapia Intensiva , Linfoma de Células B/diagnóstico , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Masculino , Estudos Retrospectivos
7.
Stem Cell Rev Rep ; 17(1): 296-299, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33403488

RESUMO

We report the case of an HIV-1-infected patient, treated with anti-CD20 monoclonal antibody for a B-cell lymphoma previously treated by autologous stem cell transplant. He suffered from chronic COVID19 and we monitored by plasma SARS-CoV-2 RNA by highly sensitive droplet-based digital PCR technology (ddPCR). Under tocilizumab therapy and despite a first clinical improvement biologically associated with decreasing inflammatory markers, a slight increase of SARS-CoV-2 RNAaemia quantified by ddPCR was highlighted, confirming the absence of viral efficacy of this treatment and predicting the subsequent observed deterioration. As expected, his complete recovery, finally achieved after COVID-19 convalescent plasmatherapy, strictly paralleled plasma SARS-CoV-2 RNA clearance. With these results, we confirmed the interest of SARS-CoV-2 RNAaemia monitoring by ddPCR in COVID-19 patients, particularly during treatment, and firstly showed that this new and specific biomarker could be helpful to select eligible patient for anti-IL6 receptors therapy considering the variable levels of efficacy recently observed with such therapy.


Assuntos
/sangue , Infecções por HIV/sangue , Linfoma de Células B/tratamento farmacológico , RNA Viral/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , /genética , Infecções por HIV/genética , Infecções por HIV/terapia , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Linfócitos/virologia , Linfoma de Células B/complicações , Linfoma de Células B/genética , Linfoma de Células B/virologia , RNA Viral/efeitos dos fármacos , /patogenicidade , Carga Viral/efeitos dos fármacos
8.
Cancer Sci ; 112(3): 1123-1131, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33492746

RESUMO

BACKGROUND: Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B-cell non-Hodgkin-type lymphoma (B-NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity. METHODS: Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28-day/cycle manner. Tazemetostat dose-limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations. RESULTS: As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B-cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59-85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment-related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment-related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment. CONCLUSIONS: Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B-NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Morfolinas/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Piridonas/efeitos adversos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Humanos , Japão , Linfoma de Células B/genética , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piridonas/administração & dosagem , Piridonas/farmacocinética , Resultado do Tratamento
9.
Anticancer Res ; 41(1): 237-247, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419818

RESUMO

BACKGROUND/AIM: Activation-induced cytidine deaminase (AID) is a DNA modifying enzyme which has an essential function in promoting antibody diversification. Its overexpression is strongly associated with B-cell derived malignancies including Burkitt lymphoma, where AID is required for the characteristic c-MYC/IGH translocation. This study aimed at defining AID's oncopathogenic role which is still poorly understood. MATERIALS AND METHODS: We created over-expressing and knock-down cell culture models of AID, and used cellular assays to provide insight into its contribution to lymphomagenesis. RESULTS: We showed that AID expression is highly specific to, and abundantly expressed in B-cell-derived cancers and that ectopic overexpression of AID leads to rapid cell death. Using a knock-down model, we revealed that AID expression significantly impacts genomic stability, proliferation, migration and drug resistance. CONCLUSION: AID is an important driver of lymphoma, impacting multiple cellular events, and is potentially a strong candidate for targeted therapy in lymphoma.


Assuntos
Citidina Desaminase/metabolismo , Resistencia a Medicamentos Antineoplásicos , Linfoma de Células B/metabolismo , Animais , Antineoplásicos/farmacologia , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/genética , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Citidina Desaminase/genética , Dano ao DNA , Doxorrubicina/farmacologia , Expressão Ectópica do Gene , Ativação Enzimática , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/patologia
10.
BMJ Case Rep ; 13(12)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33318257

RESUMO

A 48-year-old man with a history of schizophrenia was diagnosed with B-cell lymphoma of the small bowel. Neutropaenia occurred secondary to chemotherapy, which led to clozapine being discontinued, which resulted in the deterioration of his mental state, in turn, affecting the treatment of lymphoma. Clozapine was later reintroduced alongside granulocyte colony-stimulating factor, leading to improved mental state without any further incidences of neutropaenia.


Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Humanos , Linfoma de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Esquizofrenia/sangue , Resultado do Tratamento
11.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333768

RESUMO

CD37 is a tetraspanin expressed prominently on the surface of B cells. It is an attractive molecular target exploited in the immunotherapy of B cell-derived lymphomas and leukemia. Currently, several monoclonal antibodies targeting CD37 as well as chimeric antigen receptor-based immunotherapies are being developed and investigated in clinical trials. Given the unique role of CD37 in the biology of B cells, it seems that CD37 constitutes more than a docking point for monoclonal antibodies, and targeting this molecule may provide additional benefit to relapsed or refractory patients. In this review, we aimed to provide an extensive overview of the function of CD37 in B cell malignancies, providing a comprehensive view of recent therapeutic advances targeting CD37 and delineating future perspectives.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos B/metabolismo , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/imunologia , Linfoma de Células B/imunologia , Tetraspaninas/imunologia , Tetraspaninas/metabolismo , Linfócitos B/imunologia , Linfócitos B/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo
12.
Nat Commun ; 11(1): 5348, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093447

RESUMO

Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens and discovered a marked sensitivity of hematological cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma.


Assuntos
Aciltransferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Linfoma de Células B/tratamento farmacológico , Ácido Mirístico/metabolismo , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dasatinibe/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Camundongos , Camundongos SCID , Modelos Biológicos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/metabolismo
13.
Medicine (Baltimore) ; 99(44): e22490, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126303

RESUMO

RATIONALE: ALL is the most common form of leukemia (75% to 80%), it is characterized by clonal expansion of the lymphoid blasts in bone marrow, blood, and other tissues, which can be divided into T lineage and B lineage. Although relapse of acute leukemia is common, a change of immunophenotype at relapse only occurs rarely. Some of these cases have been labeled "lineage switch". PATIENT CONCERNS: A 31-year-old man had multiple lymph nodes in the neck, and the lymph nodes on the right side adhered to the surrounding tissues. His lymphocytes ratio in blood was up to 86.3%. Flow cytometry of the bone marrow aspirate showed positive results for CD2, CD5, CD7, cCD3, TDT, CD4, CD8, and CD10, negative results for CD34, CD117, CD33, HLA-DR, CD19, and CD20. Twenty six months later, the patient felt pain in the neck and shoulder after touching. His lymphocytes of blood were 109.9×109 /L. 43 fusion genes and positive BCR/ABL was detected. Flow cytometry of the bone marrow aspirate showed pro B lymphocytes accounted for 85.54%, and positive expression of CD38, CD10, CD34, CD33, TDT, CD9, and HLA-DR. Moreover, the RT-PCR data showed the patient expressed high level of T cell and B cell development transcription factors. DIAGNOSES: Upon examination, the patient was initially diagnosed with T-lineage pro cell ALL. BM morphologic analysis presented complete remission (CR) after systemic chemotherapy. Twenty six months later, we discovered the patient was diagnosed with B-lineage acute lymphocytic leukemia. INTERVENTIONS: Systemic chemotherapy is first given when a patient was diagnosed with T-cell acute lymphoblastic leukemia. After the patient happened linage switch, we adjusted the treatment plan, and the patient was complete remission after 1 course of treatment. OUTCOMES: Our case provides information of lineage switch from T-ALL to B-ALL in this report, which is never seen in our knowledge. LESSONS: This lineage switch from T-ALL to B-ALL is never reported beforemoreover, the RT-PCR data showed the patient expressed high level of T cell and B cell development transcription factors. Its early recognition can let doctor provides appropriate therapy to patient.


Assuntos
Leucemia Aguda Bifenotípica/sangue , Linfoma de Células B/sangue , Linfoma de Células T/sangue , Doença Aguda , Adulto , Linfócitos B , Linhagem da Célula , Humanos , Leucemia Aguda Bifenotípica/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Masculino , Linfócitos T
14.
Rinsho Ketsueki ; 61(8): 901-911, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32908054

RESUMO

Almost 20 years have passed after rituximab, an anti-CD20 mouse-human chimeric monoclonal antibody therapeutic, was introduced in the clinical setting for the treatment of CD20-positive B cell malignancies. Although the prognosis has significantly improved in most B cell malignancies, resistance to rituximab with/without chemotherapies is also widely recognized. With this background, newer generation antibody therapeutics and other molecular targeting drugs that show more effectiveness especially to refractory patients are critically required. In this review, molecular mechanisms of the second/third generation anti-CD20 antibodies (ofatumumab and obinutuzumab), anti-CD19 chimeric antigen-receptor T-cells (CAR-T-CD19; tisagenlecleucel, axicabtagene ciloleucel), and the anti-PD-1 antibodies (nivolumab and pembrolizumab) are presented. The therapeutic effectiveness of those drugs as monotherapy and/or combined therapy with conventional chemotherapy (immunochemotherapy) and another molecular targeting therapeutics (so-called "chemo-free" regimens) are also reviewed.


Assuntos
Linfoma de Células B , Animais , Antineoplásicos , Linfócitos B , Humanos , Linfoma de Células B/tratamento farmacológico , Radioimunoterapia , Rituximab
15.
Ann Hematol ; 99(10): 2215-2229, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32856140

RESUMO

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Subpopulações de Linfócitos B/imunologia , Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/economia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Análise Custo-Benefício , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Custos de Medicamentos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/economia , Infusões Intravenosas , Injeções Subcutâneas , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Pré-Medicação , Qualidade de Vida , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento , Carga Tumoral , Evasão Tumoral
16.
PLoS One ; 15(8): e0238183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857815

RESUMO

Lymphoma (lymphosarcoma) is the second most frequent cancer in dogs and is clinically comparable to human non-Hodgkin lymphoma. Factors affecting canine lymphoma progression are unknown and complex, but there is evidence that genetic mutations play an important role. We employed Next Gen DNA sequencing of six dogs with multicentric B-cell lymphoma undergoing CHOP chemotherapy to identify genetic variations potentially impacting response. Paired samples from non-neoplastic tissue (blood mononuclear cells) and lymphoma were collected at the time of diagnosis. Cases with progression free survival above the median of 231 days were grouped as 'good' responders and cases below the median were categorized as 'poor' responders. The average number of variants found was 17,138 per case. The variants were filtered to examine those with predicted moderate or high impacts. Many of the genes with variants had human orthologs with links to cancer, but the majority of variants were not previously reported in canine or human lymphoma. Seven genes had variants found in the cancers of at least two 'poor' responders but in no 'good' responders: ATRNL1, BAIAP2L2, ZNF384, ST6GALNAC5, ENSCAFG00000030179 (human ortholog: riboflavin kinase RFK), ENSCAFG00000029320, and ENSCAFG00000007370 (human ortholog: immunoglobin IGKV4-1). Two genes had variants found in the cancers of at least two 'good' responders but in no 'poor' responders: COX18 and ENSCAFG00000030512. ENSCAFG00000030512 has no reported orthologue in any other species. The role of these mutations in the progression of canine lymphoma requires further functional analyses and larger scale study.


Assuntos
Doenças do Cão/genética , Linfoma de Células B/veterinária , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , Ciclofosfamida/administração & dosagem , Doenças do Cão/tratamento farmacológico , Cães , Doxorrubicina/administração & dosagem , Variação Genética , Estimativa de Kaplan-Meier , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Prednisolona/administração & dosagem , Resultado do Tratamento , Vincristina/administração & dosagem , Sequenciamento Completo do Genoma
17.
Expert Opin Pharmacother ; 21(15): 1915-1926, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32686971

RESUMO

INTRODUCTION: The outcome of patients with lymphoid malignancies has markedly improved in recent years due to the implementation of new therapeutic options. Chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphomas (NHL) are characterized by the activation of the phosphatidylinositol 3-kinase (PI3 K) pathway via B-cell receptor signaling. The PI3 K delta (PI3 Kδ) p110δ isoform inhibitor, idelalisib, showed high anti-tumor activity in this group of tumors. It was the first agent from a new class of isoform-specific inhibitors to receive regulatory approvals for the treatment of refractory/relapsed CLL, as well as small lymphocytic lymphoma and follicular lymphoma. AREAS COVERED: In this paper, the authors provide a comprehensive overview of the activity and safety profile of idelalisib and other, newly developed PI3 K inhibitors in patients with indolent B-cell malignancies. EXPERT OPINION: Idelalisib is a very potent anti-lymphoma agent in CLL and other NHL. However, there are some limitations of its broad clinical use according to some important side effects observed during treatment. Consequently, the development of new PI3 K inhibitors, which will be highly active and possess better safety profiles are warranted.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/uso terapêutico , Quinazolinonas/uso terapêutico , Animais , Linhagem Celular Tumoral , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
18.
Rinsho Ketsueki ; 61(6): 598-604, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32624531

RESUMO

This retrospective study evaluated the outcomes of patients treated with combination of bendamustine and rituximab (BR) for recurrent indolent B-cell lymphoma from January 2011 to February 2018 in our department. The cohort included 36 males and 27 females, and majority of the patients (59%) were between 51 and 70 years of age. The disease types were follicular lymphoma (FL) and mantle-cell lymphoma in 42 (67%) and 15 (24%) patients, respectively. Median progression-free survival (PFS) was not reached in patients with FL who completed BR therapy. The analysis of patients who received BR therapy revealed that the number of CD4-positive lymphocytes remained around 200/µl even five years after the end of treatment. BR therapy was a useful treatment option for recurrent indolent B-cell lymphoma, especially in patients with FL, and completion of BR therapy appeared to be important for improved PFS. Furthermore, attention should be paid for potential infections for at least five years after BR therapy because cell-mediated immunodeficiency may become apparent after treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B , Idoso , Cloridrato de Bendamustina , Feminino , Humanos , Linfoma de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Retrospectivos , Rituximab
19.
Adv Exp Med Biol ; 1207: 615-623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671779

RESUMO

Lymphoma is a hematological malignancy and its incidence is growing. The use of CD20 monoclonal antibody improves the therapeutic efficacy in CD20-positive B-cell lymphoma. Despite remarkable progress in lymphoma treatment over the past decades, chemotherapy resistance and disease relapse become the main obstacles to further improve the prognosis of the patients. Therefore, the development of new treatment methods and drugs is urgently needed to improve the treatment of lymphoma. In tumors, autophagy functions to protect tumor cells from hypoxia, radiotherapy, and apoptosis. The ability to improve the prognosis of patients with lymphoma through the active regulation of autophagy represents a new approach to clinical treatment.


Assuntos
Autofagia , Linfoma , Apoptose , Autofagia/efeitos dos fármacos , Humanos , Linfoma/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico
20.
N Engl J Med ; 382(23): 2207-2219, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32492302

RESUMO

BACKGROUND: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited. METHODS: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed. RESULTS: Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion. CONCLUSIONS: Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Infecções/etiologia , Infusões Intravenosas , Estimativa de Kaplan-Meier , Linfoma de Células B/mortalidade , Masculino , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão , Rituximab/efeitos adversos
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