RESUMO
PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative disease in the elderly of the western world. Immune defective responses and treatment can worsen the immune system's competence of CLL patients. Consequently, they may present a higher incidence of recurrent severe infections, second malignancies, and reduced efficacy of vaccines. The outbreak of COVID-19 is an ongoing pandemic, and patients with comorbidities experience more severe forms of the disease. Hematological malignancies are associated with higher case fatality rates (CFRs) than other cancers. Knowledge about COVID-19 incidence, clinical course, and immune response to the infection and vaccination in CLL may contribute to design strategies that improve the outcomes of patients in the future. RECENT FINDINGS: The prevalence of SARS-CoV-2 positivity in CLL is not significantly higher than seen in the general population. CFRs for CLL patients are 16.5-fold more elevated than the median reported worldwide and even higher in older patients, those who require hospitalization have significant comorbidities or need oxygen therapy. CLL status decreases the anti-SARS-CoV-2 positivity after infection or vaccination by around 40%, and the spike-specific antibody titers are 74-fold lower than healthy age-matched controls. The response rate to COVID-19 vaccines is even worse in patients with active CLL-directed therapies like BTKi, BCL-2 antagonists, or anti-CD20 monoclonal antibodies. CLL patients are at a greater risk of death from COVID-19. Inherent immunosuppression of CLL and immune deficiencies caused by treatment significantly decrease the ability to produce natural or vaccine-induced anti-SARS-CoV-2 immune responses.
Assuntos
COVID-19/epidemiologia , Leucemia Linfocítica Crônica de Células B/imunologia , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , VacinaçãoRESUMO
Hypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.
Assuntos
Imunoglobulinas Intravenosas/imunologia , Imunomodulação , Leucemia Linfocítica Crônica de Células B/imunologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Imunoglobulinas Intravenosas/farmacologia , Imunomodulação/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/sangue , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Sulfonamidas/farmacologiaRESUMO
PURPOSE: The PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells. Its ligand, programmed cell death ligand-1 (PD-L1), is expressed on the surface of dendritic cells or macrophages. The PD-1/PD-L1 interaction ensures prevention of autoimmunity by activating the immune system only when needed. In cancers, PD-L1 expressed on the tumour cells binds to PD-1 receptors on the activated T cells, leading to inhibition of the cytotoxic T cells and immunosuppression. PD-1/PD-L1 pathway is upregulated in EBV infection that is known to worsen the CLL prognosis. Therefore, we aimed to study the association between PD-1 and PD-L1 expressions, EBV status and the CLL prognosis. METHODS AND PATIENTS: The study was conducted on 80 newly diagnosed CLL patients and 80 controls. We analyzed PD-1 and PD-L1 expressions and EBV-DNA load by real-time PCR. The cytogenetic abnormalities and expression of ZAP70 and CD38 were detected by FISH and Flow cytometry, respectively. RESULTS: PD-1/PD-L1 expressions were significantly upregulated in CLL patients compared to controls. In addition, their mRNA levels were significantly higher in EBV( +) versus EBV( -) patients. High expression of PD-1/PD-L1 was associated with poor prognostic markers (RAI stages of CLL, del 17p13, ZAP70, and CD38 expression), failure of complete remission, shorter progression-free survival, and overall survival. CONCLUSION: High expression of PD-1 and PD-L1, together with high EBD-DNA load were linked to worse prognosis in CLL. In addition, PD-1 and PD-L1 might represent suitable therapeutic targets for patients suffering from aggressive CLL.
Assuntos
Antígeno B7-H1/genética , Infecções por Vírus Epstein-Barr , Expressão Gênica , Herpesvirus Humano 4/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Receptor de Morte Celular Programada 1/genética , ADP-Ribosil Ciclase 1/análise , Autoimunidade , Antígeno B7-H1/metabolismo , Estudos de Casos e Controles , DNA Viral/sangue , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Humanos , Terapia de Imunossupressão , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Intervalo Livre de Progressão , RNA Mensageiro/metabolismo , Análise de Sobrevida , Linfócitos T/metabolismo , Linfócitos T Citotóxicos , Regulação para Cima , Carga Viral , Proteína-Tirosina Quinase ZAP-70/análiseAssuntos
Anticorpos Antivirais/isolamento & purificação , Betacoronavirus/isolamento & purificação , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Leucemia Linfocítica Crônica de Células B/imunologia , Pneumonia Viral/diagnóstico , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Betacoronavirus/genética , Betacoronavirus/imunologia , COVID-19 , Teste para COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Reações Falso-Negativas , Humanos , Hospedeiro Imunocomprometido/imunologia , Leucemia Linfocítica Crônica de Células B/complicações , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , RNA Viral/isolamento & purificação , Radiografia Torácica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Aspergillus fumigatus/imunologia , Candida albicans/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Macrófagos/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Neutrófilos/imunologia , Inibidores de Proteínas Quinases/efeitos adversos , Tirosina Quinase da Agamaglobulinemia/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Macrófagos/patologia , Proteínas de Neoplasias/imunologia , Neutrófilos/patologia , Inibidores de Proteínas Quinases/administração & dosagemRESUMO
PURPOSE: To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS: Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS: At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups (P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not (P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR (P < .0001). Toxicity was comparable in both dose groups. CONCLUSION: In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.
Assuntos
Imunoterapia Adotiva/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Idoso , Antígenos CD19/imunologia , Síndrome da Liberação de Citocina/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/imunologia , Recidiva , Taxa de Sobrevida , Linfócitos T/imunologia , Linfócitos T/transplanteRESUMO
Despite significant therapeutic improvements chronic lymphocytic leukemia (CLL) remains an incurable disease and there is a persistent pursuit of new treatment alternatives. Lurbinectedin, a selective inhibitor of active transcription of protein-coding genes, is currently in phase II/III clinical trials for solid tumors such as small-cell lung cancer (SCLC). In this study, we aimed to evaluate the activity of Lurbinectedin on circulating mononuclear cells from CLL patients and to determine whether Lurbinectedin could affect the cross-talk between B-CLL cells and the tumor microenvironment. We found that Lurbinectedin induced a dose- and time-dependent death in all cell types evaluated, with B cells, monocytes and monocytic myeloid derived suppressor cells (Mo-MDSC) being the most susceptible populations. At sub-apoptotic doses, Lurbinectedin decreased the expression of CCR7 in B-CLL cells and impaired their migration towards CCL19 and CCL21. Furthermore, low concentrations of Lurbinectedin stimulated the synthesis of pro-IL1ß in monocytes and nurse-like cells, without inducing the inflammasome activation. Altogether, these results indicate that Lurbinectedin might have antitumor activity in CLL due to its direct action on leukemic cells in combination with its effects on the tumor microenvironment. Our findings encourage further investigation of Lurbinectedin as a potential therapy for CLL.
Assuntos
Carbolinas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Quimiocina CCL19/imunologia , Quimiocina CCL19/metabolismo , Quimiocina CCL21/imunologia , Quimiocina CCL21/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Cultura Primária de Células , Receptores CCR7/imunologia , Receptores CCR7/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/imunologiaAssuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Ativação Linfocitária/efeitos dos fármacos , Proteínas de Neoplasias , Sulfonamidas/farmacologia , Quinase Syk , Linfócitos T , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Rituximab/farmacologia , Quinase Syk/antagonistas & inibidores , Quinase Syk/imunologia , Quinase Syk/metabolismo , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
BACKGROUND: Flow cytometric immunophenotyping is deemed a fundamental tool for the diagnosis of B-cell neoplasms. Currently, the investigation of novel immunophenotypic markers has gained importance, as they can assist in the precise subclassification of B-cell malignancies by flow cytometry. Therefore, the purpose of the present study was to evaluate the expression of CD307a during normal B-cell maturation and in B-cell malignancies as well as to investigate its potential role in the differential diagnosis of these entities. METHODS: CD307a expression was assessed by flow cytometry in normal precursor and mature B cells and in 115 samples collected from patients diagnosed with precursor and mature B-cell neoplasms. CD307a expression was compared between neoplastic and normal B cells. RESULTS: B-acute lymphoblastic leukemia cases exhibited minimal expression of CD307a, displaying a similar expression pattern to that of normal B-cell precursors. Mantle cell lymphoma (MCL) cases showed the lowest levels of CD307a among mature B-cell neoplasms. CD307a expression was statistically lower in MCL cases than in chronic B lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL) cases. No statistical differences were observed between CD307a expression in neoplastic and normal plasma cells. CONCLUSION: These results indicate that the assessment of CD307a expression by flow cytometry could be helpful to distinguish CLL from MCL, and the latter from MZL. Although these results are not entirely conclusive, they provide a basis for further studies in a larger cohort of patients. © 2018 International Clinical Cytometry Society.
Assuntos
Linfócitos B/patologia , Biomarcadores Tumorais/análise , Leucemia Linfocítica Crônica de Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma de Célula do Manto/imunologia , Adulto , Antígenos CD/análise , Diferenciação Celular/imunologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease that affects B lymphocytes in most cases. Leukemic lymphocytes have prolonged longevity, defined by resistance to apoptosis. These cells can accumulate in peripheral blood, bone marrow, and solid lymphoid organs. CLL may be indolent or aggressive and has a range of prognostic factors such as expression of CD38 and ZAP-70, immunophenotypic and cytogenetic changes, imbalanced apoptosis proteins, and others. Although CLL has a low mortality rate, this disease is generally not considered curable until today. CLL treatment involves alkylating agents and glucocorticoids, purine analogs, monoclonal antibody therapies, and bone marrow transplantation. In recent decades, new drugs have appeared focusing on new targets and specific molecules, such as the BCR receptor, Bruton's tyrosine kinase, phosphatidylinositol 3-kinase, spleen tyrosine kinase, apoptosis proteins and microRNAs. The most appropriate treatment for CLL is one that involves in its protocol a combination of drugs according to the prognostic factors presented by each patient. In this sense, treatment individualization is essential. This article examines standard treatments for CLL and explores new treatments and potential new targets, as well as schematic protocols to understand where we are, how the treatment has evolved, and the advantages and disadvantages of new targets for CLL therapy.