RESUMO
Cholesterol has many critical functions in cells. It is a key component of membranes and cell-signalling processes, and it functions as a chemical precursor in several biochemical pathways, such as Vitamin D and steroid synthesis. Cholesterol has also been implicated in the development and progression of various cancers, in which it is thought to promote cell proliferation, migration, and invasion. Chronic lymphocytic leukemia (CLL) is an example of a lipid-avid cancer that relies on lipid metabolism, rather than glycolysis, to fuel cell proliferation. However, data regarding the role of cholesterol in CLL are conflicting. Studies have shown that dyslipidaemia is more common among CLL patients than age-matched healthy controls, and that CLL patients who take cholesterol-lowering drugs, such as statins, appear to have improved survival rates. Therefore, defining the roles of cholesterol in CLL may highlight the importance of monitoring and managing hyperlipidaemia as part of the routine management of patients with CLL. In this review, we discuss the roles of cholesterol in the context of CLL by examining the literature concerning the trafficking, uptake, endogenous synthesis, and intracellular handling of this lipid. Data from clinical trials investigating various classes of cholesterol and lipid-lowering drugs in CLL are also discussed.
RESUMO
The clinical significance of low-frequency deletions of 17p13 [tumour protein p53 (TP53)] in patients with chronic lymphocytic leukaemia (CLL) is currently unclear. Low-frequency del17p clones (<25%) were identified in 15/95 patients in the Australasian Leukaemia and Lymphoma Group (ALLG)/CLL Australian Research Consortium (CLLARC) CLL5 trial. Patients with low del17p, without tumour protein p53 (TP53) mutation, had significantly longer progression-free survival and overall survival durations than patients with high del17p clones. In 11/15 cases with low-frequency del17p, subclones solely with del17p or del13q were also noted. These data suggest that low-frequency del17p does not necessarily confer a poor outcome in CLL and challenges the notion of del13q as a founding event in CLL.
Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/mortalidade , Adulto , Austrália/epidemiologia , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genéticaRESUMO
Chronic lymphocytic leukaemia (CLL) is a malignant lymphoproliferative disorder characterised by the accumulation of dysfunctional B-lymphocytes in the blood and lymphoid tissues. It is a clonally complex disease with a high degree of both intra-tumoural and inter-patient heterogeneity. This variability leads to a wide range of clinical outcomes and highlights the critical need for accurate prognostic tests in CLL. With the advent of a range of new targeted agents for CLL in recent years, there is also a clinical need for improved predictive tests to therapy. This review of laboratory testing in CLL focuses on emerging technologies for prognostication including single nucleotide polymorphism microarray for karyotypic analysis, targeted next generation sequencing analysis of the immunoglobulin heavy chain variable region gene as well as genes recurrently mutated in the disease such as TP53, and detection of minimal residual disease.
Assuntos
Leucemia Linfocítica Crônica de Células B/diagnóstico , Polimorfismo de Nucleotídeo Único/genética , Técnicas de Laboratório Clínico , Sequenciamento de Nucleotídeos em Larga Escala , Cariotipagem , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Neoplasia Residual , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Análise de Sequência de DNAAssuntos
Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Integrina alfa4/genética , Leucemia Linfocítica Crônica de Células B/genética , Idoso de 80 Anos ou mais , Anemia/complicações , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Linfocitose/complicações , Masculino , MutaçãoRESUMO
INTRODUCTION: Vosaroxin is a first-in-class anti-cancer quinolone that inhibits topoisomerase-II leading to cell cycle arrest and apoptosis. It has shown efficacy in a range of solid organ and haematopoietic tumours in vitro, and several clinical trials are underway or completed in the field of Acute Myeloid Leukaemia (AML). The treatment of relapsed and refractory AML is a clinical challenge, where long-term survival is rare without allogeneic haematopoietic stem cell transplantation. AREAS COVERED: We review the data from the published clinical trials of vosaroxin, including the recently presented Phase III VALOR study. In combination with intermediate dose cytarabine, vosaroxin almost doubled complete response (CR) rates in relapsed and refractory AML compared with cytarabine alone, and prolonged median survival by 1.4 months. EXPERT OPINION: Vosaroxin is a promising new agent in the treatment of AML, with the potential to improve CR rates in a high-risk group of patients with relapsed and refractory AML. However, higher CR rates have been associated with higher rates of treatment-related morbidity and mortality, especially in elderly/unfit patients. Maximising the potential of vosaroxin will therefore require the identification of patients most likely to benefit from vosaroxin-containing combination regimens.
