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• W3196277711 abstract "Despite advances in therapies for diffuse large B-cell lymphoma (DLBCL), the most common subtype of lymphoma, a third of patients relapse or are refractory to primary treatment, underscoring the need for further research into the pathophysiology of these diseases to improve outcomes. Interactions between lipid pathways and lymphomagenesis would suggest a potential role for lipid-lowering agents in disease prevention and treatment.1-4 To date, a role for HMG-CoA reductase inhibitors, or statins, in the prevention or treatment of lymphoma remains unclear. While some studies report a risk reduction of up to 40% in lymphoma development due to statin exposure,1, 2 their impact on lymphoma outcomes remains controversial, with conflicting results from in-vitro and in-vivo studies. Based on in-vitro studies, it has been proposed that statins induce apoptosis of lymphoma cells through inhibition of geranylgeranylation pathways, leading to impaired formation of cholesterol-rich lipid microdomains within cell membranes.1 Through blockade of the mevalonate pathways, statins are postulated to reduce lymphoma risk by inhibiting BCL-2, NFkB and other oncogenic proteins.3, 5 Conflicting reports exist surrounding the potential interaction of statins on lymphoma therapy. Statins may potentiate the therapeutic effects of radiation therapy, chemotherapy, and biologics in lymphoma.2 The addition of simvastatin to CHOP [cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), prednisone] demonstrated synergistic activity and improved responses, through enhanced sensitisation, in CHOP-resistant cell lines.1 A cardioprotective role for statins in anthracycline-mediated cardiotoxicity is amassing interest: a recent study of statin-exposed women treated for breast cancer identified a lower risk of hospital presentations for heart failure compared to unexposed, matched cohorts.6 In contrast, in-vitro studies have demonstrated statins, through cholesterol depletion, cause a conformational change in the structure of CD20, resulting in altered rituximab binding.7 Decreased binding may impede rituximab-mediated antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity of B lymphoma cells.7, 8 In the era of chemo-immunotherapy, smaller clinical studies have demonstrated no improvement in lymphoma outcomes with statin exposure.8-10 Similar negative findings were observed in a meta-analysis.2 However, mechanisms by which statins may impact lymphoma outcomes likely vary according to lymphoma subtype and biology. One study found an association with statin exposure and improved outcome in follicular lymphoma (FL), including patients treated with rituximab-containing regimens and clinical surveillance only, but not in DLBCL.10 Another group proposed statins may act as novel histone deacetylase inhibitors, providing new cancer prevention and therapeutic strategies.11 In another study, statin exposure was associated with inferior outcomes in non-germinal centre B-cell-like (non-GCB) DLBCL cohorts only.12 In contrast, our group identified that statin exposure prior to commencement of lymphoma therapy was associated with improved survival in newly diagnosed DLBCL or transformed FL older patients, following adjustment for relevant confounders. The time-dependant varying analysis identified that greater statin exposure within one year of lymphoma diagnosis was associated with improved survival.13 A link between lipid metabolism and chronic lymphocytic leukaemia (CLL) has also been established, with high rates of hypercholesterolaemia documented in CLL patients.14 Lipoprotein lipase, when expressed in CLL cells but absent in normal lymphocytes, is associated with inferior outcomes.15, 16 It has also been proposed that low-density lipoproteins amplify proliferation of CLL cells to inflammatory stimuli.17 However, clinical responses in statin-exposed CLL patients are again contradictory. A population-based study reported a lower risk of CLL development with low-potency lipophilic statins but no difference in incidence rates with hydrophilic or high-potency lipophilic statins.18 In contrast, other studies have shown that patients on statins at the time of CLL diagnosis have prolonged time to first treatment12 as well as improved survival after exposure to lipid lowering therapies.19 In their paper, Brånvall et al.20 describe the impact of statin exposure, pre and post CLL or non-hodgkin lymphoma (NHL) diagnosis, on mortality in a Swedish population-based study. The study included 16 098 patients, including those undergoing expectant management. Twenty percent of the cohort were exposed to statin at the time of diagnosis. They identified no improvement in survival outcomes in NHL patients either before diagnosis [hazard ratio (HR) 0.95, range 0.85–1.06] or post diagnosis (HR 0.93, 0.77–1.12). These findings were consistent across all lymphoma subtypes, apart from NK-T cell lymphoma where survival outcomes were improved with statin use post diagnosis. Similarly, in the CLL cohort, statin exposure pre diagnosis (HR 0.91; 0.69–1.21) and post diagnosis (HR 0.79; 0.55–1.12) had no association with survival outcomes. However, in a nested case-control analysis, statin use at any time post diagnosis demonstrated reduced lymphoma-related mortality (HR 0.59; 0.41–0.87). The authors concluded that, whilst safe, statin exposure and dose intensity were not associated with improved survival outcomes. The study by Brånvall et al.20 has much to commend. The population-based study enabled the evaluation of real-world unselected patients treated according to current standards of care. Their administrative data sets comprised ˜95% of all lymphoma diagnoses in the population, while including enough granular detail to ensure that relevant patient- and disease-specific variables could be adjusted for in their analyses. The authors further validated the cause-of-death reporting by chart review in a subset of patients and assessed for a potential healthy-user bias in statin users by adjusting for surrogate drugs (including proton pump inhibitors). Understandably, limitations in the available data sets preclude a comprehensive understanding of treatment details and outcomes. Time to progression data were not available, limiting the ability to differentiate the impact of statins on lymphoma-related versus cardiovascular-related outcomes. Chemotherapy regimens and details on dose intensity and density were not available. These may have differed between statin users, who were typically older and affected by more comorbidities, and non-statin users. The median follow-up of 2.28 years (0.0–7.00) for non-statin users and 1.90 years (0.0–7.00) for the statin-exposed group is significantly shorter than the expected median time to next therapy for most indolent lymphomas and CLL. Although not an objective of this paper, whether this shorter follow-up time allows for a true assessment of the impact of statin exposure on disease progression remains unknown. Similarly, studying a six-month exposure to statins may not be adequate to capture the extent of benefit from these medications. We find it provocative that a duration of statin exposure >2 years was associated with improved disease-specific survival in the CLL nested case-control analysis. Further studies that capture an extended and consistent duration of statin exposure may still be warranted. Significant evidence exists to support the implication of lipid pathways in lymphomagenesis. However, whether manipulation of these pathways is associated with survival outcomes remains controversial. This study by Brånvall et al. adds further support to the clinical evidence to date that has failed to show an impact of statin therapy on outcomes in B-cell malignancies. Still, it remains unclear as to why differences in outcome across various population-based studies exist. Undoubtedly, this often contradictory landscape is in part due to the complexity and heterogeneity of lymphoma, a group of many clinicopathologically distinctive entities which may require different therapeutic strategies. Ultimately, the role of statins in lymphoma and whether statin therapy can lead to clinically significant improvement in outcomes is yet to be determined through well-designed, randomized controlled trials." @default.
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• W3196277711 date "2021-08-16" @default.
• W3196277711 modified "2023-09-26" @default.
• W3196277711 title "Statins in mature B‐cell lymphomas and leukaemias" @default.
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• W3196277711 doi "https://doi.org/10.1111/bjh.17778" @default.
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