PDF(Pubmed)
Abstract：
Isocitrate dehydrogenase (IDH) mutations are present in 70% of World Health Organization grade II and III gliomas. IDH mutation induces accumulation of the oncometabolite 2-hydroxyglutarate. Therefore, therapies targeting reversal of epigenetic dysregulation in gliomas have been suggested. However, the utility of epigenetic treatments in gliomas remains unclear. Here, we present the first clinical systematic review of epigenetic therapies in treatment of IDH-mutant gliomas and highlight their safety and efficacy.
We conducted a systematic search of electronic databases from 2000 to January 2021 following PRISMA guidelines. Articles were screened to include clinical usage of epigenetic therapies in case reports, prospective case series, or clinical trials. Primary and secondary outcomes included safety/tolerability of epigenetic therapies and progression-free survival/overall survival, respectively.
A total of 133 patients across 8 clinical studies were included in our analysis. IDH inhibitors appear to have the best safety profile, with an overall grade 3/grade 4 adverse event rate of 9%. Response rates to IDH-mutant inhibitors were highest in nonenhancing gliomas (stable disease achieved in 55% of patients). In contrast, histone deacetylase inhibitors demonstrate a lower safety profile with single-study adverse events as high as 28%.
IDH inhibitors appear promising given their benign toxicity profile and ease of monitoring. Histone deacetylase inhibitors appear to have a narrow therapeutic index, as lower concentrations do not appear effective, while increased doses can produce severe immunosuppressive effects. Preliminary data suggest that epigenetic therapies are generally well tolerated and may control disease in certain patient groups, such as those with nonenhancing lesions.
We conducted a systematic search of electronic databases from 2000 to January 2021 following PRISMA guidelines. Articles were screened to include clinical usage of epigenetic therapies in case reports, prospective case series, or clinical trials. Primary and secondary outcomes included safety/tolerability of epigenetic therapies and progression-free survival/overall survival, respectively.
A total of 133 patients across 8 clinical studies were included in our analysis. IDH inhibitors appear to have the best safety profile, with an overall grade 3/grade 4 adverse event rate of 9%. Response rates to IDH-mutant inhibitors were highest in nonenhancing gliomas (stable disease achieved in 55% of patients). In contrast, histone deacetylase inhibitors demonstrate a lower safety profile with single-study adverse events as high as 28%.
IDH inhibitors appear promising given their benign toxicity profile and ease of monitoring. Histone deacetylase inhibitors appear to have a narrow therapeutic index, as lower concentrations do not appear effective, while increased doses can produce severe immunosuppressive effects. Preliminary data suggest that epigenetic therapies are generally well tolerated and may control disease in certain patient groups, such as those with nonenhancing lesions.
摘要：
异柠檬酸脱氢酶（IDH）突变存在于世界卫生组织II和III级神经胶质瘤的70％中。IDH突变诱导瘤代谢物2-羟基戊二酸的积累。因此,针对逆转神经胶质瘤表观遗传失调的治疗方法已被提出.然而,表观遗传学治疗在神经胶质瘤中的应用尚不清楚.这里,我们首次对表观遗传疗法治疗IDH突变型神经胶质瘤进行了临床系统综述,并强调了其安全性和有效性.
我们根据PRISMA指南，从2000年到2021年1月对电子数据库进行了系统搜索。文章进行了筛选，包括在病例报告中的表观遗传疗法的临床使用，前瞻性病例系列，或临床试验。主要和次要结局包括表观遗传疗法的安全性/耐受性和无进展生存期/总生存期。分别。
在我们的分析中纳入了8项临床研究中的133名患者。IDH抑制剂似乎具有最佳的安全性，总体3级/4级不良事件率为9%。在非增强性神经胶质瘤中，对IDH突变抑制剂的反应率最高（55％的患者病情稳定）。相比之下,组蛋白去乙酰化酶抑制剂的安全性较低,单一研究不良事件高达28%.
鉴于其良性毒性特征和易于监测，IDH抑制剂似乎很有希望。组蛋白去乙酰化酶抑制剂似乎具有狭窄的治疗指数，由于较低的浓度似乎无效，而增加剂量会产生严重的免疫抑制作用。初步数据表明，表观遗传疗法通常具有良好的耐受性，并且可以控制某些患者群体的疾病。比如那些没有增强的病变。
我们根据PRISMA指南，从2000年到2021年1月对电子数据库进行了系统搜索。文章进行了筛选，包括在病例报告中的表观遗传疗法的临床使用，前瞻性病例系列，或临床试验。主要和次要结局包括表观遗传疗法的安全性/耐受性和无进展生存期/总生存期。分别。
在我们的分析中纳入了8项临床研究中的133名患者。IDH抑制剂似乎具有最佳的安全性，总体3级/4级不良事件率为9%。在非增强性神经胶质瘤中，对IDH突变抑制剂的反应率最高（55％的患者病情稳定）。相比之下,组蛋白去乙酰化酶抑制剂的安全性较低,单一研究不良事件高达28%.
鉴于其良性毒性特征和易于监测，IDH抑制剂似乎很有希望。组蛋白去乙酰化酶抑制剂似乎具有狭窄的治疗指数，由于较低的浓度似乎无效，而增加剂量会产生严重的免疫抑制作用。初步数据表明，表观遗传疗法通常具有良好的耐受性，并且可以控制某些患者群体的疾病。比如那些没有增强的病变。
