VASCERN HHT Reference Center, ASST Maggiore Hospital, Crema, Italy.
Department of Cell and Molecular Medicine Centro de Investigaciones Biológicas, CSIC, U707 CIBERER, Madrid, Spain.
Orphanet J Rare Dis. 2019 Feb 4;14(1):28. doi: 10.1186/s13023-018-0982-4.
Hereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events.
Sixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11 months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4 months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1-3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1-3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p < 0.001). Thalidomide AEs occurred at more similar rates in males (25 AEs in 41 men, 60.9%) and females (12 in 26 (46.2%), but were more common in ENG patients (17 in 17) than in ACVRL1 (14 in 34, p < 0.0001). For bevacizumab, the most common reports were of joint pains (7/69, 10%), headache (3/69, 4.4%) and proteinuria (2/69, 3%), and for thalidomide, peripheral neuropathy (12/67, 18%); drowsiness (8/67, 12%); and dizziness (6/67, 9%). Fatal adverse events were more common in males (p = 0.009), and in patients with ENG pathogenic variants (p = 0.012). One fatal AE was possibly related to bevacizumab (average incidence rate: 1.5 per 100 person-years); 3 fatal AEs were possibly related to thalidomide (average incidence rate: 4 per 100 person-years).
With potential increase in use of Bevacizumab and Thalidomide in HHT patients, data presented support appropriate weighing of the toxicities which can arise in HHT settings and the practice recommendations for their prevention and management.
遗传性出血性毛细血管扩张症（HHT）是一种多系统遗传性血管发育不良，可导致鼻出血和内脏动静脉畸形（AVM）。沙利度胺和贝伐珠单抗等抗血管生成药物已被越来越多地超适应证使用，效果不一。欧洲罕见多系统血管疾病网络（VASCERN）的 HHT 工作组开发了一种基于问卷的回顾性不良事件（AE）捕获方法，这些 AE 使用常见不良事件术语标准进行分类。
69 例 HHT 患者接受了贝伐珠单抗治疗，37 例（50.6%）用于高输出心力衰竭/肝 AVM，32 例（49.4%）用于出血；69 例患者接受贝伐珠单抗治疗，平均 11 个月，共治疗 63.8 人/年。67 例患者接受沙利度胺治疗，均用于鼻出血和/或胃肠道出血；他们接受沙利度胺治疗的平均时间为 13.4 个月/患者，共治疗 75 人/年。58 例患者报告了 AE，其中 33 例与贝伐珠单抗相关，37 例与沙利度胺相关。报告了 32 例与贝伐珠单抗相关的 1-3 级 AE，其平均发生率为每 100 人年 50 例。报告了 34 例与沙利度胺相关的 1-3 级 AE，其平均发生率为每 100 人年 45.3 例。贝伐珠单抗相关的 AE 在女性（46 名女性中有 27 例）中比男性（23 名男性中有 6 例）更为常见（p<0.001）。沙利度胺相关的 AE 在男性（41 名男性中有 25 例，60.9%）和女性（26 名女性中有 12 例，46.2%）中的发生率相似，但在 ENG 患者中更为常见（17 例中的 17 例），而在 ACVRL1 患者中则较少见（34 例中的 14 例，p<0.0001）。贝伐珠单抗最常见的报告是关节疼痛（7/69，10%）、头痛（3/69，4.4%）和蛋白尿（2/69，3%），而沙利度胺最常见的报告是周围神经病（12/67，18%）；嗜睡（8/67，12%）和头晕（6/67，9%）。致命的 AE 在男性中更为常见（p=0.009），在携带 ENG 致病性变异的患者中更为常见（p=0.012）。1 例致命 AE 可能与贝伐珠单抗有关（平均发生率：每 100 人年 1.5 例）；3 例致命 AE 可能与沙利度胺有关（平均发生率：每 100 人年 4 例）。
随着贝伐珠单抗和沙利度胺在 HHT 患者中应用的潜在增加，目前的数据支持对 HHT 环境中可能出现的毒性进行适当权衡，并为其预防和管理提供实践建议。
