Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Spanish Bone Marrow Donor Program, Josep Carreras Leukemia Foundation and Leukemia Research Institute, Barcelona, Spain.
Blood Adv. 2018 Jun 26;2(12):1495-1509. doi: 10.1182/bloodadvances.2017008375.
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of conditioning during hematopoietic stem cell transplantation (HSCT) or chemotherapy without HSCT, with a historically reported mean incidence of 13.7% post-HSCT. Typical symptoms of VOD/SOS may include hyperbilirubinemia, painful hepatomegaly, weight gain, and ascites. Defibrotide, a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotides, is currently the only therapy approved to treat hepatic VOD/SOS with pulmonary/renal dysfunction (ie, multiorgan dysfunction/multiorgan failure [MOD/MOF]) following HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the European Union. In preclinical and human studies, defibrotide has demonstrated profibrinolytic, antithrombotic, anti-inflammatory, and angio-protective actions, thus promoting an anticoagulant phenotype of the endothelium that protects and stabilizes the function of endothelial cells. In a phase 3, historically controlled, multicenter trial in adults and children with VOD/SOS and MOD/MOF (defibrotide: n = 102; controls treated before defibrotide availability: n = 32), defibrotide resulted in significantly greater day +100 survival following HSCT (38.2%) vs controls (25.0%; propensity analysis-estimated between-group difference: 23%; = .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graft-versus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.
肝静脉闭塞病/窦状隙阻塞综合征（VOD/SOS）是造血干细胞移植（HSCT）或无 HSCT 的化疗期间潜在的危及生命的并发症，HSCT 后 VOD/SOS 的历史报告发生率为 13.7%。VOD/SOS 的典型症状可能包括高胆红素血症、肝肿大伴疼痛、体重增加和腹水。地夫可特是一种主要由单链多脱氧核苷酸组成的多分散混合物，是目前唯一在美国批准用于治疗 HSCT 后伴有肺/肾功能障碍（即多器官功能障碍/多器官衰竭[MOD/MOF]）的肝 VOD/SOS 的治疗药物，以及用于治疗欧盟 HSCT 后严重肝 VOD/SOS 的药物。在临床前和人体研究中，地夫可特显示出纤维蛋白溶解、抗血栓、抗炎和血管保护作用，从而促进内皮细胞的抗凝表型，保护和稳定内皮细胞的功能。在一项针对 VOD/SOS 和 MOD/MOF 成人和儿童的 3 期、历史对照、多中心试验中（地夫可特：n = 102；地夫可特可用前接受治疗的对照组：n = 32），地夫可特在 HSCT 后第 100 天的生存率显著更高（38.2% vs 对照组：25.0%；倾向分析估计的组间差异：23%；=.0109）。最常见的不良事件（AE）是低血压和腹泻；地夫可特组和历史对照组常见出血性 AE 发生率相似（分别为 64%和 75%）。在一项 3 期预防试验中，地夫可特被发现可降低儿童（未批准的适应证）VOD/SOS 的发生率，并降低移植物抗宿主病的发生率。本综述描述了地夫可特的开发和临床应用，重点介绍了其在 HSCT 后 VOD/SOS 和 MOD/MOF 患者中的适应证内应用。
