Richardson Paul G, Smith Angela R, Kernan Nancy A, Lehmann Leslie, Ryan Robert J, Grupp Stephan A
Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
Transplant Cell Ther. 2021 Jan;27(1):88.e1-88.e6. doi: 10.1016/j.bbmt.2020.09.008. Epub 2020 Sep 17.
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.
肝静脉闭塞病/窦性阻塞综合征（VOD/SOS）是造血细胞移植（HCT）后发生的一种可能危及生命的并发症。据报道，未经治疗的伴有多器官功能障碍（MOD）的VOD/SOS的死亡率>80%。去纤苷的推荐剂量为6.25mg/kg，每6小时一次，通过2小时静脉输注给药，至少持续21天或直至VOD/SOS体征和症状消退。本分析的目的是评估接受去纤苷治疗的HCT后VOD/SOS患者的完全缓解（CR）时间。在一项扩大准入研究（T-IND；ClinicalTrials.gov NCT00628498；n = 1000）中，因CR导致去纤苷停药的时间作为CR时间的替代指标，并与从一项2期随机剂量探索研究（NCT00003966；n = 74例接受25mg/kg/天的患者）和一项3期历史对照研究（NCT00358501；n = 102）汇总的CR时间数据分开分析。对于所有研究，CR定义为总血清胆红素<2mg/dL且VOD/SOS相关的MOD（肾和/或肺功能障碍）消退；2期研究还要求中枢神经系统功能障碍消退。在T-IND中，390例患者因CR停药且有足够的数据进行分析。停药的中位时间为22天（范围为2至64天）。235例患者（60%）在21天之后因CR停药，57例患者（15%）在28天之后停药。汇总的2期和3期研究包括60例达到CR的患者，CR的中位时间为24.5天（范围为7至123天）。32例患者（53%）在21天之后达到CR，24例患者（40%）在28天之后达到CR。与未因CR停药的患者相比，因CR停药的患者第100天的Kaplan-Meier生存率估计值显著更高（92.5%对37.3%）。在T-IND中，390例因CR停药的患者中有185例（47%）发生治疗中出现的不良事件，在汇总的2期和3期研究中，60例达到CR的患者中有55例（92%）发生治疗中出现的不良事件，且发生率根据治疗持续时间（≤21天对>21天）无差异。综上所述，这些结果强调了按照批准的产品标签目前所示，持续使用去纤苷治疗直至VOD/SOS体征和症状消退的重要性，这可能发生在推荐的最短21天之后。
