Treatment Duration, Symptom Resolution, and Survival in Defibrotide-Treated Patients with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation: Analysis of a Multinational, Prospective, Observational Registry Study

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). Clinical guidelines endorse prompt defibrotide initiation after VOD/SOS diagnosis. In order to collect safety and outcomes data and assess patterns of defibrotide utilization in the post-approval setting, a registry of patients who received defibrotide was established.

This multicenter, multinational, prospective, observational study (NCT03032016), performed by the European Society for Blood and Marrow Transplantation, enrolled defibrotide-treated patients from April 2015 to July 2018. Investigators diagnosed VOD/SOS using classical/standard criteria (including, but not limited to, hyperbilirubinemia, hepatomegaly, ascites, and weight gain >5%). Severity grading criteria were not predefined in the protocol; investigators graded VOD/SOS severity based on their clinical expertise. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. This analysis evaluated time to diagnosis, treatment initiation, and resolution of VOD/SOS, as well as treatment duration and survival, in patients given defibrotide for the treatment of severe or non-severe VOD/SOS post-HCT.

Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were included (62 with severe VOD/SOS [45% adults, ≥18 years] and 42 with non-severe VOD/SOS [40% adults]). The median age was 14.4 (range: 0, 69) years; 90 (87%) patients received allogeneic HCT. Most (89%) patients had received 1 HCT and most (82%) were given a myeloablative conditioning regimen. HCT type and conditioning regimen were similar between adult and pediatric patients.

The median time from HCT to VOD/SOS diagnosis was 14 (range: 2, 123) days and 13 (range: 2, 36) days in patients with severe VOD/SOS or non-severe disease, respectively. Defibrotide treatment for VOD/SOS was generally initiated on the same day as diagnosis (median days from diagnosis was 0 days in both severe [range: 0, 8] and non-severe [range: 0, 11] VOD/SOS patients). Among patients with severe VOD/SOS, 73%, 13%, and 15% received defibrotide at 0, 1, and ≥2 days after diagnosis; correspondingly this was 74%, 21%, and 5% for patients with non-severe VOD/SOS. Most patients (severe: 79%; non-severe: 76%) received the recommended dose of 25 mg/kg/day. The median duration of treatment was similar for both severe and non-severe VOD/SOS (16.5 [interquartile range [IQR]: 11, 25] days and 15.5 [IQR: 13, 21] days, respectively).

Resolution of VOD/SOS was achieved in 47 (76%) patients with severe VOD/SOS and 40 (95%) with non-severe VOD/SOS. The median time from diagnosis to resolution of VOD/SOS was 20.0 (range: 5, 112) days and 15.5 (range: 2, 29) days in patients with severe VOD/SOS or non-severe disease, respectively. Resolution of VOD/SOS occurred after Day 21 in 19 (40%) and 11 (28%) patients with severe VOD/SOS or non-severe disease, respectively. Among patients with severe VOD/SOS, the Kaplan-Meier (KM)-estimated Day 100 post-HCT survival rate was 89% (95% confidence interval [CI]: 76%, 95%) in patients who achieved resolution of VOD/SOS and 20% (95% CI: 5%, 42%) in those who did not. In patients with non-severe VOD/SOS, the KM-estimated Day 100 post-HCT survival rate was 95% (95% CI: 82%, 99%) in patients who achieved resolution of VOD/SOS; the two patients with non-severe disease who failed to achieve resolution of VOD/SOS were not alive at Day 100 post-HCT.

A SAE of interest occurred in 32% (95% CI: 21%, 44%) of patients with severe VOD/SOS and in 21% (95% CI: 9%, 34%) of patients with non-severe VOD/SOS. The most common individual SAEs of interest (≥5% of patients) were pneumonia, sepsis, gastrointestinal bleeding, and urinary tract bleeding. Few patients discontinued defibrotide due to an adverse event: 1 (2%) patient with severe VOD/SOS and 0 patients with non-severe VOD/SOS.

These results highlight the importance of prompt diagnosis and of continuing treatment until a response is achieved. These findings are consistent with the product labeling, which recommends continued administration for at least 21 days and until full resolution of VOD/SOS signs and symptoms. The safety profile of defibrotide in the real-world setting was consistent with reports from previous studies.