High Dose Defibrotide as Therapy for Pediatric Patients with Veno-Occlusive Disease of the Liver.
Authors: Hale Gregory A. , Madden Renee M. , Kasow Kimberly A. , Woodard Joseph , Leung Wing H. , Barfield Raymond C. , Yusuf Usman , Horwitz Edwin M. , Handgretinger Rupert 
Published: October 2019

Abstract
Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and certain chemotherapy regimens. Presently, there is no effective treatment for this disorder, with potential therapies resulting in hemorrhage. In adults with VOD, defibrotide, an investigational agent consisting of a single strand polydexoyribonucleotide, has been shown to improve survival rates at doses up to 60 mg/kg/day. Even with this improvement, a significant proportion of patients with VOD still die of multi-system organ failure. However, there is limited published data in pediatric patients and no data on administering doses of defibrotide > 60 mg/kg/day to patients who do not respond at standard dosages. In 2003, we initiated a compassionate use prospective clinical trial studying defibrotide therapy for patients with VOD. All transplant patients had received heparin 100 units/kg/day as a continuous infusion for VOD prophylaxis. A diagnosis of VOD was made if either of the following criteria were met:Bilirubin ≥ 2 mg/dl with 2 of the following criteria --hepatomegaly, weight gain ≥ 5%, and ascites; orultrasonographic evidence of VOD.
Defibrotide therapy was initiated at 10 mg/kg/day escalated every 24 hours by 10 mg/kg/day to 60 mg/kg/day over 6 days. Doses were administered intravenously at 6-hour intervals. Patients who did not have improvement in VOD at the maximum dose level were further escalated in 10 mg/kg/day increments to a maximum dose of 110 mg/kg/day. We enrolled 21 patients from August 2003 to July 2006. The median patient age, was 7.7 years (range, 0.5 to 21.6); 16 were male. Eighteen had received allogeneic HSCT (4 matched related, 6 unrelated, and 8 mismatched related donors), two had received autologous HSCT, and one was receiving chemotherapy for recurrent ALL. Diagnoses included ALL (n=5), AML (n=4), CML (n=1), NHL (n=2), JMML (n=1), neuroblastoma (n=4), Wilms’ tumor (n=1), and non-malignant disease (n=3). The non-HSCT patient had active disease at the time of enrollment. Of the 17 HSCT patients with malignancies, 5 had refractory/active disease, 5 were in CR1/CP1, 4 were in CR2, and 3 had PR. Five patients underwent second allogeneic HSCT. Thirteen patients had resolution of VOD at defibrotide doses ≤60 mg/kg/day. Eight patients required additional dose escalation: 70 mg/kg/day in 4 pts; 80 mg/kg/day in 2 pts; 100 mg/kg/day in 1 pt; and 110 mg/kg/day in 1 pt. VOD resolved in all but one. Only one patient died of VOD. Eight of 19 patients who have completed defibrotide therapy survive as outpatients with performance scores ≥ 90. Two other patients continue to receive defibrotide with resolving VOD--one who was treated at a maximum defibrotide dose of 70 mg/kg/day and the other at 110 mg/kg/day. Eleven patients expired--five of relapse, three of infection, and one each from graft failure, GVHD, and VOD. There were no defibrotide infusion-related adverse events. No unexpected adverse events related to the defibrotide occurred. Two of 3 patients with concomitant thrombotic microangiopathy at time of enrollment experienced resolution of the microangiopathy at a median of 14 days after initiating defibrotide. Defibrotide does improve survival for pediatric patients with VOD, that many patients with persistent VOD at standard doses will respond to higher doses of defibrotide, and that defibrotide can be safely administered at doses up to 110 mg/kg/day.