Defibrotide Prophylaxis after Second Hematopoietic Cell Transplant in Pediatric Patients at Very High Risk for Veno-Occlusive Disease

Introduction Veno-occlusive disease (VOD) is a serious complication after hematopoietic cell transplant (HCT). Incidence of VOD in children is ∼15-20% and particular risk factors portend some patients to be very high risk (VHR). VOD is potentially fatal in up to 85% of patients who experience severe grades of VOD. Use of defibrotide for prophylaxis can be considered for those at VHR for developing VOD, but it is expensive. The cost of treating VOD is significant and the disease processes may result in long-term health effects. At our institution, for patients planned for 2nd allogeneic HCT, we limit the use of prophylactic defibrotide to VHR patients. We sought to provide justification for the use of prophylactic defibrotide in this smaller, more selective group. Objective The aim of the study was to evaluate whether prophylactic defibrotide in VHR pediatric patients undergoing their 2nd HCT had an impact on Day 100 VOD incidence (CI) or Day 180 overall survival (OS). Method To assess the impact of defibrotide prophylaxis on VOD in VHR patients after 2nd HCT, we compared the use of prophylactic defibrotide plus ursodiol versus ursodiol alone for VOD prevention. This single-center, retrospective review evaluated all pediatric patients (< 23 years) who underwent their second allogeneic HCT between 2018 and 2022. VHR was defined as ≥1 of the following risk factors: pre-HCT iron overload (ferritin > 1000, elevated liver iron concentration, use of iron chelators), received inotuzumab/gemtuzumab, osteopetrosis or inherited hemophagocytic lymphohistiocytosis (HLH). VOD was diagnosed by Seattle or modified Baltimore criteria. Prophylactic defibrotide dose was 25 mg/kg/day div Q6H beginning on first day of conditioning, continued until neutrophil engraftment. Patients with VOD were treated with defibrotide starting day of diagnosis, continued until the resolution of symptoms. Results A total of 44 pediatric patients underwent their second HCT between 2018 and 2022. Seventeen were classified as VHR. Baseline characteristics are in Table 1. Day 100 VOD CI was 20% and Day 180 OS was 82%. In the VHR group, defibrotide prophylaxis was administered to 7/17 (41%), 1 in the control group. Of the VHR with defibrotide ppx, 2/7 (29%) developed VOD compared to 6/10 (60%) ursodiol only VHR (p = 0.2). Day 100 OS was 45% in the VHR group who received prophylactic defibrotide compared to 55% in the ursodiol only group (p=0.89). Conclusion The results of withholding VOD prophylaxis may be devastating. This study was not adequately powered to detect if prophylactic defibrotide lowered the incidence of VOD in VHR pediatric patients after 2nd HCT. A larger cohort will be reviewed. There was a clear trend towards lower CI of VOD in the prophylaxis cohort. Given this trend towards lower incidence, use of prophylactic defibrotide should be strongly considered as a clinical option for this specific subset of pediatric HCT patients.