A pilot trial of prophylactic defibrotide to prevent serious thrombotic microangiopathy in high‐risk pediatric patients

Abstract Background Transplant‐associated thrombotic microangiopathy (TA‐TMA) is an endothelial injury complication of hematopoietic stem cell transplant (HSCT) leading to end‐organ damage and high morbidity and mortality. Defibrotide is an anti‐inflammatory and antithrombotic agent that may protect the endothelium during conditioning. Procedure We hypothesized that prophylactic use of defibrotide during HSCT conditioning and acute recovery could prevent TA‐TMA. A pilot single‐arm phase II trial (NCT#03384693) evaluated the safety and feasibility of administering prophylactic defibrotide to high‐risk pediatric patients during HSCT and assessed if prophylactic defibrotide prevented TA‐TMA compared to historic controls. Patients received defibrotide 6.25 mg/kg IV q6h the day prior to the start of conditioning through day +21. Patients were prospectively monitored for TA‐TMA from admission through week 24 post transplant. Potential biomarkers of endothelial injury (suppression of tumorigenicity 2 [ST2], angiopoietin‐2 [ANG‐2], plasminogen activator inhibitor‐1 [PAI‐1], and free hemoglobin) were analyzed. Results Twenty‐five patients were enrolled, 14 undergoing tandem autologous HSCT for neuroblastoma and 11 undergoing allogeneic HSCT. Defibrotide was discontinued early due to possibly related clinically significant bleeding in 12% (3/25) of patients; no other severe adverse events occurred due to the study intervention. The other 22 patients missed a median of 0.7% of doses (0%–5.2%). One patient developed nonsevere TA‐TMA 12 days post HSCT. This observed TA‐TMA incidence of 4% was below the historic rate of 18%–40% in a similar population of allogeneic and autologous patients. Conclusions Our study provides evidence that defibrotide prophylaxis is feasible in pediatric patients undergoing HSCT at high risk for TA‐TMA and preliminary data indicating that defibrotide may reduce the risk of TA‐TMA.