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

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.