A Pilot Trial of Pre-Transplant Risk Stratification and Prophylactic Defibrotide to Prevent Serious Thrombotic Microangiopathy in High-Risk Pediatric Hematopoietic Stem Cell Transplant Patients

Background: Transplant associated thrombotic microangiopathy (TA-TMA) is a known complication of hematopoietic stem cell transplant (HSCT) associated with endothelial injury that leads to end organ damage and high morbidity and mortality. No proven method for prevention of TA-TMA exists. One strategy is to decrease or even prevent the initial endothelial injury during conditioning. Defibrotide is an anti-inflammatory and anti-thrombotic agent that has been shown to protect the endothelium from damage and treat TA-TMA. We hypothesize that prophylactic use of defibrotide during HSCT conditioning and acute recovery may potentially prevent TA-TMA.

Methods: We initiated a pilot single-arm phase II trial (NCT#03384693) to evaluate the safety and feasibility of administering prophylactic defibrotide to pediatric patients at high risk for the development of TA-TMA following HSCT. Additionally, we sought to determine if administration of prophylactic defibrotide would prevent the development of TA-TMA in clinically high-risk patients compared to historic controls. High-risk patients were defined as either patients with high-risk neuroblastoma whose treatment plan included autologous tandem transplants conditioned with cyclophosphamide/thiotepa (Cy/TT) and carboplatin/etoposide/melphalan (CEM), or allogeneic transplant patients undergoing myeloablative conditioning, with at least three of the following: age ≥10 years old, race/ethnicity other than Caucasian, ABO minor incompatibility, or haploidentical donor. Based on prior analysis at our center, we anticipated an incidence of TA-TMA of 28% in the high-risk patients undergoing allogeneic transplants and 40% in the neuroblastoma patients.

Patients received defibrotide 6.25mg/kg IV q6h the day prior to the start of conditioning through day +21 and received supportive care per institution guidelines, including maintaining platelets above 30 x10^9/L. Patients were prospectively monitored for TA-TMA from admission through week 24.

Results: Twenty-five patients were enrolled, 14 with neuroblastoma and 11 undergoing allogeneic HSCT. The median age was 3.45 (2.1-10.1) and 15.7 (0.8-27.4) years for autologous and allogeneic patients, respectively. Ten of the allogenic transplants were with an alpha-beta T-cell depleted haploidentical HSCT, while one was with a matched unrelated HSCT. Follow-up is complete on all patients.

Defibrotide was stopped early due to clinically significant bleeding in 3 patients (day +3, +6 and +10, respectively). Bleeding episodes were excessive bleeding from oral hematoma, diffuse alveolar hemorrhage, and melanic stools and epistaxis and were classified as "possibly related" to the study drug. The other 22 patients missed a median of 0.7% of doses (0-5.2%), most often due to concomitant medication infusions. There were no allergic or hypersensitivity reactions. One patient with acute lymphoblastic leukemia (ALL) in CR4 died during the study period from respiratory failure in the setting of disseminated aspergillus and veno-occlusive disease (VOD), leading to a TRM of 0% and 9.1% in the autologous and allogeneic patients, respectively. Of the neuroblastoma patients, 4 did not go on to receive a second transplant; three due to development of moderate to severe VOD and one per parental preference. Five of the 14 neuroblastoma patients developed VOD, 4 after Cy/TT (1 mild, 2 moderate, 1 severe) and 1 after CEM (mild); all of which resolved.

One patient developed non-severe TA-TMA, diagnosed 12 days post-HSCT (4% incidence). She received an alpha-beta T-cell depleted peripheral blood HSCT from her mother for ALL after conditioning with total body irradiation, cyclophosphamide, thiotepa, and ATG. Her course was complicated by diffuse alveolar hemorrhage on day +6 for which defibrotide was stopped. Her TA-TMA was treated with eculizumab and resolved without sequelae.

Conclusions: 12% (3/25) patients required early discontinuation of defibrotide due to clinically significant bleeding; no other severe adverse events occurred due to the study intervention. The observed TA-TMA incidence of 4% was far below the anticipated rate of 28-40%. Our study provides preliminary evidence that defibrotide prophylaxis is safe and feasible in children and adolescents undergoing HSCT at high risk for TA-TMA and may reduce the risk of TA-TMA. Future larger randomized studies are needed to verify these findings.