Pediatric Stem Cell Transplantation: Defibrotide for the Prevention of Hepatic Veno-Occlusive Disease (VD) #ASH09

The 100-day survival rates for pediatric patients who have received stem cell transplants has steadily increased. However, it is still associated with significiant mortality and morbidity including   complications such as veno-occlusive disease, a disease in which the small vessles in the liver become obstructed. This life-threatening condition has a particularly high incidence in children undergoing allogeneic stem cell transplantation. In this study, researchers from the University of Ulm in Germany assessed the safety and efficacy of defibrotide, an investigational drug, for the prevention of this disease in the largest-ever, international, multicenter study of high-risk pediatric patients undergoing stem cell transplants. The study was co-sponsored by the European Group for Blood and Marrow Transplantion (EBMT).

A total of 360 high-risk patients with a median age of five years were enrolled in the study (24 percent infants, 52 percent children ages 2-11, and 23 percent adolescents ages 12-18). Sixty-eight percent of the patients underwent allogeneic stem cell transplant (a procedure in which a person receives blood-forming stem cells from a genetically similar, but not identical donor), and 31 percent received an autologous stem cell transplant (a procedure in which blood-forming stem cells are removed from a patient, stored, and then re-injected following high-dose chemotherapy to accelerate the “rescue” of blood formation). Patients were prospectively randomized prior to stem cell transplantation to receive either defibrotide or no preventive therapy for veno-occlusive disease. The patients who were randomized to the defibrotide arm received intravenous infusions (25 mg/kg/day) from the start of conditioning (the time before transplant when a patient is given chemotherapy to suppress the immune system, to make room for donor marrow cells to grow, or to destroy remaining cancer cells) until 30 days post stem cell transplant or discharge from the hospital, whichever came first. In the control arm, patients did not receive any preventive therapy. The primary endpoint of this study was to measure the incidence of veno-occlusive disease after 30 days, which was adjudicated by a blinded, independent review committee of three expert hematologists. Secondary endpoints of the study were to measure veno-occlusive disease-associated morbidity, mortality, and the incidence and severity of graft-versus-host disease.

According to the study results, preventive use of defibrotide resulted in a 40 percent reduction in the overall incidence of veno-occlusive disease in these pediatric patients. Consistent with the role of defibrotide in protecting endothelial cells (the thin layer of cells that line the inside of  blood vessels), both the incidence of renal failure (1 percent with defibrotide versus 6 percent in control) and also the overall incidence and severity of acute graft-versus-host disease (32 percent in defibrotide versus 43 percent in control) were significantly lower in the defibrotide arm. In addition, the safety of defibrotide was confirmed by the lack of significant toxicity; the defibrotide and control arms had similar numbers of adverse events reported. Results from this study also confirm that the mortality at 100 days post-transplant in patients who developed veno-occlusive disease was four times higher than the mortality in patients who had not developed this disease.

“For pediatric stem cell transplant patients who develop veno-occlusive disease, we unfortunately have limited diagnostic tools, poor understanding of potential risk factors and mechanisms of the disease, and no established therapies to help prevent or treat this condition,” said lead study author Selim Corbacioglu, MD, Assistant Professor of the Department of Hematology, Oncology, Immunology, and Stem Cell Transplantation at the University of Ulm in Germany. “Our study confirms that defibrotide is safe and effective for preventing veno-occlusive disease in this high-risk population.”