Patients Taking Defibrotide See Improvement in Complete Response and Day 100 Survival Rates

Orlando—A meta-analysis of phase 2 and phase 3 trials found that patients taking defibrotide to treat severe hepatic veno-occlusive disease with multiorgan failure (VOD/MOF) had significantly higher complete response (CR) rates compared with a control group. The defibrotide group also had a significantly improved day 100 survival rate. The results were presented during a poster session at the ASH meeting. The poster was titled Meta- Analysis of Defibrotide in the Treatment of Severe Hepatic Veno-Occlusive Disease with Multi-Organ Failure with Comparison to a Historical Control. VOD/MOF is a life-threatening disorder after stem cell transplantation. A phase 2 trial of 149 patients comparing 25-mg/kg and 40- mg/kg daily doses of defibrotide found CR rates of 43% and 39%, respectively. In addition, there was a CR rate of 24% in a phase 3 trial with 102 patients who had more severe VOD/MOF and received 25 mg/kg of defibrotide per day. The researchers in the phase 3 trial also reviewed 6864 medical charts at 35 bone marrow transplant centers to create a 32-patient control group. The phase 3 results indicated that patients taking defibrotide had a significantly higher CR rate than the control group (P=.0148). In this meta-analysis, the authors combined the 102 patients in the phase 3 trial with 31 patients in the phase 2 trial who met eligibility criteria and compared them with the control group. Both defibrotide groups had a similar total number of doses (median, 63 and 57, respectively), but the median length of treatment (15 days vs 22 days) was shorter in the phase 2 patients and the average defibrotide dose (21.0 mg/kg vs 18.6 mg/kg) was higher in the phase 2 patients. Eligibility criteria included a VOD diagnosis based on the Baltimore criteria of bilirubin ≥2.0 mg/dL with ≥2 of the following: hepatomegaly, ascites, and/or >5% weight gain. Patients also had to have renal and/or pulmonary dysfunction. The researchers defined renal dysfunction as a 3-fold increase in serum creatinine or <40% reduction in baseline creatinine clearance, glomerular filtration rate, or dialysis dependent. Pulmonary dysfunction was defined as <90% oxygen saturation. The requirement for CR was bilirubin <2.0 mg/dL and a resolution of MOF. The researchers assessed CR and mortality 100 days after diagnosis. Demographics were similar for the 3 groups. Of the phase 2 patients included in the meta-analysis, 61% were male compared with 63% males in the phase 3 group and 53% in the control group. The median age was 20 years in the phase 2 patients, 22 in the phase 3 group, and 18 in the control group. There were 45% pediatric (≤16 years of age) patients in the phase 2 group compared with 43% in the phase 3 group and 44% in the control group. The overall CR was significantly higher in the patients receiving defibrotide compared with the control group (29% vs 9%; P=.0021). The day 100 survival rate was also significantly higher in the defibrotide group (40% vs 25%; P=.0408). The authors also performed a subset analysis and found several groups had significantly improved outcomes, including children <16 years, patients who were not dependent on ventilators or dialysis when the study began, and patients undergoing their first stem cell transplantation. In addition, the incidence of graft-versus-host disease was lower in the defibrotide group compared with the control group (6% vs 25%), while the toxicity was similar between the groups.