Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially fatal complication of allogeneic or autologous hematopoietic cell transplantation (HCT), and is estimated to occur in 13.7 percent of patients receiving HCT (range = 0-62.3%). In cases of severe VOD/SOS, when patients also experience multi-organ failure, the mortality risk is greater than 80 percent.
Preclinical data have suggested that defibrotide, a sodium salt of complex single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA, can stabilize and protect endothelial cells – restoring the balance between the coagulation and fibrinolytic cascades.
Paul G. Richardson, MD, from the Dana-Farber Cancer Institute, assessed rates of survival and complete response (CR) with defibrotide in patients with hepatic VOD/SOS with multi-organ failure in a multi-center, open-label, phase III study in which outcomes of patients receiving the intervention were compared with historical controls.
“Although HCT practice has changed greatly over the past decades, hepatic VOD/SOS with multi-organ failure remains a very real and life-threatening complication post-HCT, for which there are no approved therapies,” Dr. Richardson and colleagues wrote. “In this context, defibrotide provides a promising treatment option for patients with a high unmet medical need.”
The study was conducted at 35 centers in the United States, Canada, and Israel, and included pediatric and adult patients who were split into two cohorts:
- Those treated with intravenous defibrotide 25 mg/kg/day in 4 divided doses, each infused over 2 hours every 6 hours for a minimum of 21 days (enrolled prospectively from July 2006 through June 2008; n=102)
- Historical controls who were selected retrospectively by an independent medical review committee from January 1995 through November 2007 (n=32)
This study’s historical control selection methodology is “unique for such an uncommon and frequently fatal HCT complication,” the authors commented. “While randomized controlled trials represent the gold standard, the historical-control methodology provides a feasible mechanism for comparison when a randomized controlled trial is not possible due to ethical issues.”
Patients receiving defibrotide could continue treatment past 21 days until resolution of VOD/SOS or until discharge from the hospital.
Patients were excluded from the study if they had:
- Preexisting liver cirrhosis
- Prior solid organ transplant
- Dialysis dependence at the time of HCT
- Oxygen dependence during conditioning
- Hemodynamic instability
Efficacy was assessed as the difference of survival rate at 100 days post-HCT between the two treatment groups. Secondary endpoints included the differences in CR at day 100 post-HCT and survival at 180 days post-HCT.
The median time to VOD/SOS diagnosis post-HCT was 13 days in the defibrotide cohort (range = 1-25) and 11 days in the control group (range = 4-19), while the median times to multi-organ failure were 13 and 12.5 days, respectively.
At 100 days post-HCT, 39 patients in the defibrotide-treated group (38.2%) and eight patients in the control group (25%) were alive, with an estimated between-group difference in survival of 23 percent (95% CI 5.2-40.8; p=0.0109).
CR more than doubled in defibrotide-treated patients compared with historical controls: 25.5 percent versus 12.5 percent (95% CI 3.5-34.6; p=0.0160). The median time to CR was 34.5 days in the defibrotide group (95% CI 33-48.1), compared with 39.5 days in the control group (95% CI 10.8-85.7).
The researchers also observed a strong association between CR and survival to 100 days post-HCT (95% CI 0.467-0.779).
At 180 days post-HCT, 33 patients in the defibrotide group (32.4%) and eight patients in the control group (25%) were alive, but the differences in survival at this time point did not reach statistical significance (95% CI 1.2-34.1; p=0.0669). See the TABLE for expanded study results.
The median duration of defibrotide treatment was 21.5 days (range = 1-58), and 11 patients discontinued treatment prematurely due to drug-related toxicity (10.7%).
Adverse event (AE) rates were similar in both groups, and defibrotide was generally well tolerated, the authors reported. All but one of the defibrotide-treated patients and all historical-control patients experienced one or more AEs, the most common being hypotension (39.2% vs. 50%, respectively) and diarrhea (23.5% vs. 37.5%, respectively). There was no difference in incidence of hemorrhagic AEs, though median time to hemorrhage onset was longer in the defibrotide group (7 days) compared with the control group (3.5 days). Sixty-five patients in the defibrotide group (64%) and 22 patients in the control group (69%) experienced a fatal AE. “Importantly, all deaths in both groups after 100 days post-HCT were considered to be related to a cause other than VOD/SOS,” the researchers added.
The small size of the patients in the control group is a noted limitation of the study, as the statistical power of the analysis in this trial is limited. Additionally, this was not a truly randomized study, and selection of controls could have introduced bias favoring the defibrotide arm.
“[This is the] first treatment to be shown to be effective in serious VOD/SOS [with multi-organ failure] with a favorable safety profile,” Dr. Richardson told ASH Clinical News. “In the absence of any other treatments, this constitutes an important breakthrough for the management of this life-threatening complication of HCT. There is the real potential for its use in prevention and as earlier intervention to further improve patient outcomes.”
Dr. Richardson and co-authors noted that additional research is needed to assess defibrotide in combination with other therapies and in high-risk patient groups, such as those who are exposed to sirolimus and VOD/SOS prophylaxis for patients undergoing allogeneic or high-risk autologous HCT.
Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 January 29. [Epub ahead of print]
|Table. Observed Survival at 100 Days, CR at 100 Days, and Survival at 180 Days Post-HCT|
|Defibrotide Treatment Cohort(n=102, %)||Historical-Control Cohort(n=32)||Adjusted Difference in Rate, %||p Value (95% CI)|
|Survival by day 100||39 (38.2%)||8 (25%)||23%||0.0109|
|CR at day 100 byDay +100||26 (25.5%)||4 (12.5%)||19%||0.0160|
|Survival by day 180||33 (32.4%)||8 (25%)||16.4%||0.0669|
|HCT = hematopoietic cell transplantation; CR = complete response|