Defibrotide Under Review for Transplant-Related Complication

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Paul Richardson, MD

Using a propensity adjustment, we saw a 23% improvement in survival with defibrotide in this critically ill population.

—Paul Richardson, MD

A potentially fatal complication of hematopoietic stem cell transplantation may be reversed with the use of a novel drug currently under priority review at the U.S. Food and Drug Administration (FDA).

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome is usually a serious complication of conditioning regimens for hematopoietic stem cell transplantation and is more common in the allogeneic setting. Its estimated incidence is about 14% (8% with reduced-intensity regimens), and in the setting of life-threatening multiorgan failure, the fatality rate exceeds 80%.

There is currently no FDA-approved treatment, but defibrotide, a deoxyribonucleic acid derivative, recently approved in Europe, is now under FDA priority review based on results of an open-label trial presented at the 2015 American Society of Hematology (ASH) Annual Meeting by Paul Richardson, MD, of Dana-Farber Cancer Institute, Boston.1

The multicenter study included 102 patients with veno-occlusive disease/sinusoidal obstruction syndrome and advanced multiorgan failure. The recommended treatment consisted of infusions of defibrotide every 6 hours for 21 days. Results were compared with those of 32 untreated historical controls in whom best supportive care was used; these cases were gleaned from a rigorous, independent, and sequential review of almost 7,000 stem cell transplants starting 6 months before the use of defibrotide at each site, which, in turn, generated a robust and contemporaneous historic control. Baseline prognostic variables, treatment characteristics, and disease characteristics proved generally well balanced between the groups.

Survival Improvement

“Using a propensity adjustment, we saw a 23% improvement in survival with defibrotide in this critically ill population,” Dr. Richardson reported. At day +100, survival was 38.2% for the defibrotide group and 25% for controls (P = .0109), and complete responses were observed in 25.5% vs 12.5%, respectively (P = .0160).

“The day +100 mortality rate in the control arm of this study was comparable to that observed in previous analyses,” Dr. Richardson noted, where mortality rates ranged from 84% to 90%.

In the defibrotide group, 26 of patients achieved a complete response by day +100, and 22 of them had a durable complete response as of their last observation. In the control group, only one patient had a durable response. There was a strong association between complete response and survival to day +100 after stem cell transplant, he added.

Defibrotide for Veno-occlusive Disease/ Sinusoidal Obstruction Syndrome

■ Hepatic veno-occlusive disease/sinusoidal obstruction syndrome is a potentially fatal complication of conditioning regimens for hematopoietic stem cell transplantation, and currently there is no drug approved for treating it. ■ Defibrotide, a deoxyribonucleic acid derivative, is undergoing priority review at the FDA. ■ An open-label, historically controlled trial showed that defibrotide reduced mortality by 23% vs historical controls in a critically ill population with advanced multiorgan failure.

Adverse Events

“The adverse events were consistent with those expected in this very sick group of patients and were similar between the groups,” reported Dr. Richardson.

Adverse events of any severity that were possibly related to defibrotide occurred in 45% of patients, with 21% experiencing a serious adverse event. There was no difference in the overall incidence of hemorrhagic adverse events, observed in approximately two-thirds of patients in both groups, and it was consistent with the hemorrhagic risk observed in patients with hepatorenal failure in the setting of stem cell transplant.

Dr. Richardson suggested that defibrotide should next be studied in combination with other endothelial-targeting agents, with further studies in prophylaxis in allogeneic stem cell transplant and high-risk autologous transplant patients where results to date have already been very promising. Moreover, defibrotide could potentially improve outcomes in specific high-risk groups, such as patients exposed to sirolimus or gemtuzumab and those undergoing mismatched unrelated allogeneic transplant. Finally, defibrotide may also have a role in other syndromes characterized by microangiopathy and as an adjunct to graft-vs-host disease prevention, he said. ■

Disclosure: Dr. Richardson has served as an advisory board member to Jazz Pharmaceuticals and has received research funding from Jazz Pharmaceuticals, who supported the study.


  1. Richardson PG, Riches M, Kernan NA, et al: Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome with multi-organ dysfunction: Final results from a pivotal, historically controlled, phase 3 trial. 2015 ASH Annual Meeting. Abstract 737. Presented December 7, 2015.


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Expert Point of View: Sergio A. Giralt, MD

Sergio A. Giralt, MD, Chief of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center, New York, told The ASCO Post that defibrotide could be helpful in high-risk patients and applauded the investigators for completing the trial to prove it.