Defibrotide Prophylaxis Reduces Veno-Occlusive Disease in Pediatric Transplant Patients

Roxanne Nelson

December 10, 2009

December 10, 2009 (New Orleans, Louisiana) — Hepatic veno-occlusive disease (VOD) is a life-threatening complication that can occur after either allogeneic or autologous stem cell transplantation; the risk is particularly high for pediatric patients. However, the use of prophylactic defibrotide, an experimental polydisperse oligonucleotide manufactured by Gentium SpA, resulted in a 40% reduction in the incidence of VOD.

"There was also a significant reduction in morbidity and mortality among the patients who received defibrotide prophylactically, compared with those who received defibrotide for treatment," said lead study author Selim Corbacioglu, MD, assistant professor in the Department of Hematology, Oncology, Immunology, and Stem Cell Transplantation at the University of Ulm in Germany.

In addition, he said, researchers were quite surprised that prophylactic defibrotide reduced the incidence and morbidity rate of acute graft-versus-host disease (GvHD).

Dr. Corbacioglu presented his findings here at the American Society of Hematology 51st Annual Meeting.

VOD is one of the most frequently encountered serious complications associated with stem cell transplantation. "Veno-occlusive disease 'hits you in dark'," explained Dr. Corbacioglu during a press briefing. "Unfortunately, we don't really know the risk factors that can lead to severe veno-occlusive disease."

Although there are some patients that are at risk, VOD is not limited to a well-defined group of high-risk patients who have undergone transplantation; the disease frequently occurs outside this group.

The pathophysiology of VOD is also not completely understood. "We don't really have good diagnostic criteria," said Dr. Corbacioglu, "and we do not have a gold standard therapeutic option for the treatment and prevention of this complication."

Severe VOD, which is defined by the development of multiorgan failure, is associated with substantial morbidity and mortality (up to 80% or 90%). Beyond that, VOD is a substantial economic burden, similar to that of GvHD disease, he added.

Several small nonrandomized trials that assessed defibrotide as prophylaxis for VOD have shown promising results, and without significant anticoagulant effects. In the current study, the largest-ever international multicenter trial of high-risk pediatric patients undergoing stem cell transplantation, Dr. Corbacioglu and colleagues assessed the safety and efficacy of defibrotide for the prevention of VOD.

The cohort consisted of 360 pediatric patients who were enrolled between January 2006 and January 2009, from 28 centers in the European Union and Israel. Within this group, 24% were infants, 52% were between the ages of 2 and 11 years, and 23% were adolescents. Approximately two thirds of patients (68%) underwent allogeneic stem cell transplantation and 31% underwent autologous stem cell transplantation.

The participants were randomized into 2 groups: intravenous defibrotide 25 mg/kg daily, from the start of conditioning until 30 days after the transplant or until hospital discharge; or the control group. All patients in the control group who were subsequently diagnosed with VOD received treatment with defibrotide. There were no significant differences between the 2 groups in disease types or risk factors.

The primary end point of the study was the incidence of hepatic VOD by day 30 using modified Seattle criteria (2 or more of the following: bilirubin >2 mg/dL, hepatomegaly, ascites, and unexplained weight gain of more than 5%). Secondary end points included mortality, morbidity, and the incidence and severity of GvHD.

"Although the study wasn't powered to assess mortality, a composite score was used to assess VOD-associated multiorgan failure and mortality," said Dr. Corbacioglu.

He pointed out that an important aspect of this trial was its quality. "Every single patient was monitored and assessed and every single case was followed."

Overall, patients with VOD had much higher mortality at 100 or more days after transplantation than those without VOD (25% vs 6%; P < .0001). In the intent-to-treat analysis, 12% (22 of 180) of the patients in the defibrotide group and 20% (35 of 176) of those in the control group developed VOD by day 30 (P = .054).

In the per-protocol analysis, the incidence of VOD was 12% (20 of 164) in the defibrotide group and 21% (35 of 169) in the control group (P = .037).

The use of prophylactic defibrotide reduced the incidence of VOD in the intent-to-treat analysis of all randomized patients by 40% (from 20% to 12%).

Reduced Multiorgan Failure

As for secondary end points, Dr. Corbacioglu explained that VOD-related multiorgan failure was significantly reduced with the use of prophylactic defibrotide. "The incidence of renal failure was reduced to 1% [compared with 6% in the control group]," he said.

VOD mortality was also reduced — from 6% to 2%, and the overall incidence and severity of acute GvHD were significantly lower in the defibrotide group (32% vs 43%).

The rate of serious adverse events was comparable in both groups, including rates of infection (24% in the defibrotide group vs 27% in the control group) and respiratory disorders (12% vs 9%). In addition, 9 hemorrhagic events were observed in the defibrotide group and 21 were observed in the control group.

Eventually, we might have . . . a drug that can be looked at as the gold standard for prevention and potentially the treatment of this serious complication.

"Prophylaxis was better than treatment," said Dr. Corbacioglu. "Eventually, we might have, with a very high level of evidence, a drug that can be looked at as the gold standard for prevention and potentially the treatment of this serious complication."

Armand Keating, MD, director of the Division of Hematology and professor of medicine at the University of Toronto in Ontario, and moderator of the press briefing, noted that this is a "substantial advance."

The approach that was taken in this study was to prevent disease, he said, "which is the best strategy. In this study, they were able to demonstrate this."

Encouraging, But Concerns Remain

Karen Ballen, MD, director of the Center for Leukemia, Massachusetts General Hospital, and associate professor of medicine at Harvard Medical School in Boston, noted that the data are encouraging, but caution is needed when looking at the results. "It looks only at a pediatric population, and it is a small study with preliminary data," she said. "But I think it suggests that there may be a role for defibrotide given earlier in the course of the disease."

Dr. Ballen, who was approached by Medscape Oncology for independent comment, pointed out that the incidence of VOD is decreasing in the adult population because of the use of less-intensive conditioning regimens. "But it is still an issue, and certainly more so in pediatrics, where they do more ablative transplants," she said.

"But these data are very encouraging. I commend the authors, and I hope we hear more about this in the next 1 to 2 years," she said.

The study was cosponsored by the European Group for Blood and Marrow Transplantation. Dr. Corbacioglu reports consulting for Gentium SpA and receiving research funding; several of the coauthors report financial relationships with Gentium SpA.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 653. Presented December 7, 2009.

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