For the first time, patients in the United States who develop the rare life-threatening complication of hepatic veno-occlusive disease (VOD) following a hematopoietic stem cell transplant (HSCT) have a treatment.
Defibrotide sodium (Defitelio, Jazz Pharmaceuticals) has just been approved by the US Food and Drug Administration (FDA) for use in severe VOD. The drug is already available in Europe, having been approved there in April 2014.
"The approval of defibrotide fills a significant need in the transplantation community to treat this rare but frequently fatal complication in patients who receive chemotherapy and HSCT," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.
In hepatic VOD, some of the veins in the liver become blocked, causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage, the FDA explains. In the most severe form of hepatic VOD, the patient may also develop failure of the kidneys and lungs.
Fewer than 2% of patients who receive a stem cell transplant develop severe hepatic VOD, but as many as 80% of patients who develop severe hepatic VOD do not survive, the FDA notes.
The approval is based on efficacy data from 528 patients treated in three studies, two of which were prospective clinical trials and the third was an expanded access study. All these patients had developed the complication following a stem cell transplant, and were diagnosed with hepatic VOD with liver or kidney abnormalities. All were treated with defibrotide sodium.
Across the three studies, 38% to 45% of these patients were alive 100 days after the HSCT.
The expected survival rate would be 21% to 31%, based on published reports and analyses of patient-level data.
The FDA lists the most common adverse effects as hypotension, diarrhea, vomiting, nausea, and nosebleeds (epistaxis), and serious potential adverse effects as hemorrhage and allergic reactions. The agency warned that the drug should not be used in patients who are having bleeding complications or who are taking anticoagulants.
Phase 3 Trial Results Recently Published
A portion of the clinical results cited by the FDA in the approval notice for the drug come from a phase 3 clinical trial that was recently published online in Blood, as reported last month by Medscape Medical News
In this study, 102 patients given defibrotide were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by a blinded independent medical review committee.
"We used a novel methodology to generate rigorously selected historical controls, which is in itself a novel approach to the investigation of a life-threatening orphan disease," lead author Paul G. Richardson, MD, from the Dana-Farber Cancer Institute in Boston, told Medscape Medical News. He explained that in these patients, use of best supportive care as a direct comparator could not be justified, as defibrotide had already shown efficacy in a number of phase 2 trials and the complication has a high mortality rate.
In this trial, 102 patients with severe VOD and advanced multiorgan failure received defibrotide 25 mg/kg per day intravenously for 21 days.
Survival rates 100 days post HSCT were 38.2% for the defibrotide group and 25.0% for the control group (estimated difference, 23.0%; 95.1% confidence interval [CI], 5.2% - 40.8%; P = .0109).
Complete response rates were 25.5% for the defibrotide patients and 12.5% for the control persons (19% difference; 95.1% CI, 3.5% - 34.6%; P = .0160).
"Defibrotide has lifesaving potential in my view, and this trial demonstrates this with a significant reduction in mortality," Dr Richardson told Medscape Medical News. "Given that over 80% of patients died without treatment and 40% survived with the use of defibrotide therapy as part of this trial, the results are particularly compelling. This is additionally significant because these were patients with very advanced multiorgan failure in whom little or no survivorship would be expected."
"The difference in complete response is also highly significant, and further supports a treatment effect," he added.
Data from other trials show that defibrotide is more effective when given early, or even prophylactically, Dr Richardson said, citing a study by Dr Selim Corbacioglu and colleagues, published in 2012 in the Lancet, in which defibrotide was given prophylactically in high-risk children undergoing transplant, and the incidence of VOD was reduced by 50%.
Potentially Lifesaving Drug
"Defibrotide is a potentially lifesaving drug, in my opinion, and to see it demonstrated to be effective in such sick patients with no other treatment options is very gratifying," Dr Richards concluded.
"I concur," said Linda J. Burns, MD, medical director at the Health Services Research Center for International Blood and Marrow Transplant Research in Minneapolis, who was not involved in the defibrotide studies, but has used the drug in her patients.
"Before, we did not have anything to offer these patients. I've been in the transplant field for almost 30 years. I've had many patients die from this syndrome because of the drugs I've had to give them that are vital to be used for transplant. My hope is that this will be very helpful, and also that this research will provide guidance to physicians on how to use the drug safely and effectively," she said.
The study was supported by Jazz Pharmaceuticals. Dr Richardson is a member of advisory committees for and has received research funding from Jazz Pharmaceuticals. Dr Burns has disclosed no relevant financial relationships.