Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, is a major complication of hematopoietic stem cell transplantation (HSCT) and carries a high mortality. In severe cases, it is associated with multiorgan failure, characterized by pulmonary and/or renal dysfunction, with mortality rates exceeding 80%.
Treatment with defibrotide (Defitelio, Jazz Pharmaceuticals, Inc) resulted in a significant improvement in survival in patients with VOD, as demonstrated by findings from three trials that were presented at the 2015 BMT Tandem Meeting, held in San Diego.
Overall, there were favorable results for all subgroups ― pediatric, adult, allograft, and autograft subgroups after HSCT or chemotherapy with severe VOD/multiorgan failure and VOD without multiorgan failure.
Defibrotide was approved by the European Medicines Agency in October 2013 for the treatment of severe VOD following a recommendation for approval after a resubmission and reevaluation of the data.
Submission of a new drug application to the US Food and Drug Administration for defibrotide is expected to be completed this year.
"The development of this drug is so important, because when you inflict this devastating toxicity on your patient ― from a clinician's point of view, it's a nightmare," said Paul Richardson, MD, clinical program leader and director of clinical research, Jerome Lipper Multiple Myeloma Center, at the Dana-Farber Cancer Institute in Boston, and lead author of two of the articles.
"Your patient is dying from a syndrome that is essentially toxicity from the transplant, in the worst case scenario," he told Medscape Medical News in an interview. "So to have a safe, effective, biologically derived treatment that can reverse that process is what we have been striving for. We went from clinical observation to laboratory evaluation and then to a series of both European and American partnerships to get it where it needs to be."
The oncology community has been struggling to address VOD, Dr Richardson added, "and now we have this agent that really seems to do its job."
In the first article, which was an expanded access, protocol-directed treatment IND (T-IND) study, the cohort comprised 641 patients with severe and nonsevere VOD post-HSCT, as well as those who were postchemotherapy alone. The +100 day survival in post-HSCT patients was 52%.
In the second study, which formed the basis of the defibrotide approval in the European Union, 23.5% of 102 patients with severe VOD who received defibrotide achieved complete response by day 100, as compared with 9.4% of the historical control patients (P = .013).
The third trial was an update from an international compassionate use program that was conducted in Europe, the United States, Asia, and the Middle East in 710 patients. Defibrotide was generally well tolerated in this cohort, and the side-effect profile proved consistent with that seen in other studies, note the authors. Survival was also consistent with prior defibrotide studies, at 54% at day +100.
First Approved Drug
Hepatic VOD is the most common of the regimen-related toxicities accompanying HSCT, but despite aggressive therapies, including the combination of tissue plasminogen activator and heparin, severe VOD is almost uniformly fatal. Thus, a great need exists for more effective treatments.
Defibrotide is a polydisperse oligonucleotide that has been shown to have antithrombotic, anti-inflammatory, and anti-ischemic properties, but it is without significant systemic anticoagulant effects. It binds to the vascular endothelium, modulates platelet activity, promotes fibrinolysis, decreases thrombin generation and activity, and reduces circulating levels of plasminogen activator inhibitor type 1.
Dr Richardson was instrumental in the development of defibrotide, which was based on a hypothesis that he first proposed. The agent was initially developed by Pharma Research Srl, a spinoff from Crinos Industria Farmacobiologica SpA, an Italian company that was focused on developing compounds to correct coagulation and thrombotic disorders but that also had a better safety profile than current treatments.
The first data showing the clinical benefit of defibrotide were from 19 patients with severe VOD treated on a compassionate basis (Blood. 1998;92:737-744). Resolution of VOD (bilirubin F2 mg/dL with improvement in other symptoms and signs) was observed in eight patients (42%); among these responders, six survived past day +100, as compared with the 2% predicted survival reported in comparable patients.
Dr Richardson noted that it has "taken a long time to get to where we are now." The development of the drug began with a unique partnership with a small Italian pharmaceutical company that was willing to test this agent in such a difficult and challenging population.
Defibrotide "has significantly improved patient outcomes in allogeneic and autologous transplants, and reduced the incidence of VOD," commented Elaine Smyth, RGN, RSCN, nurse specialist in transplant at Our Lady's Children's Hospital, in Crumlin, Dublin, when the drug was launched in the EU. She has treated patients with defibrotide under trial conditions for about 6 years.
"Prior to this, children just received symptom management and still suffered terribly," said Symth. "Now we have reduced admissions to the ICU and hospital stays, with much better results overall."
Updated Results of US Treatment IND Study
Because there are currently no approved therapies for VOD in the United States, defibrotide is available through an expanded access, protocol-directed T-IND. The T-IND gathers data on safety/efficacy of defibrotide in patients with severe and nonsevere VOD post-HSCT, as well as postchemotherapy alone.
The original T-IND protocol required patients to have VOD diagnosed by Baltimore criteria (total bilirubin ≥2.0 mg/dL with ≥2 of hepatomegaly, ascites, or 5% weight gain) with multiorgan failure (renal and/or pulmonary failure) following HSCT. But it was then amended to include patients with nonsevere VOD (defined as no multiorgan failure) post-HSCT or postchemotherapy.
In this cohort, defibrotide was administered as a 2-hour infusion at 6.25 mg/kg IV q6h (25 mg/kg/d) for a recommended period of 21 days or longer.
"More than half of the patients had severe disease, and with that as a background, the results we presented demonstrated that in the context of this expanded access program, we were able to show that survival ― in 526 transplant patients who were evaluable ― was a remarkable 52%," explained Dr Richardson, who was lead author of this study.
Survival at day +100 in post-HSCT patients was 58% in pediatric patients and 45% in the adult subgroup.
For postchemotherapy patients, day +100 survival was 83% in pediatric patients and 60% in adults.
Survival at day +100 in post-HSCT patients was 50% in allograft patients and 66% in autograft patients.
"This was the largest prospective evaluation of defibrotide to date in VOD, and we found that as for safety, it continued to be very well tolerated and associated with a low incidence of defibrotide-associated side effects," said Dr Richardson. "The most important aspect is that there is a small risk of increased bleeding, but this is very manageable and typically not associated with life-threatening complications."
Patients with severe VOD and multiorgan failure had a 45% day +100 survival, but this was also impressive, he noted, because the survival for this group is generally less than 10%.
"These results were met with considerable enthusiasm at the meeting, as you can well imagine," Dr Richardson pointed out. "There was a conclusion proposed that the higher survival rates in VOD without multiorgan failure indicate that further study is warranted to determine impact of treatment earlier in the course of VOD."
That said, some professional societies are already recommending its use earlier in the treatment paradigm. On the basis of phase 2/3 studies, the British Committee for Standards in Haematology and the British Society for Blood and Marrow Transplantation recommend defibrotide for the prevention and treatment of VOD.
The toxicity profile was consistent with those seen in prior studies of difibrotide, and it was generally well tolerated. Adverse events most commonly observed were hypotension (13%), respiratory failure (8%), diarrhea (8%), pyrexia (7%), pulmonary hemorrhage (7%), and renal failure (7%).
Dr Richardson also noted that despite being an expanded access study, the results remained robust. "Oftentimes when you have a drug that's on the track to approval and it is moved out to the expanded access phase, you will see results diminish when compared to those in controlled trials," he said. "But in this case, we have seen the opposite. The drug performed just as well as it did in rigorously controlled trials, and in some subsets, maybe even better."
Number Needed to Treat Trial
In this phase 3 trial, Dr Richardson and colleagues evaluated the efficacy and safety of defibrotide 25 mg/kg/day in patients with severe VOD (n = 102) in comparison with historical control patients (n = 32). The study's primary endpoint was complete response (in terms of improvements in total bilirubin and resolution of multiorgan failure, as measured by renal and/or pulmonary dysfunction) by 100 days post HSCT.
They also calculated the number needed to treat (NNT) with defibrotide to achieve one complete response and the NNT to prevent one death 100 days post HSCT, as compared with historical control patients. This was done to evaluate how defibrotide compared with other efficacious treatments for acute, life-threatening conditions in the critical care setting.
NNT is the reciprocal of the absolute risk reduction (ARR), and ARR is the event rate in the historical control group minus the event rate in the defibrotide group.
To compare results of this NNT analysis with results of similar acute life-threatening conditions, the authors conducted a literature search.
"We looked at conditions with comparable dismal outcomes, such as acute respiratory distress syndrome, cerebral infarction, traumatic brain injury, and acute kidney injury following cardiac surgery," said Dr Richardson.
The NNT for defibrotide to achieve one complete response 100 days post HSCT was 7, and the NNT to prevent 1 death at day +100 was 8.
"The NNTs with defibrotide are comparable to or lower than those with other therapeutic medical interventions in critical care," said Dr Richardson. In the literature, NNT in other conditions with high short-term mortality ranged from 1 to 59.
The most common adverse events in this cohort were hypotension (39% vs 50% historical control patients), diarrhea (25% vs 41%), vomiting (21% vs 25%), nausea (15% vs 31%), and pyrexia (15% vs 34%).
Compassionate Use
The third study, led by Selim Corbacioglu, MD, of the University of Regensburg, Germany, was conducted from 1998 to 2009 and included patients who were post-HSCT or post-chemo/radiotherapy.
"This was more of a registry experience, based upon access to compassionate use, and different from the T-IND study, which was a rigorous, prospective study," said Dr Richardson.
The dataset was very robust, with about 400 patients with severe disease.
There was no protocol for this study. Instead, treating physicians were asked to complete a form with patient eligibility and demographic/clinical characteristics. Data were then requested on defibrotide use, safety, and outcomes.
The dose was initially 10 mg/kg/day (4 divided doses) titrated to 60 mg/kg/day on the basis of tolerability/response, but then on the basis of the results of a US phase 2 study, the recommended defibrotide dose was amended to be 25 mg/kg/day (Biol Blood Marrow Transplant. 2010;16:1005-1017). The duration of treatment was decided at the discretion of the investigator; the mean duration was 15 days.
A total of 378 (53%) patients experienced adverse events, with 69 of 378 cases (18%) possibly being treatment related. The related events were primarily gastrointestinal hemorrhage (n = 12; 2%), hemorrhage (n = 10; 1%), and pulmonary hemorrhage (n = 8; 1%).
The studies were supported by Jazz Pharmaceuticals. Dr Richardson reports membership on advisory committees and research funding with Jazz Pharmaceuticals, the manufacturer. Several coauthors on all three articles report relationships with Jazz Pharmaceuticals and other companies.
2015 BMT Tandem Meeting. Abstracts 109, 111, 112. Presented on February 12, 2015.
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Cite this: Defibrotide Significantly Boosts Survival in VOD Post-Transplant - Medscape - Feb 24, 2015.
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