The Role of Defibrotide to Inhibit Cell Injury



Sergio A. Giralt, MD: There is another study from Jeffrey Laurence, MD, where he was looking at the potential beneficial effects of defibrotide on markers of endothelial damage. And he did show that defibrotide could protect endothelial cells from damage induced by chemotherapy or radiation. Interestingly enough, there have been randomized trials of defibrotide as prevention of sinusoidal obstructive syndrome, which is another endothelial damage disorder. In the pediatric population, it actually was effective in not only reducing veno-occlusive disease, but it also reduced the risk of severe graft vs. host disease. Similar results are not available in adults. I just think it gives us more evidence that the endothelial cell can be a target for damage by high-dose chemotherapy and radiation. And endothelial cell damage is a trigger event for a lot of post-transplant complications that can result in morbidity and mortality.

Dr Laurence presented, also at the American Society of Hematology 2019 annual meeting, an interesting experiment where he showed that defibrotide in vitro actually blocked caspase-8. And caspase-8 is known to be one of the pathways through which endothelial cells die after they get damaged. One of his questions and his hypothesis would be that in patients who have treatment-refractory transplant-associated thrombotic microangiopathy [TMA], would actually benefit from the addition of defibrotide. This obviously has to be shown in clinical trials, but it is thought provoking. Does that mean I’m going to start using defibrotide tomorrow for transplant-associated TMA [thrombotic microangiopathy]? The answer is no, but I do think that we should start considering doing well done prospective clinical trials asking this question.

I have extensive experience using defibrotide for the treatment of sinusoidal obstructive syndrome with multi-organ failure, which is its labeled indication. I think more importantly than treating sinusoidal obstructive syndrome is preventing sinusoidal obstructive syndrome. And how do we prevent it? We prevent it, 1) by identifying patients at high risk for this disorder, older patients, patients having received prior inotuzumab or prior gemtuzumab ozogamicin, patients who are going to get double alkylators.

In pediatric populations, patients with neuroblastoma or patients with osteopetrosis are definitely at high risk for developing sinusoidal obstructive syndrome. What should these patients get? In the pediatric population, defibrotide is indicated for prevention. In the adult population, it is not. For both adults and pediatrics, it has been shown that ursodiol or ursodeoxycholic acid can reduce the risk of sinusoidal obstructive syndrome. And the next thing is when we have what we call very high awareness for veno-occlusive disease that when patients start developing signs or symptoms of veno-occlusive disease, rapid installation of defibrotide treatment will actually change the natural course of the disease.

I think what’s interesting is transplant-associated TMA is part of a spectrum of disorders that we call endothelial damage disorders. This includes sinusoidal obstructive syndrome, idiopathic pneumonia syndrome, fluid overload or capillary leak syndrome, and then transplant-associated TMA. All these disorders have as a common, we’ll say triggering event, endothelial damage. So strategies that may prevent endothelial damage or mitigate endothelial damage from high-dose chemotherapy and radiation will definitely go a long way in preventing non-relapse mortality and giving patients a better life, a better quality of life, and an easier transplant journey.

Transcript Edited for Clarity

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