Post-Conference Perspectives: Advances in the Treatment of HSCT-TMA - Episode 4

TMA Management: Agents That Inhibit Endothelial Cell Injury


Vincent T. Ho, MD: Defibrotide has been around for many years. It is the only drug that is currently FDA approved for the treatment of transplant-associated hepatic veno-occlusive disease, which is a condition that also involves endothelial damage in the sinusoidal and the central veins of the liver. Because defibrotide has broad anti-inflammatory, as well as anti-thrombotic, activity and is specific to the microendothelial vasculature, there’s been great interest in exploring this drug for the use in TMA [thrombotic microangiopathy].

Defibrotide has been used for many years and is more often used in Europe for TMA. There are now at least 16 publications in the literature looking at this drug in patients with TMA. Although these are all small-case series that range from about 1 to 60 patients, they all tend to show response rates somewhere around of 60% to 70%, although it’s hard to compare literature because every paper has its own different criteria for response. Nonetheless, the drug is fairly safe, and based on its properties, it appears to be encouraging in this disease, although there is no FDA label for its use in this condition.

At the ASH [American Society of Hematology Annual Meeting & Exposition] this year 2019, Jeffrey Laurence, MD, presented a poster abstract in which they assessed the protective effect of defibrotide on the microvascular endothelium. In this study, they took plasma samples from many patients with different types of TMA, including TTP [thrombotic thrombocytopenic purpura], HUS [hemolytic uremic syndrome], as well as transplant-associated TMA. They used this plasma from these patients and exposed them to the endothelial cells showing that plasma from these patients exert a damaging effect on the endothelium because they have TMA.

When they co-incubated the plasma with defibrotide in these patients, they were able to show that defibrotide reduced the apoptosis of the endothelial cells in the presence of this plasma, especially from patients with TTP and HUS and also some patients with transplant-associated TMA. They measured endothelial apoptosis by measuring activation of caspase-8, and in many of these patients there was at least a 20% decrease in caspase-8 activity when defibrotide was introduced. The overall conclusion from the abstract was that in these TMA processes in which there are agents in the plasma that damage endothelial cells, defibrotide will protect the endothelium from apoptosis.

As I mentioned, defibrotide is currently FDA approved only for the use as treatment in patients with hepatic veno-occlusive disease and sinusoidal obstruction. It is not FDA approved for use in defibrotide, but it’s being used as off-label in certain cases. I have not personally used it at our center, Dana-Farber Cancer Institute, for TMA, but I’m aware there’s at least 1 clinical trial that is using it in the prophylaxis setting.

In fact, defibrotide may be most effective as a prophylaxis in this setting because it works by just

protecting the endothelium from early insult from the immune prophylaxis as well as from the conditioning regimen. Certainly, more studies are needed to confirm the efficacy of this drug in the treatment and prevention of TMA.

Although we do have a number of papers that have been published suggesting efficacy, those are all case series and not prospective clinical trials. So I do believe that a prospective clinical trial would be important. Defibrotide, if effective, could have a role in the treatment of this disease, especially in combination with complement blockade to protect the vascular endothelium.

Transcript Edited for Clarity