Post-Conference Perspectives: Advances in the Treatment of HSCT-TMA - Episode 7
Sergio A. Giralt, MD: Jeffrey Laurence, MD et al, who’s been an expert in the field, has been conducting a prospective study of patients undergoing an allogeneic transplant and looking for those who develop criteria for transplant-associated TMA [thrombotic microangiopathy]. He’s been looking for different biomarkers, and in the abstract that he presented at the American Society of Hematology [ASH 2019 annual] meeting, he specifically reported on the levels of MASP-2. MASP-2 is the enzyme that actually does complement activation through the lectin pathway. What he showed is that all patients undergoing allogeneic transplant have high MASP-2 levels.
But interestingly, the patients who developed transplant-associated TMA actually had higher MASP-2 levels than the control. He also showed that patients with persistent transplant-associated TMA that did not resolve despite withdrawal of the offending agent or treatment of the infection, had continued elevated levels of MASP-2. What this suggests is that MASP-2 may be involved in the pathogenesis of transplant-associated TMA, and therefore is an appropriate target for therapeutic intervention.
Allesandro Rambaldi MD, et al, presented at the European Hematology Association [2019 annual meeting], a very interesting preliminary results of a phase II trial of narsoplimab for patients who develop transplant-associated TMA. It was a dose escalation study, so it was a dose finding study. A total of 19 patients were treated, 18 were adults, who had transplant-associated TMA. What was important is that in this study, in all patients who received narsoplimab, there was at least some objective evidence of improvement of transplant-associated TMA. That means that creatinine improved, LDH [lactate dehydrogenase] decreased, hemolysis and platelet counts improved. More importantly, the primary end point, which was 100-day survival, was significantly better for patients receiving narsoplimab versus historical controls. That’s 53% versus 10%. This suggests that narsoplimab might be a very effective agent for the treatment of transplant-associated TMA or for the prevention of endothelial damage. And those are subjects of current and future studies.
The inclusion criteria was to be within 30 days of transplant, have criteria for transplant-associated TMA based on the standard criteria, decreased platelet counts of less than 150 x 109/L, doubling of creatinine, increased LDH, and presence of schistocytosis in a peripheral blood smear.
The Rambaldi trial was very important because the 100-day survival, which was a primary end point, was 53% for the patients treated versus 10% for a group of historical controls.
We need to remember that there is no drug that has been approved for the treatment of transplant-associated TMA in the United States. The group in Cincinnati has pioneered very effective data showing that eculizumab, which is an inhibitor of complement activation that does not go through the lectin pathway, has been effective in the treatment of transplant-associated TMA in children primarily. The results in adults have not been as promising, but again, it suggests that transplant-associated TMA in children might have a different pathway than transplant-associated TMA in adults.
The narsoplimab data that were provided by Rambaldi, et al, suggests that the lectin pathway may also be involved in this transplant-associated TMA. I think as we move forward, we are going to see that 1) There will be more awareness of transplant-associated TMA, 2) We will be looking more at markers of complement activation, such as CH50, C5B9, and 3) that many of us will be participating in collaborative trials of either narsoplimab, or eculizumab, or other complement inhibitors to be able to prevent this devastating complication of allogeneic transplant.
Actually, most of the experience with transplant-associated TMA and a lot of what we’ve learned from transplant-associated TMA has emerged from the group in Cincinnati, including Stella Davies, MBBS, PhD, Sonata Jodele, MD. And what they’ve done is, when they look for transplant-associated TMA, they actually see it in 30% of the patients, of which a third can have severe transplant-associated TMA. They also have very clear algorithms for the use of complement inhibition, and they actually monitor complement activation throughout the transplant course. And this has resulted in their reporting the beneficial effects of eculizumab as treatment for transplant-associated TMA. Similar results have not been observed in adults, though there are cases that have responded to eculizumab.
Is transplant-associated TMA more common in children than adults? The reality is we don’t know. Prospective trials are now being performed to get a better handle. One of the problems is that schistocytosis, which is a hallmark of thrombotic microangiopathy, is not a very trustworthy test. You can get the same slide being read by different people and different number of schistocytes.
Transcript Edited for Clarity