Christopher E. Dandoy, MD, MSc
Higher levels of soluble suppression of tumorigenicity-2 (ST2) and soluble terminal complement complex (sC5b-9) were associated with high-risk thrombotic microangiopathy (TMA), a severe complication related to stem cell transplantation (SCT), according to data presented at the 2019 Transplantation & Cellular Therapy (TCT) Meetings. These elevated levels could potentially predict severe complications of SCT.
Both levels of sC5b-9 and ST2 were elevated in pediatric patients who developed TMA or high-risk TMA compared with those who did not. This leads investigators to believe that other complications, such as complement activation and endothelial injury, may be occurring before SCT or early on in the treatment course for these patients.
"Patients may be coming in to SCT that have complement activation or endothelial injury, and that might just be exacerbated by the preoperative regimen they receive or any other complications, then they go on to develop worsening symptoms," said Christopher E. Dandoy, MD, MSc.
If TMA is identified early, physicians can treat patients earlier in an effort to make a bigger difference in the outcomes.
In an interview with OncLive
during the 2019 TCT Meetings, Dandoy, an assistant professor of pediatrics at Cincinnati Children’s Hospital, discussed the findings from this study and what it means for this patient population. In addition, he highlights the next steps and how these data can be applied to the current treatment landscape.
OncLive: What was the rationale for conducting this study?
: About 4 or 5 years ago, we determined that the complication of SCT, TMA, is associated with increased mortality, morbidity, and leads to poor outcomes after SCT. We went a little bit further than that and determined that patients who have proteinuria as well as complement activation have very severe TMA. We decided to evaluate some specific biomarkers of endothelial injury, as well as complement [activation] early on, to see if it may show us differences in patients who go on to develop TMA later on.
What was the design of this clinical trial?
It was a longitudinal observational study. We looked at biomarkers at 2 specific time points: prior to the start of the preoperative regimen in allogenic SCT recipients and then again at 7 days posttransplant. We looked at 2 specific biomarkers, ST2 as well as sC5b-9, and then we compared those levels between patients who did develop TMA or high-risk TMA versus those who did not.
What were your findings?
It was significantly elevated. Both sC5b-9 and ST2 were significantly elevated over those time points in patients who developed TMA or high-risk TMA over those who did not. Further, we did not see that association in patients who went on to develop grade 3/4 graft-versus-host disease.
It leads us to think that this complement activation as well as endothelial injury may be occurring early on in transplant. Patients may be coming in to SCT with complement activation or endothelial injury, and that might just be exacerbated by the preoperative regimen they receive or any other complications, then they go on to develop worsening symptoms.
Could you explain what this means for the field?
First of all, I hope that we are able to identify those patients who are at risk. The next step will be to not only treat them earlier but potentially identify the patients at risk for TMA and then mitigate it before the symptoms lead to an organ injury.
Again, severe TMA has an overall survival rate of roughly 10% to 15%. If you can catch it early and treat it, which we do have mechanisms to treat it with before the tissue injury occurs, it could really make a significant difference in this population. Not only can it lead to improved survival but improved organ function, improved morbidity, and decreased healthcare resource utilization.
Patients undergoing SCT are at high-risk for developing TMA. Again, our data and other data show that it can occur in roughly 30% of patients. We need to be looking for this to occur earlier in transplant, as early as 7 days after transplant. Once you identify that TMA is present, you need to treat it. Again, hopefully, we can use these tools we found in this study along with others to identify these patients even earlier than we currently are.
What are the next steps planned for these data?
We had an area under the curve at roughly 0.8, but we need to get it a little closer to 0.9 or 0.95 before we can use it as a predictive biomarker, whether that is by taking in more information or patient-specific information on demographics, or if it is additional biomarkers that still need to be seen. We need to use this as a catapult to find out a little bit more about what complement activation and endothelial injury is occurring in these [pediatric] and adult [patients].
What other research are you involved in?
We have been working in this area for a long time. We’re also looking at why these patients with TMA have a significantly higher rate of bloodstream infections, how those patients who develop bloodstream infections go on to have other issues after transplant, and particularly, going back to TMA, [we want to find out] who are the patients, why they get it, and the path of physiology that leads to these poor outcomes.
Dandoy CE, Stegman A, Pate AR, et al. Thrombotic microangiopathy after pediatric allogeneic stem cell transplant: potential early markers to predict individuals at high-risk. Presented at: 2019 Transplantation and Cellular Therapy Meetings; February 20-24, 2019; Houston TX. Abstract 58.
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