ORLANDO – A composite score based on day 28 plasma levels of the angiogenic factors follistatin and endoglin predicts 1-year nonrelapse mortality in patients who have undergone myeloablative allogeneic hematopoietic cell transplantation, based on findings from the randomized Blood and Marrow Transplant Clinical Trials Network acute graft-versus-host prophylaxis study 0402 (BMT CTN 0402).
Elevations in these factors at day 28 may reflect susceptibility to regimen-related and other toxicities that adversely affect tissue repair and survival, Shernan Holtan, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
Sharon Worcester/Frontline Medical News
Dr. Shernan Holtan
“Without important trophic angiogenic factors, the body may not be able to heal well after injury such as graft-versus-host disease [GVHD]. We previously reported that such angiogenic factors are indeed altered at the onset of acute graft-versus-host disease based upon samples from BMT CTN 0302 and 0802,” said Dr. Holtan of the University of Minnesota, Minneapolis. “Specifically, we found that repair factors of epidermal growth factor and VEGF-A are low at the onset of acute GVHD, and that damage-associated angiogenic factors are high at the onset of acute graft-versus-host disease.”
These damage-associated factors include follistatin, endoglin, placental growth factor, and angiopoietin-2, she added.
Based on the previous results, Dr. Holtan and her colleagues hypothesized that a pattern of tissue damage as illustrated by these markers at 28 days after treatment would be associated with 1-year nonrelapse mortality.
Of 221 patients from BMT CTN 0402 with pretreatment and day 28 plasma samples available for analysis, 25 had died at 1 year of causes unrelated to relapse. In a univariate analysis, nonrelapse mortality was associated with levels of follistatin, endoglin, and angiopoietin-2. When combined to assess for an overall pattern of damage, only follistatin and endoglin were significantly associated with nonrelapse mortality.
The relative risk of death unrelated to relapse was 4.5-fold higher in patients with the highest score (score of 3) on multivariate regression analysis of follistatin and endoglin levels. Grade II-IV acute GVHD was not significantly associated with 1-year nonrelapse mortality in multivariate analyses, but age over 50 years was.
“Notably, the composite score was a better predictor than any factor alone,” Dr. Holtan said.
The composite score was also predictive of the development of acute GVHD.
“We found that a moderate score of 2 was associated with a 2.3-fold increased risk of acute GVHD prior to day 100. Interestingly, the higher score [3] was not associated with acute GVHD. There was no association of the composite score with chronic GVHD,” she said.
The risk of nonrelapse mortality was less than 10% in patients with a composite score of 1.
Among patients in the study with a score of 3, more than half of the deaths were related to organ toxicity, including liver failure and respiratory failure, which were predominantly infection-related. Those with a low composite score had very few deaths associated with organ toxicity, she noted.
While there are many unanswered questions, these findings highlight possible opportunities to improve survival after allogeneic hematopoietic cell transplantation that warrant further study, she said.
“We need to learn how to constrain this angiogenic inflammatory response with the ultimate goal of hopefully identifying novel treatment strategies to mitigate nonrelapse mortality in our patients,” she concluded.
Dr. Holtan is an investigator for Alexion and is site principal investigator on the GI GVHD clinical trial.