TY - JOUR
T1 - Follistatin and Soluble Endoglin Predict 1-Year Nonrelapse Mortality after Allogeneic Hematopoietic Cell Transplantation
AU - Newell, Laura F.
AU - DeFor, Todd E.
AU - Cutler, Corey
AU - Verneris, Michael R.
AU - Blazar, Bruce R.
AU - Miller, Jeff S.
AU - Antin, Joseph H.
AU - Howard, Alan
AU - Wu, Juan
AU - MacMillan, Margaret L.
AU - Panoskaltsis-Mortari, Angela
AU - Weisdorf, Daniel J.
AU - Holtan, Shernan G.
N1 - Publisher Copyright:
© 2019
PY - 2020/3
Y1 - 2020/3
N2 - Damage-associated angiogenic factors (AFs), including follistatin (FS) and soluble endoglin (sEng), are elevated in circulation at the onset of acute graft-versus-host disease (GVHD). We hypothesized that regimen-related tissue injury also might be associated with aberrant AF levels and sought to determine the relevance of these AF on nonrelapse mortality (NRM) in patients with acute GVHD and those without acute GVHD. To test our hypothesis, we analyzed circulating levels of FS, sEng, angiopoietin-2 (Ang2), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) A and B, placental growth factor (PlGF), and soluble VEGF receptor (sVEGFR)-1 and -2, in plasma samples from patients enrolled on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 (n = 221), which tested GVHD prophylaxis after myeloablative hematopoietic stem cell transplantation (HCT). We found that the interaction between FS and sEng had an additive effect in their association with 1-year NRM. In multivariate analysis, patients with the highest levels of day +28 FS and sEng had a 14.9-fold greater hazard ratio (HR) of NRM (95% confidence interval, 3.2 to 69.4; P <. 01) when compared with low levels of FS and sEng. We validated these findings using an external cohort of patients (n = 106). Pre-HCT measurements of FS and sEng were not associated with NRM, suggesting that elevations in these factors early post-HCT may be consequences of early regimen-related toxicity. Determining the mechanisms responsible for patient-specific vulnerability to treatment toxicities and endothelial damage associated with specific AF elevation may guide interventions to reduce NRM post-HCT.
AB - Damage-associated angiogenic factors (AFs), including follistatin (FS) and soluble endoglin (sEng), are elevated in circulation at the onset of acute graft-versus-host disease (GVHD). We hypothesized that regimen-related tissue injury also might be associated with aberrant AF levels and sought to determine the relevance of these AF on nonrelapse mortality (NRM) in patients with acute GVHD and those without acute GVHD. To test our hypothesis, we analyzed circulating levels of FS, sEng, angiopoietin-2 (Ang2), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) A and B, placental growth factor (PlGF), and soluble VEGF receptor (sVEGFR)-1 and -2, in plasma samples from patients enrolled on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 (n = 221), which tested GVHD prophylaxis after myeloablative hematopoietic stem cell transplantation (HCT). We found that the interaction between FS and sEng had an additive effect in their association with 1-year NRM. In multivariate analysis, patients with the highest levels of day +28 FS and sEng had a 14.9-fold greater hazard ratio (HR) of NRM (95% confidence interval, 3.2 to 69.4; P <. 01) when compared with low levels of FS and sEng. We validated these findings using an external cohort of patients (n = 106). Pre-HCT measurements of FS and sEng were not associated with NRM, suggesting that elevations in these factors early post-HCT may be consequences of early regimen-related toxicity. Determining the mechanisms responsible for patient-specific vulnerability to treatment toxicities and endothelial damage associated with specific AF elevation may guide interventions to reduce NRM post-HCT.
KW - Allogeneic hematopoietic cell transplantation
KW - Follistatin
KW - Non-relapse mortality
KW - Soluble endoglin
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U2 - 10.1016/j.bbmt.2019.11.006
DO - 10.1016/j.bbmt.2019.11.006
M3 - Article
C2 - 31715306
AN - SCOPUS:85077150993
SN - 1083-8791
VL - 26
SP - 606
EP - 611
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 3
ER -