Circulating angiogenic factors (AF) reflect tissue healing capacity, although some AF can also contribute to inflammation and are indicative of endothelial dysfunction. The AF milieu in acute graft-versus-host disease (aGVHD) has not been broadly characterized. We hypothesized that patients with abundant AF involved in repair/regeneration versus those mediating damage/inflammation would have improved outcomes. Circulating AF known predominantly for repair/regeneration (epidermal growth factor [EGF], fibroblast growth factor-1 and -2, heparin binding-EGF-like growth factor, and vascular endothelial growth factor-A [VEGF-A], -C, and -D) and for damage/inflammation (angiopoietin-2, endothelin-1, soluble endoglin [sEng], follistatin [FS], leptin, and placental growth factor [PlGF]) were measured in a discovery set of hematopoietic cell recipients with grade III and IV aGVHD and compared with controls, then validated in 2 aGVHD cohorts enrolled in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials 0302 (n = 105, serum) and 0802 (n = 158, plasma) versus controls without aGVHD (n = 53, serum). Levels of EGF and VEGF-A were lower than in controls at the onset of aGVHD in both trials and higher with complete response to first-line aGVHD therapy in CTN 0802. FS and PlGF were elevated in aGVHD measured in either serum or plasma. At day 28 after initial aGVHD therapy, elevated FS was an independent negative prognostic factor for survival in both cohorts (hazard ratio, 9.3 in CTN 0302; 2.8 in CTN 0802). These data suggest that circulating AF are associated with clinical outcomes after aGVHD and, thus, may contribute to both pathogenesis and recovery.
Bibliographical noteFunding Information:
The authors gratefully acknowledge the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0302 and 0802 study investigators and participating centers. The studies conducted by the BMT CTN were completed with the support of grant U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute at the National Institutes of Health . The authors also thank Mr. Michael Ehrhardt from the Cytokine Reference Laboratory of the University of Minnesota for laboratory analyses. This study was supported in part by the Office of Research on Women's Health and the National Institute of Child Health and Human Development , Oregon BIRCWH Award Number 2K12HD043488 (S.G.H. and L.F.N.), the Medical Foundation of Oregon (S.G.H.), and by NIH P30 CA77598 and P01CA111412 , utilizing the Biostatistics and Bioinformatics Shared Resource of the Masonic Cancer Center.
- Acute graft-versus-host disease
- Allogeneic hematopoietic cell transplantation
- Angiogenic factor
- Epidermal growth factor
- Placental growth factor
- Vascular endothelial growth factor