title: Circulating angiogenic factors associated with response and survival in patients with acute graft-versus-host disease: results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802.
abstract: 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.
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota. Electronic address: sgholtan@umn.edu.
authors.forename: Shernan G
authors.initials: SG
authors.lastname: Holtan
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.affiliation: Division of Pediatric Hematology/Oncology/BMT, BC Children's Hospital, Vancouver, University of British Columbia; Blood and Marrow Transplant Clinical Trials Network, Rockville, Maryland.
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
authors.affiliation: Blood and Marrow Transplant Program, Oregon Health & Science University, Portland, Oregon.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Newell
authors.affiliation: Blood and Marrow Transplant Program, Oregon Health & Science University, Portland, Oregon.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Meyers
authors.affiliation: School of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Fiona
authors.initials: F
authors.lastname: He
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Todd E
authors.initials: TE
authors.lastname: DeFor
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Arne
authors.initials: A
authors.lastname: Slungaard
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: MacMillan
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Cooley
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota; Blood and Marrow Transplant Clinical Trials Network, Rockville, Maryland.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood; D015703:Antigens, CD / Q000097:blood; D015415:Biomarkers / Q000097:blood; D016026:Bone Marrow Transplantation; D002648:Child; D000071063:Endoglin; D004815:Epidermal Growth Factor / Q000097:blood; D005260:Female; D038681:Follistatin / Q000097:blood; D006086:Graft vs Host Disease / Q000097:blood* / Q000175:diagnosis* / Q000276:immunology / Q000401:mortality; D019337:Hematologic Neoplasms / Q000097:blood / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000097:blood; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000097:blood; D016019:Survival Analysis; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D042702:Angiopoietin-2; D015703:Antigens, CD; D015415:Biomarkers; C064206:ENG protein, human; D000071063:Endoglin; D038681:Follistatin; D008565:Membrane Proteins; C098069:PIGF protein, human; D011956:Receptors, Cell Surface; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor
keywords: Acute graft-versus-host disease; Allogeneic hematopoietic cell transplantation; Angiogenic factor; Epidermal growth factor; Follistatin; Placental growth factor; Vascular endothelial growth factor