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

Shernan G. Holtan; Michael R. Verneris; Kirk R. Schultz; Laura F. Newell; Gabrielle Meyers; Fiona He; Todd E. DeFor; Gregory M. Vercellotti; Arne Slungaard; Margaret L. MacMillan; Sarah A. Cooley; Bruce R. Blazar; Angela Panoskaltsis-Mortari; Daniel J. Weisdorf

doi:10.1016/j.bbmt.2015.02.018

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

Shernan G. Holtan, Michael R. Verneris, Kirk R. Schultz, Laura F. Newell, Gabrielle Meyers, Fiona He, Todd E. DeFor, Gregory M. Vercellotti, Arne Slungaard, Margaret L. MacMillan, Sarah A. Cooley, Bruce R. Blazar, Angela Panoskaltsis-Mortari, Daniel J. Weisdorf

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50 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1029-1036
Number of pages	8
Journal	Biology of Blood and Marrow Transplantation
Volume	21
Issue number	6
DOIs	https://doi.org/10.1016/j.bbmt.2015.02.018
State	Published - Jun 2015

Bibliographical note

Funding 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.

Publisher Copyright:
© 2015 American Society for Blood and Marrow Transplantation.

Keywords

Acute graft-versus-host disease
Allogeneic hematopoietic cell transplantation
Angiogenic factor
Epidermal growth factor
Follistatin
Placental growth factor
Vascular endothelial growth factor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbmt.2015.02.018

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Holtan, S. G., Verneris, M. R., Schultz, K. R., Newell, L. F., Meyers, G., He, F., DeFor, T. E., Vercellotti, G. M., Slungaard, A., MacMillan, M. L., Cooley, S. A., Blazar, B. R., Panoskaltsis-Mortari, A., & Weisdorf, D. J. (2015). 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. Biology of Blood and Marrow Transplantation, 21(6), 1029-1036. https://doi.org/10.1016/j.bbmt.2015.02.018

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. / Holtan, Shernan G.; Verneris, Michael R.; Schultz, Kirk R. et al.
In: Biology of Blood and Marrow Transplantation, Vol. 21, No. 6, 06.2015, p. 1029-1036.

Research output: Contribution to journal › Article › peer-review

Holtan, SG, Verneris, MR, Schultz, KR, Newell, LF, Meyers, G, He, F , DeFor, TE , Vercellotti, GM, Slungaard, A, MacMillan, ML, Cooley, SA, Blazar, BR , Panoskaltsis-Mortari, A & Weisdorf, DJ 2015, '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', Biology of Blood and Marrow Transplantation, vol. 21, no. 6, pp. 1029-1036. https://doi.org/10.1016/j.bbmt.2015.02.018

Holtan SG, Verneris MR, Schultz KR, Newell LF, Meyers G, He F et al. 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. Biology of Blood and Marrow Transplantation. 2015 Jun;21(6):1029-1036. doi: 10.1016/j.bbmt.2015.02.018

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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.",

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author = "Holtan, {Shernan G.} and Verneris, {Michael R.} and Schultz, {Kirk R.} and Newell, {Laura F.} and Gabrielle Meyers and Fiona He and DeFor, {Todd E.} and Vercellotti, {Gregory M.} and Arne Slungaard and MacMillan, {Margaret L.} and Cooley, {Sarah A.} and Blazar, {Bruce R.} and Angela Panoskaltsis-Mortari and Weisdorf, {Daniel J.}",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2015 American Society for Blood and Marrow Transplantation.",

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T2 - Results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802

AU - Holtan, Shernan G.

AU - Verneris, Michael R.

AU - Schultz, Kirk R.

AU - Newell, Laura F.

AU - Meyers, Gabrielle

AU - He, Fiona

AU - DeFor, Todd E.

AU - Vercellotti, Gregory M.

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AU - MacMillan, Margaret L.

AU - Cooley, Sarah A.

AU - Blazar, Bruce R.

AU - Panoskaltsis-Mortari, Angela

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N1 - Funding 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. Publisher Copyright: © 2015 American Society for Blood and Marrow Transplantation.

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N2 - 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.

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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

Bibliographical note

Keywords

UN SDGs

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