Follistatin and Soluble Endoglin Predict 1-Year Nonrelapse Mortality after Allogeneic Hematopoietic Cell Transplantation

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)606-611
Number of pages6
JournalBiology of Blood and Marrow Transplantation
Volume26
Issue number3
DOIs
StatePublished - Mar 2020

Bibliographical note

Funding Information:
The authors thank the BMT CTN 0402 study investigators and participating centers, and thank Michael Ehrhardt for assistance with the circulating angiogenic factor analyses at the University of Minnesota Cytokine Reference Laboratory. Financial disclosure: Support for this study was provided to the BMT CTN from the National Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institute (U10 HL069294). BMT CTN 0402 biospecimens were obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). L.F.N. is supported by the National Institute of Child Health and Human Development (Grant 1K23 HD091369-01). S.G.H. is supported by a Women's Early Research Career Award from the University of Minnesota, Department of Medicine. Support for the collection and storage of plasma samples from the University of Minnesota validation cohort was provided by NIH P01 CA111412). Statistical support was made possible by NIH P30 CA77598 using the Biostatistics and Bioinformatics Shared Resource of the Masonic Cancer Center. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: L.F.N., S.G.H., and T.E.D. designed the project, analyzed the primary data, and wrote the manuscript. T.E.D. performed the statistical analyses and reviewed the manuscript. J.S.M. provided patient plasma samples for the validation cohort and reviewed the manuscript. A.P.-M. performed the circulating angiogenic factor analyses and reviewed the manuscript. All other authors critically reviewed and approved the final manuscript. L.F.N. and T.E.D. contributed equally to this work.

Funding Information:
The authors thank the BMT CTN 0402 study investigators and participating centers, and thank Michael Ehrhardt for assistance with the circulating angiogenic factor analyses at the University of Minnesota Cytokine Reference Laboratory. Financial disclosure: Support for this study was provided to the BMT CTN from the National Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institute (U10 HL069294). BMT CTN 0402 biospecimens were obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). L.F.N. is supported by the National Institute of Child Health and Human Development (Grant 1K23 HD091369-01). S.G.H. is supported by a Women's Early Research Career Award from the University of Minnesota, Department of Medicine. Support for the collection and storage of plasma samples from the University of Minnesota validation cohort was provided by NIH P01 CA111412). Statistical support was made possible by NIH P30 CA77598 using the Biostatistics and Bioinformatics Shared Resource of the Masonic Cancer Center. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: L.F.N. S.G.H. and T.E.D. designed the project, analyzed the primary data, and wrote the manuscript. T.E.D. performed the statistical analyses and reviewed the manuscript. J.S.M. provided patient plasma samples for the validation cohort and reviewed the manuscript. A.P.-M. performed the circulating angiogenic factor analyses and reviewed the manuscript. All other authors critically reviewed and approved the final manuscript. L.F.N. and T.E.D. contributed equally to this work. Financial disclosure: See Acknowledgments on page 610.

Publisher Copyright:
© 2019

Keywords

  • Allogeneic hematopoietic cell transplantation
  • Follistatin
  • Non-relapse mortality
  • Soluble endoglin

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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