Biomarkers for Diagnosis and Prognosis of Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation

Abstract

Reliable, non-invasive methods for diagnosing and prognosing sinusoidal obstruction syndrome (SOS) early after hematopoietic cell transplantation (HCT) are needed. We used a quantitative mass spectrometry-based proteomics approach to identify candidate biomarkers of SOS by comparing plasma pooled from 20 patients with and 20 patients without SOS. Of 494 proteins quantified, we selected six proteins [L-Ficolin, vascular-cell-adhesion-molecule-1 (VCAM1), tissue-inhibitor of metalloproteinase-1, von Willebrand factor, intercellular-adhesion-molecule-1, and CD97] based on a differential heavy/light isotope ratio of at least 2 fold, information from the literature, and immunoassay availability. Next, we evaluated the diagnostic potential of these six proteins and five selected from the literature [suppression of tumorigenicity-2 (ST2), angiopoietin-2 (ANG2), hyaluronic acid (HA), thrombomodulin, and plasminogen activator inhibitor-1] in samples from 80 patients. The results demonstrate that together ST2, ANG2, L-Ficolin, HA, and VCAM1 compose a biomarker panel for diagnosis of SOS. L-Ficolin, HA, and VCAM1 also stratified patients at risk for SOS as early as the day of HCT. Prognostic Bayesian modeling for SOS onset based on L-Ficolin, HA, and VCAM1 levels on the day of HCT and clinical characteristics showed >80% correct prognosis of SOS onset. These biomarkers may provide opportunities for preemptive intervention to minimize SOS incidence and/or severity.

Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

“…11 Univariate logistic regression was used to evaluate the association between clinical outcomes and individual biomarker at each time point for the entire cohort. Multivariate analyses were performed, including the treatment group and 6 covariates: age ($40, ,40), sex, performance score (90% to 100%, ,90%), conditioning regimen (cyclophosphamide/total body irradiation, etoposide/total body irradiation), primary malignancy (acute myeloid leukemia, acute lymphoblastic leukemia, or others), and recipient cytomegalovirus (CMV) status.…”

“…11 All of these biomarkers were measured using sequential enzyme-linked immunosorbent assay (ELISA), as previously reported. 13 The antibody pairs included Reg3a (MBL International, Ab-Match Assembly Human PAP1 [Reg3a] kit and AbMatch Universal kit), CXCL9 (RayBiotech, RayBio Human MIG ELISA Kit), L-Ficolin (Hycult Biotech, HK336 Human Ficolin-2 ELISA kit), and HA (Corgenix HA test kit).…”

“…11 The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 study that prospectively compared tacrolimus/sirolimus (Tac/Sir) with tacrolimus/methotrexate (Tac/Mtx) GVHD prophylaxis found no difference in day 114 acute GVHD-free survival in HLAmatched related donor HCT. 12 In addition, there were no differences in grade 2 to 4 acute GVHD, chronic GVHD, relapse-free survival, and overall survival (OS) at 2 years between study arms.…”

“…12 In addition, there were no differences in grade 2 to 4 acute GVHD, chronic GVHD, relapse-free survival, and overall survival (OS) at 2 years between study arms. Therefore, we investigated whether a selected set of previously validated plasmaderived biomarkers [1][2][3][4][5][6][7][8][9][10][11] would correlate with clinical outcomes using samples collected from patients within this prospective, multicenter setting of uniform GVHD prophylaxis, conditioning regimen (fullintensity), and donor source (HLA-matched related).…”

Hepatic Sinusoidal Obstruction Syndrome in the Era of Defibrotide

“…In a study, it has been shown that. L-Ficolin, HA, and vascular cell adhesion molecule-1 are prognostic biomarkers of SOS before symptoms appear and these biomarkers can stratify patients at risk for SOS as early as the day of HSCT [17].…”