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

Mohammad Abu Zaid, Juan Wu, Cindy Wu, Brent R. Logan, Jeffrey Yu, Corey Cutler, Joseph H. Antin, Sophie Paczesny and Sung Won Choi

Key points

  • High ST2 and TIM3 at day 28 after allogeneic HCT were associated with non-relapse mortality and overall survival at 2 years.

  • Low day 28 L-Ficolin was associated with VOD/SOS and high CXCL9 correlated with chronic GVHD.

Abstract

A phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) versus tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using ELISA (Tac/Sir=104, Tac/Mtx=107). High suppression of tumorigenicity-2 (ST2) and T cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year non-relapse mortality in multivariate analysis (P=0.0050, P=0.0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio [HR]: 2.43 [1.49–3.95], P=0.0038 and 4.87 [2.53–9.34], P<0.0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P=0.0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P=0.0053, AUC=0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study.

  • Submitted August 22, 2016.
  • Accepted October 26, 2016.