Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study

Abstract

Acute graft-versus-host disease (GVHD) is the primary limitation of allogeneic hematopoietic cell transplantation, and once it develops, there are no reliable diagnostic tests to predict treatment outcomes. We hypothesized that 6 previously validated diagnostic biomarkers of GVHD (IL-2 receptor-α; tumor necrosis factor receptor-1; hepatocyte growth factor; IL-8; elafin, a skin-specific marker; and regenerating islet-derived 3-α, a gastrointestinal tract-specific marker) could discriminate between therapy responsive and nonresponsive patients and predict survival in patients receiving GVHD therapy. We measured GVHD biomarker concentrations from samples prospectively obtained at the initiation of treatment, day 14, and day 28, on a multicenter, randomized, 4-arm phase 2 clinical trial for newly diagnosed acute GVHD. We found that at each of 3 time points, GVHD onset, 2 weeks into treatment, and 4 weeks into treatment, a 6-protein biomarker panel predicted for the important clinical outcomes of day 28 posttherapy nonresponse and mortality at day 180 from onset. GVHD biomarker panels can be used for early identification of patients at high or low risk for treatment nonresponsiveness or death, and they may provide opportunities for early intervention and improved survival after hematopoietic cell transplantation. The study was registered in clinicaltrials.gov as NCT00224874.

Figures

Figure 1

Biomarker concentrations at study entry (day 0) according to day 180 survival status. The boxplots show the range, median, and mean (diamond) graphed on a log-scale for each of the 6 biomarkers measured on day 0 according to the day 180 survival status (alive or dead). P values are shown for the comparison of median concentrations for each biomarker.

Figure 2

Survival from study entry stratified by day 0 biomarker panel. The optimized threshold for the biomarker panel measured at study entry was used to define a high versus low panel result. Patients with a high panel (dashed line, N = 32) were much more likely to die by day 180 compared with patients with a low panel (solid line, N = 80; P < .001).

Figure 3

Survival from study entry stratified by day 28 biomarker panel. The optimized threshold for the biomarker panel measured at day 28 of GVHD treatment was used to define a high versus low panel result. Patients with a high panel (dashed line, N = 41) were much more likely to die by day 180 compared with patients with a low panel (solid line, N = 63; P < .001).