Plasma biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements before GVHD onset and treatment

Abstract

We identified plasma biomarkers that presaged outcomes in patients with gastrointestinal graft-versus-host disease (GVHD) by measuring 23 biomarkers in samples collected before initiation of treatment. Six analytes with the greatest accuracy in predicting grade 3-4 GVHD in the first cohort (74 patients) were then tested in a second cohort (76 patients). The same 6 analytes were also tested in samples collected at day 14 ± 3 from 167 patients free of GVHD at the time. Logistic regression and calculation of an area under a receiver-operating characteristic (ROC) curve for each analyte were used to determine associations with outcome. Best models in the GVHD onset and landmark analyses were determined by forward selection. In samples from the second cohort, collected a median of 4 days before start of treatment, levels of TIM3, IL6, and sTNFR1 had utility in predicting development of peak grade 3-4 GVHD (area under ROC curve, 0.88). Plasma ST2 and sTNFR1 predicted nonrelapse mortality within 1 year after transplantation (area under ROC curve, 0.90). In the landmark analysis, plasma TIM3 predicted subsequent grade 3-4 GVHD (area under ROC curve, 0.76). We conclude that plasma levels of TIM3, sTNFR1, ST2, and IL6 are informative in predicting more severe GVHD and nonrelapse mortality.

Figure 1

Flowchart illustrating the number of patients in each analysis cohort (cohorts 1, 2, and the combined cohort landmark analysis at day 14 ± 3 days).

Figure 2

ROC curves for analytes in plasma for the prediction of more severe acute GVHD and NRM for patients in cohort 2, using the best model analytes given in Table 3.

Figure 3

ROC curves for analytes in plasma at transplant day 14 (landmark analysis, cohorts 1 and 2 combined), using the best model analytes given in Table 5 for predicting more severe from less severe GVHD to day 100.

Figure 4

Values for analytes found in blood samples from patients in cohort 1, drawn at weekly intervals. The dotted lines are cubic spline curves, for GVHD cases in red and non-GVHD cases in black.