An Early Biomarker Algorithm Predicts Lethal Graft-Vs-Host Disease and Survival after Allogeneic Hematopoietic Cell Transplantation (2017)

The graft-versus-host reaction is underway by day +7 after HCT even though graft-versus-host disease (GVHD) symptoms are not yet present. We sought to identify a blood biomarker signature that could predict lethal GVHD and sixmonth NRM at this early time point when pre-emptive treatment might be effective. Patient samples on day +7 after HCT were obtained from 1,287 patients (pts) from 11 centers in the Mount Sinai Acute GVHD International Consortium (MAGIC). Samples from two large centers (n = 929) were combined and randomly assigned to a training set (n = 620) and test set (n = 309). 358 pts from nine other centers constituted an independent validation set. The overall cumulative incidences of 6month NRM were 11%, 12%, and 13% for the training, test, and validation sets respectively. The incidence of lethal GVHD, defined as death without relapse while receiving steroids for acute GVHD, were 8%, 8%, and 9% in the same groups, respectively. The median day of GVHD onset was 28 days in the training set and 29 days in both the test and validation sets. We tested algorithms of all 13 possible combinations of four GVHD related biomarkers [ST2, REG3α, TNFR1, and IL2Rα], using samples from the training set alone to develop competing risk regression models that predicted 6month NRM. The best algorithm included ST2 and REG3α and no combination of 1, 3, or 4 biomarkers was superior to this combination. The algorithm identified high risk (HR) and low risk (LR) groups with 6month NRM of 28% and 7%, respectively (P < .001) (Figure 1A). Relapse rates did not differ between risk groups and overall survival (OS) was 60% for HR and 84% for LR (P < .001) (Figure 1B). When we applied the algorithm to both the test set (Figure 1C/D) and to the validation set (Figure 1E/F), we observed similar proportions of pts identified as HR with equally high rates of NRM and low OS. HR pts were 3 times more likely to die from GVHD than LR pts in each cohort (P < .001) (Figure 2). The GI tract, the GVHD target organ most resistant to treatment, represents a major cause of NRM; we observed twice as much severe GI GVHD (stage 3 or 4) in HR pts as in LR pts (P < .001, data not shown). We evaluated whether preclinical transplant characteristics would influence algorithm performance and observed that the algorithm successfully separated HR and LR strata in several groups with differing risks for GVHD and NRM, including donor type, degree of HLAmatch, age group, and conditioning regimen intensity (Figure 3). When an unfavorable pre-transplant risk factor increased overall NRM, the algorithm identified more pts as high risk (e.g. 21% of unrelated donors v 12% of related donors). In conclusion, we have developed and validated a blood biomarker algorithm that predicts the development of lethal GVHD at 7 days after HCT and identifies risk strata in several patient groups which should prove useful for BMT clinical research.Figure 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3View Large Image Figure ViewerDownload Hi-res image Download (PPT)