Plasma biomarkers of lower gastrointestinal and liver acute GVHD

Abstract

The lower gastrointestinal tract (LGI) and liver are the GVHD target organs most associated with treatment failure and nonrelapse mortality. We recently identified regenerating islet-derived 3-α (REG3α) as a plasma biomarker of LGI GVHD. We compared REG3α with 2 previously reported GI and liver GVHD diagnostic biomarkers, hepatocyte growth factor (HGF) and cytokeratin fragment 18, in 954 hematopoietic cell transplantation patients. All 3 biomarkers were significantly elevated in LGI GVHD compared with non-GVHD diarrhea; REG3α discerned LGI GVHD from non-GVHD diarrhea better than HGF and cytokeratin fragment 18. Although all 3 biomarkers predicted nonresponse to therapy at day 28 in LGI GVHD patients, only REG3α and HGF concentrations predicted 1-year nonrelapse mortality (P = .01 and P = .02, respectively). Liver GVHD without GI involvement at GVHD onset and non-GVHD liver complications were uncommon; all 3 biomarkers were elevated in liver GVHD, but did not distinguish GVHD from other causes of hyperbilirubinemia.

Figure 1

Biomarkers at the onset of GVHD symptoms. (A-C) REG3α, HGF, and KRT18 concentrations, respectively, at the onset of symptoms consistent with GVHD in 954 HCT patients. (D) ROC curves comparing biomarker concentrations at the onset of LGI GVHD without liver GVHD (n = 144) and non-GVHD diarrhea (n = 42). REG3α (thin solid line): AUC = 0.79; HGF (dotted line): AUC = 0.60; KRT18 (dashed line): AUC = 0.60; composite of all 3 biomarkers (thick solid line): AUC = 0.80. (E-G) NRM in patients with LGI GVHD at onset with onset concentrations above the median (solid line; n = 89) versus patients with onset concentrations below the median (dotted line; n = 89) for REG3a, HGF, and KRT18, respectively. (E) REG3a: > 135 ng/mL versus ≤ 135 ng/mL; 52% versus 33%, P = .01. (F) HGF: > 1398 pg/mL versus ≤ 1398 pg/mL; 52% versus 33%, P = .02. (G) KRT18 > 373 U/L versus ≤ 373 U/L; 47% versus 38%, P = .3. (H) ROC curves comparing biomarker concentrations at the onset of liver GVHD without GI GVHD (n = 16) and non-GVHD liver complications (n = 25); REG3α (thin solid line): AUC = 0.61; HGF (dotted line): AUC = 0.59; KRT18 (dashed line): AUC = 0.63; composite of all 3 biomarkers (thick solid line): AUC = 0.62.