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 6 3 from 167 patients free of GVHD at the time. Logistic regression and calculation of an area under a receiveroperating 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. (Blood. 2015;126(1):113-120)

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

“…Accordingly, these patients were excluded from the analysis, and possibly even diluted the power of detecting a meaningful difference. Moreover, in previously published studies of ST2, 1,3 TIM3, 3 and IL-6, 8 these biomarkers were also measured at an earlier time point post-HCT (day 14). Another difference of the current study is that all patients with acute GVHD were included regardless of organ involvement, whereas some prior studies of TIM3 3 and Reg3a 4 focused on gastrointestinal acute GVHD.…”

“…ST2, IL-6, Reg3a, and TIM3 were measured on days 28, 100, 180, and 365 as previously examined in the acute GVHD setting. [1][2][3][4][5][6][7][8] ST2, CXCL9, OPN, and MMP3 were measured at days 100, 180, and 365, as previously examined in the chronic GVHD setting.…”

“…Several plasma biomarkers that correlate with clinical outcomes after allogeneic hematopoietic cell transplantation (HCT) have been identified: suppression of tumorigenicity-2 (ST2) with therapyresistant acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) [1][2][3] ; regenerating islet-derived 3-a (Reg3a) and T-cell immunoglobulin mucin-3 (TIM3) with gastrointestinal acute GVHD [3][4][5][6][7] ; interleukin-6 (IL-6) with acute GVHD 8 ; ST2, chemokine (C-X-C motif) ligand 9 (CXCL9), matrix metalloproteinase 3 (MMP3), and osteopontin (OPN) with chronic GVHD 9,10 ; and L-Ficolin, hyaluronic acid (HA), vascular cell adhesion molecule-1 (VCAM1), and ST2 with hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS). 11 The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 study that prospectively compared tacrolimus/sirolimus (Tac/Sir) with tacrolimus/methotrexate (Tac/Mtx) GVHD prophylaxis found no difference in day 114 acute GVHD-free survival in HLAmatched related donor HCT.…”

“…12 In addition, there were no differences in grade 2 to 4 acute GVHD, chronic GVHD, relapse-free survival, and overall survival (OS) at 2 years between study arms. Therefore, we investigated whether a selected set of previously validated plasmaderived biomarkers [1][2][3][4][5][6][7][8][9][10][11] would correlate with clinical outcomes using samples collected from patients within this prospective, multicenter setting of uniform GVHD prophylaxis, conditioning regimen (fullintensity), and donor source (HLA-matched related).…”

How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver

“…[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] In upper-gut GVHD, edematous mucosa is often more impressive than histologic changes. 4 More severe cases are characterized by erythema, friability, and erosions in the pyloric gland area, often accompanied by a pool of bile and retained food in the stomach.…”