Assessment of systemic and gastrointestinal tissue damage biomarkers for GVHD risk stratification

Abstract

We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints.

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis

“…At flare onset, MAGIC biomarkers also successfully stratify patients for the risk of NRM similarly to their performance in de novo acute GVHD. 23 , 24 , 25 , 41 These findings are consistent with prior studies showing that biomarkers can predict outcomes at specified time points after initiation of treatment (eg, day 28) 13 and emphasize that the MAP reflects subclinical damage to the GI crypts when clinical symptoms are well controlled.…”

“…The MAP combines the concentrations of 2 serum biomarkers into a single value that can be considered a “liquid biopsy” of crypt damage throughout the GI tract. 13 , 23 The MAP value determines the risk of 6-month NRM and is used to calculate the AA score that has been validated as a predictive biomarker by several research groups. 34 , 35 The MAP detects damage to GI crypts even before symptoms appear, 21 and we, therefore, measured MAPs in all patients at the time of CR/VGPR.…”

“…Serum concentrations of suppressor of tumorigenicity 2 (ST2) 19 and regenerating islet-derived protein 3- α (REG3 α ) 20 were analyzed by enzyme-linked immunosorbent assays, as previously reported. 21 , 22 , 23 The MAGIC algorithm probability (MAP) was calculated as a single value between 0.001 and 0.999 according to the formula: log(–log[1 – MAP]) = –11.263 + 1.844(log 10 ST2) + 0.577(log 10 REG3α) and validated thresholds for Ann Arbor (AA) scores were used (AA1 < 0.14; 0.14 ≤ AA2 < 0.29; AA3 ≥ 0.29). 18 , 21 , 22 , 24 , 25 , 26 …”

Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects

“…Here, we found that RIP1 inhibition prevented GVHD by rescuing ISCs from apoptosis while preserving GVL effects and improving immune reconstitution. The GI tract is considered the most critical of the three acute GVHD target organs because GVHD is hardest to control in the GI tract and its response to therapy largely determines long-term outcomes such as survival (29)(30)(31). Histologic severity of GVHD in the lower GI tract is characterized by apoptotic cells near the crypt base, with crypt loss in severe cases (32)(33)(34).…”

Graft-versus-host disease: establishing IL-33 as an important costimulatory molecule

“…Subsequent work showed that combining ST2 analysis with a second serum biomarker, regenerating islet-derived 3-α, an antimicrobial peptide produced by Paneth cells, predicted long-term outcomes of GVHD ( 12 – 14 ). Each biomarker by itself has approximately the same predictive power, but only these two synergize effectively to predict long-term outcomes, probably because they reflect activation and damage of two separate components of the GI tract, the mesenchyme and epithelium ( 15 ). Thus, the combination of the two has been described as a liquid biopsy of the GI tract that can monitor intestinal GVHD damage and guide immunosuppressive therapy ( 16 ).…”