A Validated Risk Stratification That Incorporates MAGIC Biomarkers Predicts Long-Term Outcomes in Pediatric Patients with Acute GVHD

Abstract

Acute graft versus host disease (GVHD) is a common and serious complication of allogeneic hematopoietic cell transplantation (HCT) in children but overall clinical grade at onset only modestly predicts response to treatment and survival outcomes. Two tools to assess risk at initiation of treatment were recently developed. The Minnesota risk system stratifies children for risk of nonrelapse mortality (NRM) according to the pattern of GVHD target organ severity. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm of 2 serum biomarkers (ST2 and REG3α) predicts NRM in adult patients but has not been validated in a pediatric population. We aimed to develop and validate a system that stratifies children at the onset of GVHD for risk of 6-month NRM. We determined the MAGIC algorithm probabilities (MAPs) and Minnesota risk for a multicenter cohort of 315 pediatric patients who developed GVHD requiring treatment with systemic corticosteroids. MAPs created 3 risk groups with distinct outcomes at the start of treatment and were more accurate than Minnesota risk stratification for prediction of NRM (area under the receiver operating curve (AUC), .79 versus .62, P = .001). A novel model that combined Minnesota risk and biomarker scores created from a training cohort was more accurate than either biomarkers or clinical systems in a validation cohort (AUC .87) and stratified patients into 2 groups with highly different 6-month NRM (5% versus 38%, P < .001). In summary, we validated the MAP as a prognostic biomarker in pediatric patients with GVHD, and a novel risk stratification that combines Minnesota risk and biomarker risk performed best. Biomarker-based risk stratification can be used in clinical trials to develop more tailored approaches for children who require treatment for GVHD.

Keywords: Acute GVHD; Biomarkers; Pediatric; Validation.

Figure 1.. Long-term outcomes for risk groups by Minnesota risk and Ann Arbor (AA) Score at start of GVHD treatment.

(A) Receiver operating characteristic curves to predict six-month NRM. The area under the curve for the Ann Arbor score is significantly higher than for Minnesota risk (0.79 vs 0.62, p = 0.001). NRM by Minnesota risk (B): Standard risk (green), 9%; High risk (red), 27%, p<0.001). The pie chart shows the distribution of cases: Standard risk 82%, high risk 18%. NRM by AA score (C): AA1 (blue), 3%; AA2 (green), 16%; AA3 (red), 42%, overall p<0.001 (AA1 vs AA2, p=0.003; AA2 vs AA3, p=0.003). The pie chart shows the distribution of cases: AA1 59%, AA2 26%, AA3 15%.

Figure 2.. Six-month NRM within each Minnesota risk group by AA score.

(A): Minnesota Standard Risk (n=258): AA1 (blue), 3%; AA2 (green), 10%; AA3 (red), 41%, p<0.001. The pie chart shows the distribution of cases: AA1 66%, AA2 23%. AA3 11%. (B): Minnesota High Risk (n=57): AA1, 6%; AA2, 30%; AA3 43%, p=0.08. Pie chart shows proportion by AA score. The pie chart shows the distribution of cases: AA1 30%, AA2 40%. AA3 30%.

Figure 3.. Long-term outcomes for risk groups by combined Minnesota risk and Ann Arbor score classification.

Non-relapse mortality (A): Low risk (blue), 5%; High risk (red), 38%, p<0.001. Overall survival (B): Low risk, 91%; High risk, 59%, p<0.001. The pie chart shows the distribution of cases: Low risk 65%, high risk 35%.