Novel MAGIC composite scores using both clinical symptoms and biomarkers best predict treatment outcomes of acute GVHD

Abstract

Acute graft-versus-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as the Minnesota risk identify standard and high-risk categories but lack a low-risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low-risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model's prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar nonrelapse mortality (NRM); we used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs 0.64, P = .009) in the validation cohort. We integrated serum GVHD biomarker scores with Manhattan risk using patients with available serum samples and again used a CART algorithm to establish 3 MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs 0.70, P = .010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs 63% vs 30%, P < .001). We conclude that the MAGIC composite score more accurately predicts response to therapy and long-term outcomes than systems based on clinical symptoms alone and may help guide clinical decisions and trial design.

Graphical abstract

Figure 1.

NRM in the clinical risk models. Six-month cumulative incidence of NRM by Minnesota (left) and Manhattan (right) risk strata. (A) Training cohort. Minnesota standard risk: 10.2% (95% CI, 8.5-12.2); Minnesota high risk: 36.8% (95% CI, 30.5-43.0); Manhattan low risk: 7.1% (95% CI, 5.1- 9.5); Manhattan intermediate risk: 13.9% (95% CI, 11.1-16.9); Manhattan high risk: 37.8% (95% CI, 31.2-44.4). (B) Validation cohort. Minnesota standard risk: 11.0% (95% CI, 8.3-14.1); Minnesota high risk: 34.4% (95% CI, 25.3-43.6); Manhattan low risk: 7.0% (95% CI, 4.2-10.8); Manhattan intermediate risk: 14.9% (95% CI, 10.6-19.9); Manhattan high risk: 35.8% (95% CI, 26.4-45.4). Pie charts depict the percentage of each clinical risk. ∗P values for pairwise comparisons were adjusted using the Bonferroni method.

Figure 2.

NRM and AUC of the MAGIC composite scores. (A) Six-month cumulative incidence of NRM. MAGIC composite score 1: 5.7% (95% CI, 3.3-8.9); composite score 2: 28.8% (95% CI, 21.2-36.8); composite score 3: 51.5% (95% CI, 33.1-67.2). (B) Six-month cumulative incidence of relapse. MAGIC composite score 1: 8.3% (95% CI, 5.4-12.0); composite score 2: 10.8% (95% CI, 6.2-16.9); composite score 3: 6.7% (95% CI, 1.1-19.7). (C) Probability of OS at 6 months; MAGIC composite score 1: 90.6% (95% CI, 86.4-93.5); composite score 2: 64.3% (95% CI, 55.3-71.9); composite score 3: 42.4% (95% CI, 25.6-58.3). Pie charts depict the percentage of each composite score. ∗P values for pairwise comparisons were adjusted using the Bonferroni method. (D) Time-dependent area under the receiver operating characteristic curve for NRM from the time of systemic treatment.

Figure 3.

Day 28 ORR. Day 28 ORR by the Minnesota risk (left), Manhattan risk (middle), and MAGIC composite scores (right). (A) Training cohort. Minnesota standard risk: 71.5%; Minnesota high risk: 47.0%; Manhattan low risk: 72.3%; Manhattan intermediate risk: 69.6%; Manhattan high risk: 47.9%; MAGIC composite score 1: 74.8%; MAGIC composite score 2: 63.2%; MAGIC composite score 3: 35.2%. (B) Validation cohort. Minnesota standard risk: 73.3%; Minnesota high risk: 49.5%; Manhattan low risk: 77.0%; Manhattan intermediate risk: 69.7%; Manhattan high risk: 48.5%; MAGIC composite score 1: 79.8%; MAGIC composite score 2: 62.9%; MAGIC composite score 3: 30.3%. The error bars represent standard errors. ∗P values for pairwise comparisons were adjusted using the Bonferroni method.