The MAGIC Composite Response: A Novel Endpoint Integrating Clinical and Biomarker Parameters for Acute GVHD.

Changes in the clinical symptoms of acute graft versus host disease (GVHD) are currently used to assess responses to treatment. The MAGIC consortium has recently shown that the integration of serum biomarkers with clinical symptoms at the onset of treatment in a MAGIC Composite Score (MCS) more accurately predicts response to treatment and 6-month non-relapse mortality (NRM) than clinical symptoms alone. In this study we evaluated whether the integration of serum biomarkers and clinical symptoms on day 28 (D28) would also better predict NRM than clinical response only (CRO). We analyzed data from 1135 patients receiving systemic treatment for acute GVHD and created a fourth MCS category for patients with complete resolution of symptoms and low risk clinical biomarkers on D28. Using a Classification and Regression Tree (CART) model with 6-month NRM as the endpoint we identified status of MCS 0 or MCS 1 at D28 as responses, which we termed the MAGIC Composite Response (MCR). In the validation cohort (n=309), MCR more accurately predicted 6-month NRM than CRO (AUC: 0.77 vs. 0.69; P=0.014) and demonstrated higher negative and positive predictive values. MCR correctly reclassified both clinical non-responders and responders: 28/213 (13%) of clinical responders became non-responders with five-fold higher NRM (34.3% vs. 6.8%, P<0.001) and a larger group (29/96, 30%) of clinical non-responders became responders with six-fold lower NRM (7.6% vs. 50.7%, P<0.001). These findings support the use of MCR as a superior surrogate endpoint for long-term GVHD control and survival in future clinical trials.