Abstract

BACKGROUND: Response to first-line treatment in acute graft-versus-host disease (GVHD) is typically assessed at day 28 (D28) in clinical trials, but this convention was established without accounting for onset severity and thus was optimized for mild-moderate GVHD that comprises the majority of cases. Furthermore, the initiation of second-line therapy, which is considered primary treatment failure, is not based on standardized criteria and thus remains subjective and inconsistent for patients regardless of clinical trial participation. OBJECTIVE: In this study we hypothesized that an early assessment of treatment response at D7 would accurately predict long-term outcomes for patients with severe GVHD and support the initiation of second line therapy in non-responders. STUDY DESIGN: We analyzed six-month outcomes by D7 and D28 response for 1561 patients receiving systemic therapy for acute GVHD in two large trial cohorts - one observational (n = 1008) and one interventional (n = 553) after stratification for onset severity using Minnesota risk criteria. RESULTS: Patients with Minnesota standard risk GVHD comprised approximately 80% of each cohort. D7 responses predicted much smaller differences in 6-month NRM (observational: responders: 9% versus non-responders: 23%; interventional: 12% versus 24%) than D28 responses (observational: 7% versus 35%; interventional: 9% versus 36%) and second line therapy was deferred in ∼85% of patients who had not responded by D7. More than half of this "wait and see" group proved to be slow responders with low 6-month NRM of <10% and as a result the D28 response more accurately predicted 6-month NRM than D7 response (AUC: observational; 0.73 versus 0.63, P < .001; interventional: 0.70 versus 0.60, P = .002). Subset analyses confirmed the superiority of D28 over D7 in children with Minnesota standard risk GVHD and in patients with little or no lower gastrointestinal (GI) GVHD (stage 0 or 1) but not patients with stage 2 GI GVHD. In contrast, among Minnesota high risk patients, D7 (observational: 26% versus 54%; interventional: 20% versus 56%) and D28 (observational: 20% versus 57%; interventional: 22% versus 62%) responses both predicted large differences in 6-month NRM with similar AUCs (observational; 0.65 versus 0.69, P = .171; interventional: 0.68 versus 0.71, P = .581). Subset analyses demonstrated similar AUCs for both D7 and D28 in children with Minnesota high risk GVHD and in patients with severe GI GVHD (stage 2-4). Notably, second line therapy was deferred for 70% of high-risk patients without a response at D7. The "wait and see" approach was common even after the approval of ruxolitinib for steroid-resistant GVHD, and their 6-month NRM was ∼50%. CONCLUSION: These findings support the use of D7 response as an actionable assessment timepoint in high risk acute GVHD and highlight the need for severity-adapted response criteria in both clinical practice and trial design.