Performance of Treatment Response Assessment at Day 7 by Baseline Acute Graft-versus-Host Disease Severity

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.

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.

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.

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%.

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.