Sirolimus Vs. Prednisone As Initial Systemic Therapy for Minnesota Standard Risk (MN-SR), Ann Arbor 1/2 Acute Graft-Vs-Host Disease (GVHD): Primary Results of the Multi-Center Randomized Phase II BMT CTN 1501 Trial

Clinical- and biomarker-based stratification tools may identify a lower risk acute GVHD population amenable to novel, reduced intensity treatments. Previous retrospective data suggest sirolimus, a steroid-free primary therapy, may rival standard of care prednisone. We performed a multi-center, open label, randomized phase II trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs. prednisone. A key secondary endpoint was the rate of day 28 CR/PR with prednisone dose ≤ 0.25mg/kg/day. Prednisone use after sirolimus was classified as failure (no response, NR) for the primary endpoint, but not for the key secondary endpoint. Eligible patients had Minnesota standard risk (MN-SR) acute GVHD. Patients with centrally assessed Ann Arbor (AA) 1 or 2 biomarker status were included in the primary analysis. Sirolimus was given as a loading dose, followed by maintenance to continue therapeutic levels through at least 56 days. Prednisone was initiated at 2mg/kg/day x 3 days, then tapered with protocol guidance to reach ≤ 0.25mg/kg/day by day 28 among responding patients. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus n = 58, prednisone n = 64). Others were AA3 (n = 4), or AA status missing (n = 1). Baseline acute GVHD organ involvement by treatment is shown in figure 1. The enrolled MN-SR population was comparable to that previously published, except greater upper GI only GVHD. The day 28 CR/PR rates were similar for sirolimus 64.8% (90% CI 53.8%-75.8%) vs. 73% (90% CI 63.6%-82.4%) for prednisone (figure 2); an estimated difference of -8.2% (90% CI -22.4%-6.0%). The day 28 rate of CR/PR with prednisone ≤ 0.25mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs. 33.3%, p < 0.001). At day 56, the CR/PR rate for sirolimus was 64.2% (95% CI 50.8%-77.5%) vs. 79.4% (95% CI 69.1%-89.6%) for prednisone (figure 2). There was no evidence of excess grade 3-5 adverse events, infections, or steroid-refractory acute GVHD in the sirolimus-treated subjects. Estimates of 6 month disease-free survival (figure 3), relapse, non-relapse mortality, and overall survival were not significantly different. Additional data (full clinical endpoints, steroid myopathy assessment, and patient-reported outcomes) will be presented at the meeting. BMT CTN1501 represents the first multi-center randomized trial to examine clinical- and biomarker-based risk adapted therapy for acute GVHD. We have demonstrated that initial risk stratification including central biomarker assessment is feasible. Among the enrolled MN-SR AA1/2 subjects, sirolimus produced comparable day 28 CR/PR rates vs. 2mg/kg/day prednisone, improved the rate of day 28 CR/PR with prednisone ≤ 0.25mg/kg/day, and achieved similar 6 month disease-free survival. A future multicenter phase III non-inferiority study will be required to confirm these findings.