Key Points

  • Sirolimus provides similar day 28 complete/partial response rates as prednisone in initial therapy of standard risk acute GVHD

  • Sirolimus therapy was associated with reduced steroid exposure, greater immune suppression discontinuation, and improved quality of life

Clinical- and biomarker-based tools may identify a lower risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted an NHLBI/NCI-funded Blood and Marrow Transplant Clinical Trials Network (CTN) 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 as initial treatment for patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA 1/2) biomarker status. 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). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% CI 54.1%-75.5%) vs. 73% (90% CI 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone {less than or equal to} 0.25mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs. 31.7%, p < 0.001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, non-relapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2-3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based standard risk acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. Additionally, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life.

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