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 a National Heart, Lung, and Blood Institute/National Cancer Institute-funded Blood and Marrow Transplant Clinical Trials Network multicenter, open-label, randomized phase 2 trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for
sirolimus vs
prednisone as initial treatment of patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA1/2)
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% confidence interval [CI], 54.1%-75.5%) vs 73% (90% CI, 63.8%-82.2%) for
prednisone. The day 28 rate of CR/PR with
prednisone ≤0.25 mg/kg/day was significantly higher for
sirolimus than
prednisone (66.7% vs 31.7%; P < .001). No differences were detected in
steroid-refractory acute GVHD, disease-free survival, relapse, nonrelapse mortality, or overall survival.
Sirolimus was associated with reduced
steroid exposure and
hyperglycemia, reduced grade 2 to 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 SR acute GVHD,
sirolimus demonstrates similar overall initial treatment efficacy as
prednisone. In addition,
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. This trial was registered at www.clinicaltrials.gov as #NCT02806947.