Sirolimus is a novel immunosuppressant similar to tacrolimus, however, sirolimus inhibits T cell function uniquely via FKBP12/mTOR and can impair dendritic cell function. Sirolimus acts synergistically with tacrolimus and has a non-overlapping toxicity profile, making their use in combination attractive. We began employing sirolimus as GVHD prophylaxis in 2000, and herein describe our experience with this compound in the myeloablative transplant setting.

Methods: Two clinical trials were performed using sirolimus (target serum level 3–12 ng/ml) and tacrolimus (target serum level 5–10 ng/ml) as primary GVHD prophylaxis. Cytoxan (1800 mg/m2/d x 2) and TBI (14 Gy, 7 fractions) was the conditioning regimen used in all patients. Trial 1 enrolled 76 patients who received HLA-matched, unrelated or 1-Ag mismatched related or unrelated bone marrow or peripheral blood stem cells. Abbreviated methotrexate (20 mg/m2 total) was routinely given post-transplant. Trial 2 enrolled 53 patients who received HLA-matched, related peripheral blood stem cells. No methotrexate was given post-transplant.

Results: The median times to neutrophil engraftment (>500/ml) after transplantation were 17 (range 11–32) and 14 (range 9–17) days for trials 1 and 2 respectively. The median times to platelet engraftment (>20,000/ml) after transplantation were 29 (range 11–98) and 12 (range 10–47) days for trials 1 and 2. Grade II–IV acute GVHD occurred in 35% and 19% of patients in the two trials. Grade III–IV acute GVHD occurred in 21% and 4% of patients in the two trials. The median time to first hospital discharge was 33 and 19 days from transplantation for trials 1 and 2. Seven patients in trial 1 (9%) and 3 patients in trial 2 (6%) did not survive to first hospital discharge. The non-actuarial incidence of chronic GVHD in the two trials was 49 and 44%, respectively. Treatment-related mortality at 100 days was 13% and 6% in the trials. At two years, the relapse-free and overall survival estimates for trial 1 are 46 and 48% (Median follow-up of survivors: 27 months). One year relapse-free and overall survival estimates for trial 2 are 71% and 75% (Median follow-up of survivors: 15 months). Overall survival at 2 years is 72%. Toxicity related to the addition of sirolimus was modest. Among all patients (n=129), VOD occurred in 16 patients (12%), idiopathic pneumonia syndrome occurred in 9 patients (7%) and thrombotic microangiopathy occurred in 13 patients (10%).

Conclusions: Sirolimus, when added to tacrolimus after allogeneic stem cell transplantation is effective for GVHD prophylaxis. Engraftment is prompt, the incidence and severity of acute GVHD are reduced and transplant-related morbidity and mortality is reduced, regardless of stem cell source and methotrexate use. Early survival estimates are excellent due to reduced GVHD and transplant-related toxicity. Sirolimus is worthy of broader study in allogeneic transplantation.

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