Sirolimus and tacrolimus without methotrexate as graft-vs.-host disease prophylaxis after matched, related peripheral blood stem cell transplantation: low transplant related morbidity and excellent GVHD control

Abstract

Sirolimus (Rapamycin, Rap) is a novel immunosuppressant similar to tacrolimus (Tac), however, Rap inhibits T cell function via FKBP12/mTOR and may also inhibit dendritic cell function. Rap is synergistic with Tac and has no overlapping toxicity, allowing their use in combination. We have shown that Rap, Tac and low-dose methotrexate (Mtx) is effective GVHD prophylaxis after URD transplantation. Since Mtx is associated with transplant toxicity and since MRD GVHD rates are lower than URD rates, we hypothesized that Rap and Tac, without Mtx, would provide effective GVHD prophylaxis after MRD PBSCT while minimizing transplant-related morbidity and mortality (TRM). Methods: 30 subjects underwent PBSCT from 6/6 HLA-matched siblings(29) or parents(1) after Cy/TBI conditioning. GVHD prophylaxis consisted of Rap (serum level 3–12 ng/ml) and Tac (serum level 5–10 ng/ml). Filgrastim (5 μg/kg) was administered from d+12 until engraftment if needed. Results: The median age of subjects was 42 years (range 19–54). Diagnoses were AML(8), MDS(7), CML(7), NHL(6), ALL(1) and ATLL(1). The median times to neutrophil engraftment (>500/μl) and platelet engraftment (>20,000/μl and >100,000/μl) were 14 (range 11–17), 13 (range 10–47), and 19 (range 11–189) days respectively. All patients survived to discharge, at a median of 18 days from day 0 (range 15–54). Gr. II GVHD occurred in 3 patients (10%), involved the skin (3) and gut (1), and resolved with corticosteroids. No patient developed Gr. III-IV GVHD or idiopathic pneumonia syndrome. 4 patients developed thrombotic microangiopathy, but recovered normal renal function when Tac was held. VOD occurred in 3 patients. 1 patient had CMV reactivation and none had invasive fungal infections. Oral mucositis was mild and as a result, 47% of patients required no TPN. The median number of days of TPN use was 6. 9/28 evaluable patients developed chronic GVHD (3 extensive, 6 limited). 6 patients with advanced malignancies relapsed. 22/30 patients remain alive in complete remission. Causes of death include relapse(6), VOD(1) and late pulmonary toxicity(1). The median follow-up is 253 days (range 34–466). Relapse-free and overall survival at day 100 are 93 and 97%, and at 1 year are 70 and 66%. Conclusions: Rap and Tac without Mtx is effective for GVHD prophylaxis after MRD PBSCT. Due to Mtx omission, mucositis was reduced, engraftment was prompt and TRM was reduced. This combination is worthy of broader study in allogeneic transplantation.