Everolimus in combination with mycophenolate mofetil aspre- and post-transplantation immunosuppression after nonmyeloablative hematopoietic stem cell transplantation in canine littermates

摘要

The mammalian target of rapamycin inhibitor everolimus (RAD001) is a successfully used immunosuppressant in solid-organ transplantation. Several studies have already used RAD001 in combination with calcineurin inhibitors after hematopoietic stem cell transplantation (HSCT). We investigated calcineurin inhibitor-free pre- and post-transplantation immunosuppression of RAD001 combined with mycophenolate mofetil (MMF) in a nonmyeloablative HSCT setting. After nonmyeloablative conditioning with 2Gy total body irradiation, 8 dogs received HSCT from dog leukocyte antigen-identical siblings. Immunosuppressives were given at doses of 1.5mg RAD001 twice daily from day-1 to+49, then tapered until day+56, and 20mg/kg MMF from day 0 to+28, then tapered until day+42. An historical cyclosporin A (CsA)/MMF regimen was used in the control group. All dogs engrafted. Median platelet nadir amounted in all dogs to 0×109/L (median, day+10; duration 50×109/L, 22days) and median leukocyte nadir was 1.0×109/L (range, .1 to 2.5×109/L; median, day+13). Eventually, 5 of 8 (63%) animals rejected their grafts. Two dogs died of infections on day+19 and+25. Pharmacokinetics of RAD001 and MMF showed median trough levels of 19.1 (range, 10.5 to 43.2) μg/L and .3 (1 to 1.3) mg/L, respectively. The median area under the curve was 325 (range, 178 to 593) μg/L×hour for RAD001 and 29.6 (range, 7.9 to 40.5) ng/L×hour for MMF. All dogs developed clinically mucosal viral infections during the clinical course. Compared with the control group, the level of toxicities for RAD001/MMF increased in all qualities. Combined immunosuppression of RAD001 and MMF after nonmyeloablative HSCT is associated with significant toxicities, including a prolonged platelet recovery time as well as increased infections compared to the CsA/MMF regimen.