title: Everolimus in combination with mycophenolate mofetil as pre- and post-transplantation immunosuppression after nonmyeloablative hematopoietic stem cell transplantation in canine littermates.
abstract: 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 2 Gy total body irradiation, 8 dogs received HSCT from dog leukocyte antigen-identical siblings. Immunosuppressives were given at doses of 1.5 mg RAD001 twice daily from day -1 to +49, then tapered until day +56, and 20 mg/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 × 10(9)/L (median, day +10; duration <50 × 10(9)/L, 22 days) and median leukocyte nadir was 1.0 × 10(9)/L (range, .1 to 2.5 × 10(9)/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.
authors.affiliation: Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Machka
authors.affiliation: Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lange
authors.affiliation: Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Werner
authors.affiliation: Institute of Clinical Pharmacology, University of Rostock, Rostock, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Wacke
authors.affiliation: Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Killian
authors.affiliation: Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Knueppel
authors.affiliation: Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Knuebel
authors.affiliation: Clinic for Radiotherapy, University of Rostock, Rostock, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Institute of Legal Medicine, University of Rostock, Rostock, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Lindner
authors.affiliation: Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.
authors.forename: Catrin
authors.initials: C
authors.lastname: Roolf
authors.affiliation: Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.
authors.forename: Hugo
authors.initials: H
authors.lastname: Murua Escobar
authors.affiliation: Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany. Electronic address: christian.junghanss@med.uni-rostock.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Junghanss
mesh_terms: D000818:Animals; D046528:Chimerism; D003131:Combined Modality Therapy / Q000379:methods*; D004285:Dogs; D000068338:Everolimus; D018380:Hematopoietic Stem Cell Transplantation; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus
keywords: Allogeneic hematopoietic stem cell transplantation; Dogs; Everolimus; Nonmyeloablative conditioning; Pharmacokinetics