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Everolimus in combination with mycophenolate mofetil as pre- and post-transplantation immunosuppression after nonmyeloablative hematopoietic stem cell transplantation in canine littermates.
Biol Blood Marrow Transplant 2014; 20(9):1301-6BB

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+Show Affiliations

Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.Institute of Clinical Pharmacology, University of Rostock, Rostock, Germany.Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.Clinic for Radiotherapy, University of Rostock, Rostock, Germany.Institute of Legal Medicine, University of Rostock, Rostock, Germany.Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany.Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany. Electronic address: christian.junghanss@med.uni-rostock.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24923538

Citation

Machka, Christoph, et al. "Everolimus in Combination With Mycophenolate Mofetil as Pre- and Post-transplantation Immunosuppression After Nonmyeloablative Hematopoietic Stem Cell Transplantation in Canine Littermates." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 20, no. 9, 2014, pp. 1301-6.
Machka C, Lange S, Werner J, et al. Everolimus in combination with mycophenolate mofetil as pre- and post-transplantation immunosuppression after nonmyeloablative hematopoietic stem cell transplantation in canine littermates. Biol Blood Marrow Transplant. 2014;20(9):1301-6.
Machka, C., Lange, S., Werner, J., Wacke, R., Killian, D., Knueppel, A., ... Junghanss, C. (2014). Everolimus in combination with mycophenolate mofetil as pre- and post-transplantation immunosuppression after nonmyeloablative hematopoietic stem cell transplantation in canine littermates. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 20(9), pp. 1301-6. doi:10.1016/j.bbmt.2014.06.004.
Machka C, et al. Everolimus in Combination With Mycophenolate Mofetil as Pre- and Post-transplantation Immunosuppression After Nonmyeloablative Hematopoietic Stem Cell Transplantation in Canine Littermates. Biol Blood Marrow Transplant. 2014;20(9):1301-6. PubMed PMID: 24923538.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Everolimus in combination with mycophenolate mofetil as pre- and post-transplantation immunosuppression after nonmyeloablative hematopoietic stem cell transplantation in canine littermates. AU - Machka,Christoph, AU - Lange,Sandra, AU - Werner,Juliane, AU - Wacke,Rainer, AU - Killian,Doreen, AU - Knueppel,Anne, AU - Knuebel,Gudrun, AU - Vogel,Heike, AU - Lindner,Iris, AU - Roolf,Catrin, AU - Murua Escobar,Hugo, AU - Junghanss,Christian, Y1 - 2014/06/09/ PY - 2014/02/28/received PY - 2014/06/02/accepted PY - 2014/6/14/entrez PY - 2014/6/14/pubmed PY - 2015/4/18/medline KW - Allogeneic hematopoietic stem cell transplantation KW - Dogs KW - Everolimus KW - Nonmyeloablative conditioning KW - Pharmacokinetics SP - 1301 EP - 6 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol. Blood Marrow Transplant. VL - 20 IS - 9 N2 - 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. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/24923538/Everolimus_in_combination_with_mycophenolate_mofetil_as_pre__and_post_transplantation_immunosuppression_after_nonmyeloablative_hematopoietic_stem_cell_transplantation_in_canine_littermates_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(14)00351-6 DB - PRIME DP - Unbound Medicine ER -