High-dose therapy and bone marrow transplantation.
Toxicity to the bone marrow is a frequent limiting factor in the use of high doses of chemotherapeutic agents. Bone marrow transplantation overcomes the marrow toxicity problem, but it is not protective to other organs. Extensive animal studies have been carried out in the mouse, the rat, rhesus monkeys, and dogs to delineate the dose-limiting toxicity of cyclophosphamide (Cytoxan) (CY) therapy. Studies in the dog have shown 100 mg/kg of CY to be lethal with supportive care alone. Dogs given this dose followed by stored autologous marrow recovered after a period of profound pancytopenia and severe gastrointestinal toxicity. This dose of CY also permitted allogeneic engraftment in the dog. Monkeys given up to 200 mg/kg of CY have uneventful hematopoietic recovery, but doses of 240 mg/kg were generally fatal even when stored autologous marrow was infused. Cardiac toxicity was the limiting factor. CY 180 mg/kg was not lethal and permitted successful allogeneic marrow engraftment. CY is successfully used for conditioning leukemia or aplastic anemia patients for bone marrow transplantation. Patients with severe aplastic anemia are conditioned with CY 50 mg/kg on each of four days followed by allogeneic marrow transplantation. Patients undergoing transplantation before transfusion have a long-term survival rate of about 80%. Patients with genetic disorders of the marrow generally have a normocellular or hypercellular marrow, and the preparative regimen must include destruction of the abnormal marrow as well as immunosuppression sufficient to permit engraftment. Patients with thalassemia are treated with dimethylbusulfan 5 mg/kg or busulfan 14 mg/kg followed by CY 50 mg/kg on each of four days. Approximately 100 thalassemia patients have been treated, with a survival rate of approximately 75%. For patients with leukemia, radiotherapy is generally added to the CY conditioning regimen. In the early Seattle studies, 1,000 rad total body irradiation was combined with CY 60 mg/kg on each of two days. There were many early deaths, but some long-term survivors are alive and well 5 to 13 years later. Current regimens involve fractionated total body irradiation and various post-grafting immunosuppressive regimens designed to prevent graft-v-host disease. Complications and problems of current regimens are discussed, and future goals for marrow transplantation are presented.
D000741:Anemia, Aplastic / Q000628:therapy; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide / Q000633:toxicity*; D004285:Dogs; D006801:Humans; D007938:Leukemia / Q000628:therapy; D014916:Whole-Body Irradiation
D003520:Cyclophosphamide