title: A phase I dose-escalation study of etoposide continuous infusion added to busulphan/cyclophosphamide as conditioning prior to autologous or allogeneic stem cell transplantation.
abstract: Relapse of the primary disease remains the predominant cause of death following bone marrow transplantation for high-risk haematological malignancies. Improved supportive care and patient selection have resulted significant improvements in toxicity with standard conditioning regimens. Further dose intensification to reduce the risk of relapse may therefore be feasible. We determined the maximal tolerated dose (MTD) of a 5-day continuous infusion (CI) of etoposide when added to oral busulphan 16 mg/kg and intravenous cyclophosphamide 120 mg/kg (Bu/Cy) as conditioning in 44 autograft and 18 allograft recipients at high risk of relapse. The major toxicity of escalating doses of etoposide was oral and gastro-intestinal mucositis, reflected by a statistically significant increase in the requirement for total parenteral nutrition in both autografts and allograft recipients. Time to neutrophil and platelet recovery, opiate analgesia requirements, and duration of hospitalization were not affected by etoposide dose escalation. The MTD in autograft recipients was 300 mg/m(2)/day (1500 mg/m(2) total dose), and 100 mg/m(2)/day (500 mg/m(2) total dose) for allograft recipients. Mucositis and hepatotoxicity were more frequent in allograft recipients, suggesting that methotrexate may have contributed to the lower tolerable dose in these patients. As a consequence, further dose escalation may not be possible in heavily pre-treated patients undergoing allogeneic transplantation. Conversely, high dose CI etoposide can be added with relative safety to Bu/Cy in autograft recipients.
authors.affiliation: Bone Marrow Transplant Service, Department of Clinical Haematology and Medical Oncology, Royal Melbourne Hospital, Parkville, Australia.
authors.forename: D S
authors.initials: DS
authors.lastname: Ritchie
authors.forename: J
authors.initials: J
authors.lastname: Szer
authors.forename: A W
authors.initials: AW
authors.lastname: Roberts
authors.forename: P
authors.initials: P
authors.lastname: Shuttleworth
authors.forename: A P
authors.initials: AP
authors.lastname: Grigg
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity*; D002066:Busulfan / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage* / Q000633:toxicity*; D005260:Female; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007938:Leukemia / Q000150:complications / Q000628:therapy; D008223:Lymphoma / Q000150:complications / Q000628:therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009092:Mucous Membrane / Q000473:pathology; D013280:Stomatitis / Q000139:chemically induced; D019172:Transplantation Conditioning / Q000379:methods*; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
chemical_list: D005047:Etoposide; D003520:Cyclophosphamide; D002066:Busulfan