title: Phase I study of high-dose busulfan, melphalan and thiotepa with autologous stem cell support in patients with refractory malignancies.
abstract: The purpose of this study was to determine the maximal tolerated dose of thiotepa administered with busulfan 12 mg/kg and melphalan 100 mg/m2 followed by autologous stem cell transplantation in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose busulfan 12 mg/kg, melphalan 100 mg/m2 and escalating doses of thiotepa 450-550 mg/m2 followed by infusion of cryopreserved autologous peripheral blood stem cells (n = 26) or marrow (n = 2). The maximum tolerated dose was determined to be busulfan 12 mg/kg, melphalan 100 mg/m2 and thiotepa 500 mg/m2. Two of three patients receiving thiotepa 550 mg/m2 experienced grade 3 colitis. Twenty patients were enrolled at the maximum tolerated dose and the incidence of grade 3-4 regimen-related toxicity and mortality was 10% and 5%, respectively. Ninety-five per cent of patients experienced grade 1-2 mucositis, 50% grade 1-2 gastrointestinal toxicity, 35% grade I hepatic toxicity and 20% experienced grade 1-2 skin toxicity. The median time to achieve a granulocyte count of 0.5 x 10(9)/I was 10 days (range 8-20 days) and platelet transfusion independence was 10 days (range 1-26 days). Five of ten patients with stage 4 refractory breast cancer achieved a complete and two a partial remission with a complete response rate of 50% and a overall response rate of 70%. In conclusion, busulfan, melphalan and thiotepa can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy sensitive malignancies are warranted.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: C H
authors.initials: CH
authors.lastname: Weaver
authors.forename: W I
authors.initials: WI
authors.lastname: Bensinger
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: K
authors.initials: K
authors.lastname: Lilleby
authors.forename: B
authors.initials: B
authors.lastname: Sandmaier
authors.forename: M
authors.initials: M
authors.lastname: Brunvand
authors.forename: S
authors.initials: S
authors.lastname: Rowley
authors.forename: S
authors.initials: S
authors.lastname: Petersdorf
authors.forename: S
authors.initials: S
authors.lastname: Rivkin
authors.forename: T
authors.initials: T
authors.lastname: Gooley
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000628:therapy; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D004361:Drug Tolerance; D005260:Female; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000628:therapy*; D013852:Thiotepa / Q000008:administration & dosage / Q000009:adverse effects; D014182:Transplantation, Autologous
chemical_list: D013852:Thiotepa; D002066:Busulfan; D008558:Melphalan