title: Pharmacokinetic-directed high-dose busulfan combined with cyclophosphamide and etoposide results in predictable drug levels and durable long-term survival in lymphoma patients undergoing autologous stem cell transplantation.
abstract: The clinical advantage of pharmacokinetic (PK)-directed-based dosing on intravenous (i.v.) versus oral busulfan-related toxicity and survival remains unclear. We performed a retrospective cohort study of sequential cohorts of patients comparing PK-directed oral and i.v. busulfan-based conditioning regimens in lymphoma patients undergoing autologous hematopoietic cell transplantation (ASCT). Patients received oral (n = 95), every 6 hours i.v. (IV16, n = 113), or once-daily i.v. (IV4, n = 86) busulfan, cyclophosphamide, and etoposide. PK-directed dosing was performed to achieve a predefined target area under the curve (AUC) of 20,000 μM-min (range: 18,400-21,600 μM-min). PK-directed dose adjustments markedly reduced the number of patients in the oral group with total AUC higher than the targeted AUC range, and reduced the variations of total AUC values in all patient groups. One hundred-day mortality was 2.1%, 3.6%, and 3.5% for oral, IV16, and IV4 cohorts, respectively. Five-year overall survival (OS) was 57% (95% confidence interval [CI] 45%-66%) and 64% (95% CI 53%-73%) for patients who received oral and i.v. busulfan, respectively. Both multivariable and instrumental variable analyses indicated the route of delivery had no significant impact on OS, whereas refractory disease and age ≥55 were significantly associated with poorer OS. In lymphoma patients undergoing ASCT, PK-directed i.v. or oral busulfan-based conditioning regimens have comparable toxicity and OS.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365B Clifton Road NE, Atlanta,GA 30322, USA.
authors.forename: Hongzheng
authors.initials: H
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Graiser
authors.forename: Donald A
authors.initials: DA
authors.lastname: Hutcherson
authors.forename: M Olufemi
authors.initials: MO
authors.lastname: Dada
authors.forename: Stephanie
authors.initials: S
authors.lastname: McMillan
authors.forename: Zahir
authors.initials: Z
authors.lastname: Ali
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Flowers
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage; D004333:Drug Administration Routes; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous
chemical_list: D005047:Etoposide; D003520:Cyclophosphamide; D002066:Busulfan