title: Daily Weight-Based Busulfan with Cyclophosphamide and Etoposide Produces Comparable Outcomes to Four-Times-Daily Busulfan Dosing for Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.
abstract: High-dose busulfan (Bu) is an integral component of commonly used preparative regimens for both allogeneic and autologous transplantation. There is significant interest in comparing the efficacy and toxicity of administering Bu every 6 (Bu6) or every 24 hours (daily Bu). To facilitate a therapeutic dose-monitoring protocol, we transitioned from Bu6 to daily Bu dosing for patients with Hodgkin and non-Hodgkin lymphoma undergoing autologous stem cell transplantation (ASCT). Here, we retrospectively review outcomes of 400 consecutive eligible lymphoma patients who underwent ASCT from 2007 to 2013 with high-dose busulfan (Bu), cyclophosphamide (Cy), and etoposide (E). Bu was given at a fixed dose of either .8 mg/kg every 6 hours for 14 doses for 307 patients or a fixed dose of 2.8 mg/kg every 24 hours for 4 doses (days -9 through -6) for 93 patients who underwent transplantation after the transition from Bu6 to daily Bu was made. Toxicity was assessed using pulmonary and liver function tests (LFT) at specified time points before and after ASCT. Baseline patient and disease characteristics of patients dosed with Bu6 and daily Bu were similar. There was no significant difference in forced expiratory volume in 1 second or diffusing capacity of the lungs for carbon monoxide before and after transplantation in the Bu6 versus daily Bu cohorts. Changes in LFTs with daily Bu were not significantly different than those with Bu6. There were no differences in relapse, nonrelapse mortality, progression-free survival, or overall survival between Bu6 and Bu 24 administration schedules in univariable or multivariable analysis (P ≥ .34). For a subset of 23 patients who had first-dose Bu levels measured, we observed significant variation in an median estimated cumulative area under the curve (AUC) of 17,568 µM-minute (range, 12,104 µM-23,084 µM-minute). In conclusion, daily Bu with Cy/E is more convenient than Bu6, has equivalent outcomes, and results in no increase in either hepatic or pulmonary toxicity. Consistent with previous reports, there is a significant range of Bu AUC levels, with a standard deviation of 13%. These data provide rationale for our prospective clinical trial of real-time therapeutic dose monitoring of Bu.
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address: hillb2@ccf.org.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Hill
authors.affiliation: Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rybicki
authors.affiliation: Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Kelley D
authors.initials: KD
authors.lastname: Carlstrom
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Deepa
authors.initials: D
authors.lastname: Jagadeesh
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Aaron
authors.initials: A
authors.lastname: Gerds
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Betty
authors.initials: B
authors.lastname: Hamilton
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Hien
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Robert
authors.initials: R
authors.lastname: Dean
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Ronald
authors.initials: R
authors.lastname: Sobecks
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Brad
authors.initials: B
authors.lastname: Pohlman
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Steven
authors.initials: S
authors.lastname: Andresen
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Matt
authors.initials: M
authors.lastname: Kalaycio
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bolwell
authors.affiliation: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Navneet S
authors.initials: NS
authors.lastname: Majhail
mesh_terms: D000328:Adult; D000368:Aged; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D003520:Cyclophosphamide / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D006689:Hodgkin Disease / Q000150:complications / Q000188:drug therapy / Q000401:mortality; D006801:Humans; D008111:Liver Function Tests; D008223:Lymphoma / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D008228:Lymphoma, Non-Hodgkin / Q000150:complications / Q000188:drug therapy / Q000401:mortality; D008297:Male; D008875:Middle Aged; D012129:Respiratory Function Tests; D012189:Retrospective Studies; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005047:Etoposide; D003520:Cyclophosphamide; D002066:Busulfan
keywords: Autologous stem cell transplantation; Busulfan; Lymphoma