title: A phase I study of targeted, dose-escalated intravenous busulfan in combination with etoposide as myeloablative therapy for autologous stem cell transplantation in acute myeloid leukemia.
abstract: BACKGROUND
  Busulfan and etoposide have been used as myeloablative therapy for autologous hematopoietic stem cell transplantation (HSCT) in adults with acute myeloid leukemia (AML) for > 20 years. The use of targeted intravenous (I.V.) busulfan has significantly improved the tolerability and efficacy of this regimen. We designed a dose-escalation study to examine the maximum tolerated dose (MTD) of targeted I.V. busulfan with bolus etoposide as preparative therapy for autologous HSCT in AML.
  
  
  METHODS
  In this single-center, phase I study, adult AML patients received I.V. busulfan targeted to either an area under the curve (AUC) of 1250 (cohort 1) or 1400 (cohort 2) μmol/min over 16 doses. Dose adjustments based on plasma pharmacokinetics occurred before doses 2 and 11. Etoposide 60 mg/kg I.V. was administered 24 hours after the last busulfan dose and 3 days before stem cell infusion.
  
  
  RESULTS
  Twelve patients with intermediate-risk AML in first complete remission were treated. All patients in cohort 1 and 5 patients (83%) in cohort 2 were within 10% of the target AUC. The MTD was not reached, although Grade ≥ 3 mucositis occurred in 3 patients (50%) in cohort 1 and in 4 patients (66%) in cohort 2, limiting further dose escalation. Two-year relapse-free survival was 33% in cohort 1 versus 67% in cohort 2 (P = .08).
  
  
  CONCLUSIONS
  Etoposide and targeted, dose-escalated I.V. busulfan as myeloablative therapy for autologous HSCT in AML is safe, with mucositis being the most significant toxicity. A phase II study is warranted to further evaluate the activity and safety of busulfan targeted to AUC 1400 μmol/min.
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Mannis
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Andreadis
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Logan
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Lloyd E
authors.initials: LE
authors.lastname: Damon
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA.
authors.forename: Leslie Z
authors.initials: LZ
authors.lastname: Benet
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Weiyun Z
authors.initials: WZ
authors.lastname: Ai
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Karin M L
authors.initials: KM
authors.lastname: Gaensler
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Kaplan
authors.affiliation: Department of Clinical Pharmacy, University of California, San Francisco, CA.
authors.forename: Yelena B
authors.initials: YB
authors.lastname: Koplowicz
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Linker
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Olin
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sayre
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Smith
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Akshay
authors.initials: A
authors.lastname: Sudhindra
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Venstrom
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wolf
authors.affiliation: Department of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA. Electronic address: tmartin@medicine.ucsf.edu.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Martin
mesh_terms: D000283:Administration, Intravesical; D000328:Adult; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D005047:Etoposide / Q000008:administration & dosage*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012008:Recurrence; D019172:Transplantation Conditioning / Q000379:methods*; D014182:Transplantation, Autologous; D055815:Young Adult
chemical_list: D019653:Myeloablative Agonists; D005047:Etoposide; D002066:Busulfan
keywords: Acute Myelogenous Leukemia; Autologous transplant; High-dose chemotherapy; Pharmacokinetics; Phase I Clinical Trial