title: Phase I/II Trial of Dose-Escalated Busulfan Delivered by Prolonged Continuous Infusion in Allogeneic Transplant Patients.
abstract: Intensive chemotherapy or chemotherapy plus irradiation and allogeneic stem cell transplantation can be curative for patients with hematologic diseases. Reduced-intensity transplants can also achieve cure and result in less treatment-related mortality but higher relapse rates. Thus, optimizing the conditioning regimens used in allogeneic transplantation remains an important goal. We conducted a phase I/II trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a continuous infusion of busulfan over 90 hours in conjunction with fludarabine followed by allogeneic related or unrelated donor transplant. Fifty-four patients with advanced hematologic malignancies were enrolled on this study. The MTD was identified as a 24-hour area under the curve (AUC) of approximately 7095 μM/min, which represents a 43% increase over the standard total daily AUC dose of 4800 μM/min given by intermittent schedules. DLTs at doses over 8000 μM/min were identified by a desquamative skin rash and mucositis. No dose-related increase in hepatic, pulmonary, or other organ toxicities were seen, whereas efficacy appeared to be improved at higher dose levels. Continuous-infusion busulfan with intermittent fludarabine provides an alternative treatment strategy that is generally well tolerated and permits an increase in total busulfan dose with encouraging efficacy. (NCI study no. NCT00448357.).
authors.affiliation: Program in Bone Marrow and Stem Cell Transplantation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina. Electronic address: sheat@med.unc.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Shea
authors.affiliation: DeBartolo Family Personalized Medicine Institute, Division of Population Science, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Christine
authors.initials: C
authors.lastname: Walko
authors.affiliation: Department of Biostatistics, University of North Carolina School of Public Health, Chapel Hill, North Carolina.
authors.forename: Yunro
authors.initials: Y
authors.lastname: Chung
authors.affiliation: University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina; Department of Biostatistics, University of North Carolina School of Public Health, Chapel Hill, North Carolina.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ivanova
authors.affiliation: Program in Bone Marrow and Stem Cell Transplantation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Julia
authors.initials: J
authors.lastname: Sheets
authors.affiliation: Program in Bone Marrow and Stem Cell Transplantation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Kamakshi
authors.initials: K
authors.lastname: Rao
authors.affiliation: Program in Bone Marrow and Stem Cell Transplantation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
authors.forename: Don
authors.initials: D
authors.lastname: Gabriel
authors.affiliation: Stem Cell Transplant Program, St. John's Regional Hospital, New Brunswick, Canada.
authors.forename: Terry
authors.initials: T
authors.lastname: Comeau
authors.affiliation: Program in Bone Marrow and Stem Cell Transplantation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
authors.forename: William
authors.initials: W
authors.lastname: Wood
authors.affiliation: Program in Bone Marrow and Stem Cell Transplantation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
authors.forename: James
authors.initials: J
authors.lastname: Coghill
authors.affiliation: Program in Bone Marrow and Stem Cell Transplantation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
authors.forename: Paul
authors.initials: P
authors.lastname: Armistead
authors.affiliation: Division of Cellular Therapy, Duke University, Durham, North Carolina.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sarantopoulos
authors.affiliation: Program in Bone Marrow and Stem Cell Transplantation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Serody
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002066:Busulfan / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011446:Prospective Studies; D012008:Recurrence; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D019653:Myeloablative Agonists; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine
keywords: Allogeneic; Busulfan; Dose escalation; Pharmacokinetics