title: Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS.
abstract: Postulating favorable antileukemic effect with improved safety, we used intravenous busulfan and fludarabine as conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Fludarabine 40 mg/m2 and intravenous busulfan 130 mg/m2 were given once daily for 4 days, with tacrolimus-methotrexate as graft-versus-host disease (GVHD) prophylaxis. We treated 74 patients with AML and 22 patients with MDS; patients had a median age of 45 years (range, 19-66 years). Only 20% of the patients were in first complete remission (CR) at transplantation. Donors were HLA-compatible related (n = 60) or matched unrelated (n = 36). The CR rate for 54 patients with active disease was 85%. At a median follow-up of 12 months, 1-year regimen-related and treatment-related mortalities were 1% and 3%, respectively. Two patients had reversible hepatic veno-occlusive disease. Actuarial 1-year overall survival (OS) and event-free survival (EFS) were 65% and 52% for all patients, and 81% and 75% for patients receiving transplants in CR. Recipient age and donor type did not influence OS or EFS. Median busulfan clearance was 109 mL/min/m2 and median daily area-under-the-plasma-concentration-versus-time-curve was 4871 micromol-min, with negligible interdose variability in pharmacokinetic parameters. The results suggest that intravenous busulfan-fludarabine is an efficacious, reduced-toxicity, myeloablative-conditioning regimen for patients with AML or MDS undergoing HSCT.
authors.affiliation: Department of Blood and Marrow Transplantation, MD Anderson Cancer Center, Houston, TX 77030, USA. mdelima@mdanderson.org
authors.forename: Marcos
authors.initials: M
authors.lastname: de Lima
authors.forename: Daniel
authors.initials: D
authors.lastname: Couriel
authors.forename: Peter F
authors.initials: PF
authors.lastname: Thall
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Timothy
authors.initials: T
authors.lastname: Madden
authors.forename: Roy
authors.initials: R
authors.lastname: Jones
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Munir
authors.initials: M
authors.lastname: Shahjahan
authors.forename: Betty
authors.initials: B
authors.lastname: Pierre
authors.forename: Sergio
authors.initials: S
authors.lastname: Giralt
authors.forename: Martin
authors.initials: M
authors.lastname: Korbling
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.forename: Borje S
authors.initials: BS
authors.lastname: Andersson
mesh_terms: D000328:Adult; D000368:Aged; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007275:Injections, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000401:mortality / Q000628:therapy*; D018579:Patient Selection; D033581:Stem Cell Transplantation / Q000379:methods*; D016019:Survival Analysis; D013997:Time Factors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous / Q000276:immunology*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine