title: Fludarabine-Busulfan Reduced-Intensity Conditioning in Comparison with Fludarabine-Melphalan Is Associated with Increased Relapse Risk In Spite of Pharmacokinetic Dosing.
abstract: Fludarabine with busulfan (FB) and fludarabine with melphalan (FM) are commonly used reduced-intensity conditioning (RIC) regimens. Pharmacokinetic dosing of busulfan (Bu) is frequently done for myeloablative conditioning, but evidence for its use is limited in RIC transplants. We compared transplant outcomes of FB versus FM using i.v. Bu targeted to the area under the curve (AUC). A total of 134 RIC transplants (47 FB and 87 FM) for acute myelogenous leukemia and myelodysplastic syndrome were identified, and median follow-up of the cohort was 40 months (range, 0 to 63.3). A significantly higher 2-year cumulative incidence of relapse (CIR) was associated with FB versus FM at 35.6% versus 17.3%, respectively (P = .0058). Furthermore, 2-year progression-free survival rates were higher for FM versus FB at 60.5% versus 48.7%, respectively (P = .04). However, 2-year rates of nonrelapse mortality (NRM) and overall survival (OS) were similar. The need for dose adjustment based on AUC did not alter relapse risk or NRM. Patients with Karnofsky performance status ≥ 90 who received FM had a 2-year OS rate of 74.8% versus 48.3% for FB (P = .03). FB use remained prognostic for relapse in multivariable analysis (hazard ratio, 2.75; 95% confidence interval, 1.28 to 5.89; P = .0097). In summary, in spite of AUC-directed dosing, FB compared with FM was associated with a significantly higher CIR.
authors.affiliation: Division of Hematology & HSCT, Department of Oncology, King AbdulAziz Medical City, Riyadh, Saudi Arabia; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: moussab.damlaj@mail.mcgill.ca.
authors.forename: Moussab
authors.initials: M
authors.lastname: Damlaj
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Hassan B
authors.initials: HB
authors.lastname: Alkhateeb
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Hefazi
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Partain
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Shahrukh
authors.initials: S
authors.lastname: Hashmi
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Gastineau
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Aref
authors.initials: A
authors.lastname: Al-Kali
authors.affiliation: Department of Pharmacy Services, Mayo Clinic, Rochester, Minnesota.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wolf
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Naseema
authors.initials: N
authors.lastname: Gangat
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hogan
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mrinal M
authors.initials: MM
authors.lastname: Patnaik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D017567:Karnofsky Performance Status; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000628:therapy; D008297:Male; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009190:Myelodysplastic Syndromes / Q000401:mortality / Q000628:therapy; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods* / Q000401:mortality; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D019653:Myeloablative Agonists; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D008558:Melphalan
keywords: Area under the curve; Fludarabine-busulfan; Fludarabine-melphalan; Myeloablative conditioning; Reduced intensity conditioning