title: A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients.
abstract: OBJECTIVE
  Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin(®)) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/(T)busulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients.
  
  
  METHODS
  We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan, specifically busulfan concentration at steady state, and fludarabine, specifically F-ara-A area under the curve (AUC) and fludarabine triphosphate (F-ara-ATP) intracellular accumulation and concentration in separate CD4(+) and CD8(+) T-lymphocyte populations.
  
  
  RESULTS
  Acute and chronic graft versus host disease (GvHD) occurred in 11 patients and one patient, respectively. Four patients died before day +100 of non-relapse causes, which met the protocol stopping guidelines. The cumulative incidence of relapse was 25% at 3 year post-HCT. Interpatient variability in the busulfan- and fludarabine-relevant pharmacologic biomarkers was 2.1- to 2.5-fold. F-ara-A AUC and accumulated F-ara-ATP in CD8(+) cells had the highest hazard ratio for non-relapse mortality and overall survival, respectively. However, neither achieved statistical significance.
  
  
  CONCLUSIONS
  The low rates of GvHD, particularly in its chronic form, were encouraging, and further biomarker studies are warranted to optimize the fludarabine/(T)busulfan/rATG conditioning regimen.
authors: School of Pharmacy, University of Washington, Box 357630, Seattle, WA 98195-7630, USA. jmccune@u.washington.edu
authors: Jeannine S
authors: JS
authors: McCune
authors: Erica L
authors: EL
authors: Woodahl
authors: Terry
authors: T
authors: Furlong
authors: Barry
authors: B
authors: Storer
authors: Joanne
authors: J
authors: Wang
authors: Shelly
authors: S
authors: Heimfeld
authors: H Joachim
authors: HJ
authors: Deeg
authors: Paul V
authors: PV
authors: O'Donnell
mesh_terms: D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D002066:Busulfan / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000453:epidemiology; D019337:Hematologic Neoplasms / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016016:Proportional Hazards Models; D012008:Recurrence; D015996:Survival Rate; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000961:Antilymphocyte Serum; D054316:Biomarkers, Pharmacological; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; C512542:thymoglobulin; D002066:Busulfan