A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients

Jeannine S. McCune, Erica L. Woodahl, Terry Furlong, Barry Storer, Joanne Wang, Shelly Heimfeld, H. Joachim Deeg, Paul V. O'Donnell

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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/ Tbusulfan). 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/ Tbusulfan/rATG conditioning regimen.

Original languageEnglish
Pages (from-to)263-272
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume69
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • Biomarkers
  • Busulfan
  • Fludarabine
  • Hematopoietic cell transplant
  • Pharmacokinetics
  • Therapeutic drug monitoring

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