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

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.