High Busulfan Exposure Is Associated with Worse Outcome in a Daily IV Busulfan and Fludarabine Transplant Regimen.
Authors: Geddes Michelle , Kangarloo Shahbal B. , Naveed Farrukh , Diana Quinlan M. , Chaudhry Ahsan , Savoie Mary Lynn , Bahlis Nizar J. , Stewart Douglas A. , Brown Christopher , Storek Jan , Andersson Borje , Russell James A. 
Published: October 2019

Background: Intravenous busulfan formulation results in less variability in patient systemic busulfan exposure when compared to oral dosing using the plasma area under the time-concentration curve (AUC). With four times daily busulfan dosing in other regimens, low AUC is associated with relapsed leukemias and graft failure, and high AUC with toxicities. We investigated a convenient once daily IV busulfan dosing regimen, which allows complete drug clearance between doses, in combination with fludarabine as conditioning for allogeneic hematopoietic stem cell transplantation.

Purpose: To assess once daily IV busulfan together with fludarabine for interpatient variability in AUC and correlation between busulfan AUC and transplant toxicities and outcomes.

Methods: 130 patients with hematologic malignancies received IV busulfan (Busulfex, ESP Pharma) 3.2 mg/kg on days −5 to −2 and fludarabine 50 mg/m2 on days −6 to −2 prior to HCT in a myeloablative regimen. TBI 200 cGy × 2 was given to 51 patients with acute leukemias. Graft vs host disease (GVHD) prophylaxis comprised methotrexate, cyclosporine A, and Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over three days pretransplant. Busulfan concentrations were determined by UV-HPLC.

Results: Plasma AUC varied four-fold (range 2184–7794 μM.min, median 4822) with once daily IV Bu dosing. Previous studies have shown increased toxicity with four daily doses of Bu when AUC >1500μM.min/dose, therefore patients were analyzed in groups with once daily IV busulfan AUC greater than (n=16) and less than (n=114) 6000μM.min. Patient characteristics between groups were similar except for a higher rate of ABO incompatibility (p=0.02) in the group with AUC >6000μM.min. Estimated overall survival (OS) of the entire group was 70% at 12 months (95% CI 61–77%) and 62% at 36 months (95% CI 52–70%). Patients with an AUC >6000μM.min had worse overall survival than those with AUC <6000μM.min at 12 months (38% vs 74%) and 36 months (23% vs 68%, p=0.0002); this persisted after multivariate analysis adjusting for potential confounders including high risk vs standard risk disease (hazard ratio 2.1, CI 1.1–3.9), use of alternative vs matched related donors (HR 1.9, CI 1.0–3.4) and CMV positive status (HR 2.3, CI 1.1–4.7). The survival advantage in patients with AUC <6000μM.min was more apparent in standard risk patients (p=0.0001) than when AUC groups were compared in patients with high risk disease (p=0.05). Non-relapse mortality (NRM) and progression free survival (PFS) were worse in the group with AUC >6000μM.min (NRM 44% vs 14%, p=0.002; 3y PFS 16% vs 58%, p=0.0003). There was no difference in grade II-IV acute graft vs host disease (GVHD) or chronic GVHD, and no difference in specific toxicities other than a trend to less grade II-III stomatitis vs grade 0–1 stomatitis in the low AUC group (p=0.08).

Conclusion: Although daily IV busulfan dosing provides more predictable AUC than oral dosing, four-fold variability remains when it is used with fludarabine in this regimen. These data suggest AUC >6000μM.min is associated with poorer outcomes and support the role of therapeutic dose monitoring and dose adjustment.