Once Daily IV Busulfan Given with Fludarabine in Allogeneic Stem Cell Transplantation Conditioning: High vs Low Busulfan AUC Does Not Alter Toxicities or Transplant Outcome.

Background: Busulfan (Bu), a bifunctional alkylating agent used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT), has unpredictable oral intestinal absorption. Subsequent marked variability in systemic drug exposure increases the risk of relapsed leukemia or graft failure in patients with a low area under the plasma concentration-time curve (AUC), and for toxicities with a high AUC. Purpose: To assess once daily intravenous (IV) busulfan for interpatient variability in AUC, transplant outcomes and toxicities in patients with high and low systemic busulfan exposures, and to evaluate therapeutic AUC. Methods: 68 patients ages 19–63 with hematologic malignancies received once daily IV Bu (Busulfex, ESP Pharma) between July 2000 and August 2004 at a myeloablative dose of 3.2 mg/m2 on days −5 to −2 and fludarabine 50mg/m2 on days −6 to −2 inclusive prior to HSCT. Additional TBI 200cGy x 2 was given to 24 patients with acute leukemia. Graft-vs-host disease (GVHD) prophylaxis for all pts comprised cyclosporine A, short course methotrexate with folinic acid and antithymocyte globulin in divided doses over 3 consecutive days pretransplant finishing day 0. Busulfan concentrations in plasma were determined by UV-HPLC. All concentration-time plasma Bu data were analyzed by non-compartmental analysis using WinNonlin Version 4.1 software (Pharsight Corporation, Mountain View, CA, USA). Results: The range of AUC was 2184 to 7513 μ M.min (med 4822 μ M.min). Patients were analyzed in 2 groups of 34 patients with exposures below (L) or above (H) the median AUC and followed for 12–61 months (med 26). Groups consisted of diverse malignancies with no difference in median age (L 46y, H 43y), number of unrelated or mismatched related donors (L 32%, H 38%), standard-risk leukemias (L 32%, H 29%), and TBI (L 41%, H 32%). Median days of engraftment for platelets >20 (19d) and neutrophils >0.5 (16d) were identical. There was no significant difference between the low or high AUC groups in 3y projected OS (L 69±8% vs H 67±8%), treatment-related mortality (TRM, L 16±7% vs H 21±7%), median months progression-free survival (L 17, H 19), venoocclusive disease (L 0%, H 6%), stomatitis ≥ grade II (L 82%, H 97%), hemmorhagic cystitis (L 15%, H 18%), acute GVHD grade III–IV (L 6%, H 18%), or grade II liver toxicity (L 12%, H 3%). Rate of relapse did not differ between groups (L 29%, H 24%). One patient in the high AUC group with subtherapeutic dilantin levels had a seizure. There was a trend to increased TRM with death in 3 of 8 patients (38%) with an AUC >6000 μ M.min, compared to 10 of 60 patients (17%) with AUC <6000 μ M.min (p=0.09). Conclusions: Although once daily IV Bu dosing provides a more predictable AUC than oral dosing, there remains 3–4 fold variability in systemic drug exposure. In this heterogeneous group of patients, differences in AUC within this range had little impact on survival, treatment related mortality or significant toxicities. This data suggests targeting AUC around 5000–6000 μ M.min with or without TBI is feasible and that although more data is required to assess the whether high exposures (>6000 μ M.min) increase risk, in general dosing without PK monitoring is safe.