Maximally Tolerated Busulfan Area Under the Concentration-Time Curve (AUC) In Combination with Fludarabine as Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.

Abstract 3499

Intravenous busulfan (IV Bu) dosing in hematopoietic cell transplantation (HCT) conditioning regimens has been based largely on bioequivalence studies done with the oral dosage form. As systemic exposure to Bu has been correlated to both efficacy and toxicity, we used area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to IV Bu when given daily in combination with fludarabine as HCT conditioning. Three AUC levels were planned: 6000, 7500, and 9000 micromole*min/L, in cohorts of 20 patients (pts) each, with an additional 10 pts to be enrolled at the maximally tolerated AUC. To be included, pts had be 16–65 years old and have a hematologic malignancy, an HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor, Karnofsky performance status 70–100%, and adequate organ function. The initial dose of IV Bu for the first AUC level was 170mg/m²/day on day -6 and day -5 then, on day -4 and day -3 doses were adjusted based on pharmacokinetic modeling after the first dose to achieve an average daily AUC of 6000. First doses for the subsequent cohorts were based on the linear correlation between AUC and dose in the previous cohort: 180mg/m²/day for AUC 7500 and 220mg/m²/day for AUC 9000, with dose adjustment on days -4 and -3 as described. Pharmacokinetic analysis was done after the day -3 dose to verify the accuracy of the dose adjustments. The first 20 pts in the AUC 6000 cohort (DL1) were coenrolled onto a randomized trial of GVHD prophylaxis (tacrolimus and methotrexate vs tacrolimus and mycophenolate mofetil) and were analyzed separately from a second cohort of 20 pts receiving an AUC 6000 (DL1A) and GVHD prophylaxis with tacrolimus and methotrexate. 20 pts were then enrolled onto AUC 7500 (DL2), followed by 3 pts on AUC 9000 (DL3). All DL3 pts had dose limiting toxicity so accrual to that level was stopped. An additional 9 pts have been treated to date on DL2 (5 of these are <100 days posttransplant and are not evaluable for toxicity or GVHD). The median (and range) average daily AUC for each of the cohorts were: DL1 5955 (5375-6557); DL1A 6145 (4846-7018); DL2 7555 (5920-8682); DL3 8899 (8784-8955). There were no primary engraftment failures and median times to neutrophil engraftment were: DL1 15 days, DL1A 16 days, DL2 14 days, and DL3 12 days (p=0.01). The dose-limiting toxicity seen at DL3 was hepatic venoocclusive disease (VOD) which developed in all 3 pts; two of these pts died. There were no seizures attributable to IV Bu seen at any dose level. NCI CTCAE toxicities (observed in the first 100 days unrelated to infection or GVHD) that were significantly different between the dose level groups were dermatitis and VOD with more severe toxicity seen in DL2 and DL3. Diarrhea and the use of total parenteral nutrition appeared to be more common on DL2 and DL3 but not significantly so. The cumulative incidence of acute GVHD was similar across the cohorts (p=0.11). There was no difference between the dose levels in cumulative incidence of relapse (p=0.54) or event-free survival (p=0.4). Nonrelapse mortality at 6 months was significantly different: DL1 20%, DL1A 0%, DL2 17.5% and DL3 67% (p=0.008) as was overall survival at 6 months: DL1 75%, DL1A 90%, DL2 80%, DL3 33% (p=0.04). We conclude that in the pts studied, 7500 micromole*min/L is the maximally tolerated AUC based on protocol-defined criteria but exceeding an AUC of 6000 may not provide any survival benefit.