Maximally Tolerated Busulfan Systemic Exposure in Combination with Fludarabine as Conditioning before Allogeneic Hematopoietic Cell Transplantation

Department of Blood and Marrow Transplantation, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation (Impact Factor: 3.35). 12/2011; 18(7):1099-107. DOI: 10.1016/j.bbmt.2011.12.584
Source: PubMed

ABSTRACT Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 μM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ≥70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 μM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 μM-min (level 2) and 220 mg/m(2)/day for AUC 9,000 μM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 μM-min × 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 μM-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.

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