Busulfex (i.v. BU) and CY regimen before SCT: a phase II pharmacokinetics combined study

Background: Although i.v. BU has been recently introduced into clinical use worldwide, drug profiles of i.v. BU preparation have not been fully evaluated in different races, who may have different PK. As part of our pivotal study in Japan, we conducted a phase II study with PK analysis of a combined i.v. BU and CY regimen administered before allo- or auto-SCT. Patients and Methods: Patients with hematological malignancies were eligible for this study (age, 5 to 55 years). The efficacy variables were engraftment, relapse, OS and DFS. The safety variables were NRM and adverse events including seizure, VOD, GVHD. The conditioning regimen consisted of i.v. BU (at 0.8 mg/kg for 2 h every 6 h at a total of 16 doses, days -7 to -4) and CY (at 60 mg/kg for 3 h at a total of 2 doses, days -3 and -2). Seizure prophylaxis was phenytoin from day -9. For allo-SCT patients, GVHD prophylaxis consisted of CYA and short-term MTX. Multiple PK samples were taken on 1st and 9th doses. BU levels were determined by a gas chromatographic-mass spectrometric detection method. PK modeling was performed using WinNonlin. Results: Thirty patients (28 HLA-matched allo-SCT, 2 auto-SCT; median age, 30 years) were enrolled between 7/2002 and 10/2003. The diseases were 13 AML (11CR), 5 ALL (4CR), 5 CML-CP, 4 NHL (3CR) and 3 MDS. There were no significant toxicities, and all but one patient showed evidence of neutrophil engraftment at a median of 14 days for allo-SCT and 11 days for auto-SCT. Grade II-IV acute and chronic GVHD occurred in 9 (33%) and 16 patients (59%), respectively. Four patients (15%) died of non-relapse causes: MOF, chronic GVHD, hepatic failure and viral pneumonia. The relapse rate at 1-year was 26%, and 4 patients (15%) died of relapse. OS and DFS at 1-year in allo-SCT was 78% and 63%, respectively (median follow-up: 413 days). The 2 auto-SCT patients were alive disease-free at 1-year. The PK of i.v. BU showed close inter- and intrapatient consistency. The mean AUC for dose 1 and dose 9 was 1171 micromol min/L and 1242 micromol min/L, and the mean Cmax was 994 ng/mL and 1311 ng/mL, respectively. The AUC of the 1st dose was below 1500 micromol min/L in 27 patients (90%), and this was within the range of 900 to 1350 micromol min/L in 21 patients (72%). Conclusions: Since all of the profiles overlap with non-Japanese data, we conclude that racial factors may not seriously influence the bioactivity of i.v. BU and a combined i.v. BU and CY regimen may be practically useful.