Work

Amifostine does not protect against liver toxicity in patients receiving dose-escalated IV busulfan (IVBU) and standard dose cyclophosphamide in auto BMT

Year: 2006

Type: article

Abstract: Eight adult patients undergoing autologous transplant for hematological malignancies were given a conditioning regimen of 4 daily single doses of IVBU followed 24 hours later by 2 days of cyclophosphamide (CP) at 60 mg/kg/day adjusted body weight. Amifostine 740 mg/m2 was given just prior to each dose of IVBU and CP in an attempt to ameliorate toxicities and allow for IVBU dose-escalation. Dose-escalation of IVBU was based on AUC and was done in phase I fashion. There were 4 planned cohorts, with a targeted average daily AUC range for cohort 1 of 4400–5280 uMol-minute per day (midpoint 4800). This represents the AUC range commonly achieved by single daily doses of 3.2mg/kg/day. Each successive cohort of patients was to receive a dose of IVBU that would result in an AUC that was 20% greater than the previous group. Patients were given a test dose of 0.4 mg/kg of IVBU over 15 minutes between 7 and 21 days prior to conditioning. Pharmacokinetics (PK) performed around the test dose were used to base the first 2 conditioning doses of IVBU. Additional IVBU PK data was collected around conditioning doses 1and 3. If the targeted AUC range was not achieved based on the IVBU PK data for dose 1, IVBU doses were adjusted for days 3 and 4. Acetaminophen and metronidazole were held during all IVBU administration. Fungal prophylaxis was the same during IVBU test and conditioning doses. Patients received phenytoin for seizure prophylaxis. Five patients were enrolled in cohort 1. Three patients achieved the desired AUC for this cohort. The other 2 exceeded the target with AUCs that were within cohort 2 range. Despite this, there was no VOD and only grade 0 to 1 mucositis or diarrhea in this group. Three patients were enrolled in cohort 2 and met the targeted average daily AUC range of 5281–6340 uMol-minute per day (midpoint 5800) for that range. Two of 3 patients in cohort 2 developed late onset VOD (days +25, +22) and the protocol was closed. One of these patients died from complications of VOD. In cohort 2, there was 1 patient with grade 2 mucositis. Grade 0 to 1 mucositis and diarrhea was observed in the other patients. Amifostine appears to ameliorate mucositis and diarrhea in patients receiving standard doses of IVBU and CP in autologous BMT but does not protect against VOD in patients receiving dose-escalated IVBU at least when combined with CP.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2005.11.296