High-dose mitomycin-C with autologous bone marrow transplantation in patients with refractory malignancies. Influence of dose schedule on pharmacokinetics and nonhematopoietic toxicities

Thirteen courses of high-dose mitomycin-C with autologous bone marrow transplantation (ABMT) were administered to 12 patients. Four dose schedules were evaluated: A) 60 mg/M2 X 1, 60-min infusion; B) 30 mg/M2/day X 2, 15-min infusion; C) 30 mg/M2/day X 2, 60-min infusion; D) 15 mg/M2/day X 4, 60-min infusion. Pharmacokinetic studies using HPLC technique were done in nine patients. All patients have since died and autopsies were performed in nine patients. Two major nonhematopoietic toxicities were encountered and were dose-schedule dependent: hemorrhagic colitis (six of six courses in Schedules A and B; two of seven in Schedules C and D), and hepatic dysfunction (five of six in Schedules A and B; two of seven in Schedules C and D). Histopathologic evidence of venocclusive disease of the liver was present in four of five autopsies in Schedules A and B, and two of four in Schedules C and D. One patient died as a result of liver failure associated with submassive hepatic necrosis. Saturation kinetics described by other investigators cannot be confirmed by our pharmacokinetic analyses in nine patients. Severe nonhematopoietic toxicities of mitomycin-C were found at three times the conventional dose; thus, this drug is assessed as not being clinically useful as a single agent in ABMT.