A Phase I–II clinical trial of high dose single agent busulfan (16–20 mg/kg) administered over a 4-day period was undertaken. Pharmacokinetic measurements reveal that steady state total plasma busulfan levels between 2 and 10 µm were achieved by the second day and maintained through the remaining treatment period. Urinary excretion of mutagenic activity monitored by the Salmonella mutagenesis assay persisted for up to 48 h following the last dose of busulfan. The treatment showed specificity for myelocytic precursors as evidenced by selective depression of granulocytes with relative sparing of lymphocytic elements, and by differences in DNA damage as measured by a nucleoid sedimentation assay. Dose limiting toxicity was mucositis, anorexia, and hepatic toxicity. Transient autoimmune disorders were observed in three of the six patients. Partial responses were seen in two of five patients with melanoma, but these lasted for only 2 and 3 months. High dose busulfan represents an alkylating agent with marked myelocytic selectivity and may be useful for inclusion in intensive combination regimens.

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