In an attempt to further improve on the encouraging results achieved by high-dose cytosine arabinoside (HD AraC) and mitoxantrone (HAM) in refractory acute leukemias, a timely modified sequential schedule of both drugs was developed (S-HAM) and applied to 13 patients with far advanced acute leukemias, 8 of whom had been treated with the original HAM protocol before. Based on the cell kinetic and pharmacokinetic rationale outlined by Capizzi et al., HD AraC 3 g/m2 was applied every 12 h on days 1 and 2 followed by mitoxantrone 10 mg/m2/day on days 3 and 4. After 3 days without therapy the identical sequence was repeated on days 8 and 9 (HD AraC) and 10 and 11 (mitoxantrone), respectively. Of the 13 patients 9 (69%) achieved a complete remission, 2 were resistant and 2 were early deaths. Six of the 8 patients with prior HAM treatment obtained a further complete remission with S-HAM. In 2 of these patients a longer remission was induced by S-HAM than by the preceding original HAM treatment. Although these data are preliminary and need confirmation on larger numbers of patients, they strongly suggest a high antileukemic activity of the S-HAM protocol which may even be superior to the previously used HAM regimen.