Acute myeloid leukemia (AML) in the elderly is a serious problem characterized by poor response to therapy and short survival. To improve response to therapy, a timed sequential therapy (TST) approach was designed utilizing topotecan, cytosine arabinoside (ara-C) and mitoxantrone based on multiple studies suggesting that topotecan and mitoxantrone are effective in older patients. Thirty-two adults, >or=60-year-old (median age 69) were included. None had favorable cytogenetics and 44% had and antecedent myelodysplastic syndrome (MDS) or 2 degrees AML. Fifty-nine percent achieved a complete response (CR). Median overall survival (OS) was 6.5 months (95% confidence interval (CI): 3.1-12.0 months; range, 15 days to 25.3 months). Disease-free survival (DFS) for the 19 patients achieving a CR was 7.7 months (95% CI: 6.1-13.7 months; range, 2.9-25.3 months). There were no differences in OS or DFS between cytogenetic or disease etiology groups. Although TST was well tolerated, long-term results in this group of patients are not satisfactory and new approaches are needed.