Background: Topotecan is one of a new class of agents that targets topoisomerase I (Topo I) and stabilizes the DNA-topo1 complex, ultimately resulting in cell death. The rationale for the use of topotecan in chronic lymphocytic leukemia (CLL) is based on the finding that levels of Topo I are elevated in the lymphocytes of patients with this disease.
Methods: Twelve patients with CLL were treated with topotecan to assess its clinical efficacy; in addition, DNA-protein cross-linking was measured after exposure of the cells to topotecan, in an attempt to correlate potential anti-CLL effects with this parameter. The median age of the patients was 63 years; all had received prior therapy with fludarabine and four (33%) were resistant to fludarabine. Four patients (33%) had also received therapy with chlorambucil, and three of them were resistant to this agent. Seven patients (58%) were Rai stage I-II and five (42%) were Rai stage III-IV. Topotecan was given as a 30-minute infusion at a daily dose of 2 mg/m2 for 5 days, and courses were repeated monthly. Cells were obtained from the patients before treatment and exposed to 2 microM topotecan or control in vitro. In addition, cells were obtained from patients after they received the first dose of topotecan and protein-bound DNA was measured with the same technique.
Results: No patient responded to therapy with topotecan (95% confidence interval, 0-27%). Nonhematologic toxicity was mild and thrombocytopenia occurred in four of eight patients whose conditions could be evaluated. One patients died of myocardial infarction and another died of fungal pneumonia. DNA-protein cross-linking was detected in all nine patients whose cells were assessed in vitro, with levels of cleavable complex ranging from twofold to 7.5-fold that of the control cells. Only two of eight patients with evaluable conditions had increased cross-linking detectable in circulating cells after the first dose of topotecan, which was consistent with the drug's lack of effect in vivo.
Conclusions: Although exposure of cells from patients with CLL to topotecan in vitro at 2 microM resulted in detectable protein-DNA cross-linking, this effect was not seen in patients who received a bolus dose of 2 mg/m2, and no remissions were noted in 12 patients.