Dna Topoisomerase I Inhibitor Topotecan Hycamtin

Topotecan binds to DNA topoisomerase I and stabilizes the complex formed between topoisomerase I and DNA, which leads to DNA strand breakage and cell death. This agent has been successfully used as a single-agent treatment and in combination for patients with AML and MDS. The noncumulative and reversible nature of its hematologic cytotoxicity is attractive for induction therapy.

The activity of single-agent topotecan was evaluated by Beran et al. in 60 patients with MDS or CMMoL.29 The dose used was 2 mg/m2 by continuous infusion for 5 days every 4-6 weeks for 2 courses, and then at 1-2 mg/m2 for 5 days every 4-8 weeks for a maximum of 12 courses. Thirty-one percent of patients achieved a CR, including 8/11 with cytogenetic remissions. Those with no previous treatments had higher CRs (43%), but overall there were significant toxicities. These included severe mucositis and diarrhea, febrile neutropenia in 85%, and 47% patients had documented infections, with a mortality rate of 20% in the first 4 weeks. The median survival was 10.5 months, with a median remission duration of 7.5 months.

The same group used a combined regimen of topote-can at a lower dose (1.25 mg/m2) with cytarabine (1.0 mg/m2) in patients with MDS and CMMoL.30 Fifty-six percent of patients had complete responses overall, with up to 72% CR in those with poor-prognosis karyotypes and secondary MDS. This regimen was much better tolerated, with fewer hematologic and nonhematologic tox-icities. Lower response rates (33% CR and 38% PR) with topotecan and cytarabine have been reported in more recent trials.31 Forty-five MDS patients were treated at Rush University in Chicago, in a phase II trial using a combination of topotecan and thalidomide.32 Topotecan 2.0 mg/m2 was given for 5 days every 21 days for three to five cycles, with thalidomide starting at 100 mg/day (maximum dose 300 mg) for a year. This lower dose of topotecan was well tolerated; only four patients discontinued therapy due to toxicity, and three patients died of infection/progressive disease. Of 38 evaluable patients, 20% had HI and 29% had stable disease. Responses were seen in all subtypes, and one third of patients showed a >50% reduction in bone marrow blasts.

0 0

Post a comment