Topoisomerase I inhibitors

Among studies using recently developed agents, encouraging results have been obtained with the topoisomerase I inhibitor topotecan in a phase II study of 30 patients with diagnosis of CMML, both previously treated and untreated. Topotecan was given as a continuous intravenous infusion at the maximal tolerated dosage (MTD) of 10 mg/m2 over 5 days every 4-8 weeks.19 20 Topotecan induced a CR in almost one-third of the patients, and for the first time, CRs due to a single agent were characterized by karyotypic conversion of bone marrow from abnormal to diploid.1920 This result suggested that topotecan has a differential effect on normal and CMML cells. The median CR duration was 7.5 months (range 1-31 months), and median survival was 10.5 months.20 In this single-arm study, the impact on survival could not be docu-

mented.19,20

An oral preparation of topotecan with satisfactory bioavailability was investigated in two studies using three regimens.21-23 Given over 17 days at dosages varying from 0.8 to 1.9 mg/m2/day, 5 days on, 2 days off for three cycles, oral topotecan induced CRs in two of seven patients with CMML.21 The dose-limiting toxicity was nausea and vomiting, and the MTD was 1.4 mg/m2/day. In a phase II study, 1.2 mg/m2 of topote-can was given orally either twice daily for 5 days or once daily for 10 days, and both schedules delivered the same total dose.22 23 Ten patients with CMML were included. Although no patients achieved a CR, seven exhibited a response.23 The duration of responses was not reported, and the impact of the treatment with oral topotecan on the natural history of the disease is unknown.

Another orally bioavailable topoisomerase I inhibitor, 9-nitro-20-(S)-camptothecin, was studied in a phase II study as a continuous daily administration at doses adjusted according to each patient's tolerance. The study group included 23 patients with CMML; responses were observed in 10 (1 CR, 4 PRs, and 5 hematologic improvements [HI]).60

The optimal administration schedule for increasing the rate and duration of responses remains to be defined for both topotecan and 9-nitro-20-(S) -camptothecin. At present, topotecan administered intravenously at the MTD appears to be the more effective agent against CMML, with the highest documented frequency of complete hematologic and cytogenetic remissions.19 20 The potential value of these topoiso-merase I inhibitors would be best appreciated in a randomized trial comparing them with hydroxyurea, analogous to the trial that compared hydroxyurea and etoposide.10 The use of topoisomerase I inhibitors to manage CMML might be more effective in combination therapy than as single agents.18

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