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Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients
with refractory or relapsed acute leukemia
HM Kantarjian, M Beran, A Ellis, L Zwelling, S O'Brien, L Cazenave, C Koller, MB Rios, W Plunkett and MJ Keating
Department of Hematology, University of Texas, M.D. Anderson Cancer Center,
Houston 77030.
The purpose of this study was to define, in a phase I study in leukemia,
the maximally tolerated dose (MTD), major toxicities, and possible
antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor.
Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks
to patients with refractory or relapsed acute leukemia, at doses ranging
from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated,
including 17 patients with acute myelogenous or undifferentiated leukemia,
7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia
in blastic phase. Severe mucositis was the dose-limiting toxicity occurring
in two of five patients treated with Topotecan 11.8 mg/m2 per course; a
third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per
course, 1 of 12 patients had severe mucositis and 5 had mild-to- moderate
mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were
uncommon. Three patients (11%) achieved a complete response, two (7%) had a
partial response, and one (4%) had a hematologic improvement. The overall
complete plus partial response rate was 19%, and 24% in acute myelogenous
or undifferentiated leukemia. A novel in vitro assay that quantifies
Topotecan-stabilized topo I-DNA complexes in patient samples was used,
which demonstrated heterogeneity in the ability of Topotecan to interact
with topo I, the intracellular target of Topotecan. This phase I study
defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5
days every 3 to 4 weeks in patients with refractory or relapsed acute
leukemia. Severe mucositis was the dose-limiting toxicity. Future studies
will define the precise activity of Topotecan in different leukemia
subsets, its efficacy in combination with other antileukemic drugs, and
correlations between Topotecan-induced topo I-DNA complex formation and
individual patient response to Topotecan.
Volume 81,
Issue 5,
pp. 1146-1151,
03/01/1993
Copyright © 1993 by The American Society of Hematology
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