Phase I clinical and laboratory evaluation of topotecan and cytarabine in patients with acute leukemia

Purpose: To determine the maximal-tolerated dose (MTD) of topotecan with cytarabine in acute leukemia patients, and to evaluate leukemia cell apoptosis in these patients. Patients and Methods: Fifty-three patients with acute leukemia not responsive to standard therapy were treated at eight dose levels of topotecan (2.5 mg/m(2)/d to 7.75 mg/m(2)/d). Topotecan was given as a 30-minute infusion daily with cytarabine 1 g/m(2)/d, both for 5 days, Using a flow-cytometric technique, the percent apoptotic cells in blood and bone marrow samples was determined, and the cell cycle distribution of the leukemic cells studied. Results: Oropharyngeal mucositis wets dose-limiting, The MTD of topotecan wets 4.75 mg/m(2)/d for 5 days in high-risk patients and 7.0 mg/m(2)/d for 5 days in low-risk patients, The mean percent apoptotic cells in the peripheral blood reached a peak of 18.8%, a median of 48 hours following the first dose of topotecan. Patients with higher S-phase fractions, either before treatment or following cytarabine, were more likely to achieve bone marrow aplasia than those with lower S-phase fractions (P =.01 and P <.05, respectively), Clinical responses were seen in four of 39 patients with acute myelogenous leukemia (AML; of wham 32 had received prior high-dose cytarabine), three of six with acute lymphoblastic leukemia (ALL), and one of eight with chronic myelogenous leukemia in blast phase (CML-BP). Conclusion: The recommended phase II dose of topotecan with intermediate-dose cytarabine is 4.75 mg/m(2)/d far high-risk patients and 7.0 mg/m(2)/d for low-risk patients, The percentage of cells in S phase was important in determining response to treatment. (C) 1997 by American Society of Clinical Oncology.