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/m²/d to 7.75 mg/m²/d). Topotecan was given as a 30-minute infusion daily with cytarabine 1 g/m²/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 was dose-limiting. The MTD of topotecan was 4.75 mg/m²/d for 5 days in high-risk patients and 7.0 mg/m²/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 whom 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/m²/d for high-risk patients and 7.0 mg/m²/d for low-risk patients. The percentage of cells in S phase was important in determining response to treatment.