Phase I clinical and laboratory evaluation of topotecan and cytarabine in patients with acute leukemia.
OBJECTIVE
To determine the maximal-tolerated dose (MTD) of topotecan with cytarabine in acute leukemia patients, and to evaluate leukemia cell apoptosis in these patients.


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).


CONCLUSIONS
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.
Seiter
K
K
Division of Oncology/Hematology, New York Medical College, Valhalla 10595, USA.
Feldman
E J
EJ
Halicka
H D
HD
Traganos
F
F
Darzynkiewicz
Z
Z
Lake
D
D
Ahmed
T
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis; D001752:Blast Crisis / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D003561:Cytarabine / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D019772:Topotecan
D003561:Cytarabine; D019772:Topotecan; D002166:Camptothecin