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- Title
Sequential administration of irinotecan and cytarabine in the treatment of relapsed and refractory acute myeloid leukemia.
- Authors
Minderman, Hans; O'Loughlin, Kieran; Smith, Patrick; Pendyala, Lakshmi; Greco, William; Sweeney, Kimberly; Ford, Laurie; Wetzler, Meir; Baer, Maria; O'Loughlin, Kieran L; Smith, Patrick F; Greco, William R; Sweeney, Kimberly G; Ford, Laurie A; Baer, Maria R
- Abstract
<bold>Purpose: </bold>Based on reported synergy of the topoisomerase-I (topo-I) inhibitor irinotecan with antimetabolites, irinotecan and cytarabine (Ara-C) were administered sequentially to patients with acute myeloid leukemia (AML) refractory to or relapsed following high-dose Ara-C and anthracycline therapy. Pharmacokinetic and pharmacodynamic studies were performed with the first irinotecan dose.<bold>Experimental Design: </bold>In vitro synergy of irinotecan followed by Ara-C was confirmed in a human AML cell line as a basis for the clinical trial. Irinotecan was administered daily for 5 days, with Ara-C 1 g/m2 12 h after each irinotecan dose. Irinotecan was initiated at 5 mg/m2, and the dose was escalated by 5 mg/m2 increments in cohorts of three patients and in individual patients. Pre-treatment samples were studied for topo-I activity and serial samples after the first irinotecan dose were analyzed for pharmacokinetics and for pharmacodynamic effects, including DNA damage and DNA synthesis rate.<bold>Results: </bold>The irinotecan dose reached 15 mg/m2 in three-patient cohorts without reaching the maximum tolerated dose, and reached 30 mg/m2 in individual patients. The AUC and Cmax of both irinotecan and its active metabolite SN38 increased linearly in proportion to dose, and the mean half-lives of irinotecan conversion to SN38 and SN38 elimination were 6.2 h (CV 171%) and 7.2 h (CV 48%). Irinotecan rapidly induced DNA damage, and DNA synthesis inhibition varied among patients and treatment cycles. All courses resulted in rapid cytoreduction, and two patients achieved complete remission. Topo-I activity did not predict response.<bold>Conclusion: </bold>Irinotecan can be safely administered with Ara-C. This combination is active in refractory AML and warrants further study.
- Subjects
MYELOID leukemia; BONE marrow diseases; PHARMACOKINETICS; CHEMICAL kinetics; CELL lines; DNA damage; DNA; ENZYME metabolism; ANTINEOPLASTIC agents; CAMPTOTHECIN; CLINICAL trials; COMPARATIVE studies; DRUG synergism; DOSE-effect relationship in pharmacology; RESEARCH methodology; MEDICAL cooperation; RESEARCH; DISEASE relapse; EVALUATION research; ACUTE diseases; CYTARABINE; THERAPEUTICS
- Publication
Cancer Chemotherapy & Pharmacology, 2006, Vol 57, Issue 1, p73
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-005-0017-4