Sequential administration of irinotecan and cytarabine in the treatment of relapsed and refractory acute myeloid leukemia

• Published in: Cancer chemotherapy and pharmacology 2006, Vol.57 (1), p.73-83
• Main Authors: MINDERMAN, Hans, O'LOUGHLIN, Kieran L, SMITH, Patrick F, PENDYALA, Lakshmi, GRECO, William R, SWEENEY, Kimberly G, FORD, Laurie A, WETZLER, Meir, BAER, Maria R
• Format: Article
• Language: English
• Subjects: Acute Disease; Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Camptothecin - therapeutic use; Cytarabine - administration & dosage; Cytarabine - adverse effects; Cytarabine - pharmacokinetics; Cytarabine - therapeutic use; DNA Damage; DNA Topoisomerases, Type I - metabolism; DNA, Neoplasm - biosynthesis; Dose-Response Relationship, Drug; Drug Synergism; Female; Hematologic and hematopoietic diseases; HL-60 Cells; Humans; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Recurrence
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-005-0017-4

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. 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. 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. Irinotecan can be safely administered with Ara-C. This combination is active in refractory AML and warrants further study.