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

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Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: Irinotecan can be safely administered with Ara-C. This combination is active in refractory AML and warrants further study.

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Acknowledgements

Supported by Grant CA 89938 from the National Cancer Institute, shared resources of the Roswell Park Cancer Center Support Grant (P30 CA16056), the Leonard S. LoVullo Memorial Fund for Leukemia Research, the Dennis J. Szefel Jr., endowed fund for Leukemia Research at Roswell Park Cancer Institute and a grant from Pfizer, Inc.

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Authors and Affiliations

  1. Leukemia Section, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Hans Minderman, Kieran L. O’Loughlin, Meir Wetzler & Maria R. Baer

  2. Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Hans Minderman, Kieran L. O’Loughlin, Patrick F. Smith, Lakshmi Pendyala, Meir Wetzler & Maria R. Baer

  3. Department of Biostatistics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    William R. Greco

  4. Clinical Research Services, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Kimberly G. Sweeney & Laurie A. Ford

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  1. Hans Minderman
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Correspondence to Hans Minderman.

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Minderman, H., O’Loughlin, K.L., Smith, P.F. et al. Sequential administration of irinotecan and cytarabine in the treatment of relapsed and refractory acute myeloid leukemia. Cancer Chemother Pharmacol 57, 73–83 (2006). https://doi.org/10.1007/s00280-005-0017-4

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