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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1762-1769. Prepublished online as a Blood First Edition Paper on June 11, 2007; DOI 10.1182/blood-2007-03-081364. This Article Full Text (PDF) All Versions of this Article: blood-2007-03-081364v1 110/6/1762    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Karp, J. E Articles by Gandhi, V. Search for Related Content PubMed PubMed Citation Articles by Karp, J. E Articles by Gandhi, V. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 21, 2007 Accepted June 3, 2007 A phase I clinical-laboratory study of clofarabine followed by cyclophosphamide for adults with refractory acute leukemias Judith E Karp*, Rebecca M Ricklis, Kumudha Balakrishnan, Janet Briel, Jacqueline Greer, Steven D Gore, B Douglas Smith, Michael A McDevitt, Hetty Carraway, Mark J Levis, and Varsha Gandhi Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, United States Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States * Corresponding author; email: jkarp2{at}jhmi.edu. Clofarabine has shown impressive response rates in patients with acute leukemias. In vitro investigations with clofarabine in combination with cyclophosphamide in primary cells have demonstrated synergistic cytotoxicity and inhibition of DNA repair. Based on these clinical and laboratory observations we designed a mechanism-based combination protocol with clofarabine and cyclophosphamide for patients with relapsed acute leukemias. Eighteen patients were treated with cytoxan (200 mg/m2) alone on day 0 and with clofarabine plus cyclophosphamide on day 1. Clinical responses, toxicity, DNA damage measured as H2AX phosphorylation, and accumulation of clofarabine triphosphate (TP) were analyzed. At dose level 1 (20 mg/m2 clofarabine + cyclophosphamide, 6 patients) and dose level 0 (10 mg/m2 clofarabine + cyclophosphamide, 12 patients) overall response rates were 50 and 30%, respectively, with responses in 4/6 (67%) patients with refractory acute lymphoblastic leukemia. Dose limiting toxicity occurred at dose level 1 with prolonged marrow aplasia. Four (22%) patients died from prolonged aplasia (1), fungal pneumonia (1), or multiorgan failure (2). In 12 of 13 patient samples, increased DNA damage (H2AX) was observed with clofarabine and cyclophosphamide compared to cyclophosphamide alone. In conclusion, pharmacodynamic endpoints along with clinical results suggest usefulness of this combination strategy while toxicity data suggest reduction in chemotherapeutic intensity. This clinical trial is registered with the National Cancer Institute's PDQ at www.clinicaltrials.gov as #JHOC-J0561. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. E. Perl, M. T. Kasner, D. E. Tsai, D. T. Vogl, A. W. Loren, S. J. Schuster, D. L. Porter, E. A. Stadtmauer, S. C. Goldstein, N. V. Frey, et al. A Phase I Study of the Mammalian Target of Rapamycin Inhibitor Sirolimus and MEC Chemotherapy in Relapsed and Refractory Acute Myelogenous Leukemia Clin. Cancer Res., November 1, 2009; 15(21): 6732 - 6739. [Abstract] [Full Text] [PDF] A. Vitale, S. Grammatico, S. Capria, C. Fiocchi, R. Foa, and G. Meloni Advanced Philadelphia chromosome positive acute lymphoblastic leukemia patients relapsed after treatment with tyrosine-kinase inhibitors: successful response to clofarabine and cyclophosphamide Haematologica, October 1, 2009; 94(10): 1471 - 1473. [Full Text] [PDF] S. Jeha, B. Razzouk, M. Rytting, S. Rheingold, E. Albano, R. Kadota, L. Luchtman-Jones, L. Bomgaars, P. Gaynon, S. Goldman, et al. Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia J. Clin. Oncol., September 10, 2009; 27(26): 4392 - 4397. [Abstract] [Full Text] [PDF] J. E. Karp, K. Flatten, E. J. Feldman, J. M. Greer, D. A. Loegering, R. M. Ricklis, L. E. Morris, E. Ritchie, B. D. Smith, V. Ironside, et al. Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide Blood, May 14, 2009; 113(20): 4841 - 4852. [Abstract] [Full Text] [PDF] D. Hochhauser, T. Meyer, V. J. Spanswick, J. Wu, P. H. Clingen, P. Loadman, M. Cobb, L. Gumbrell, R. H. Begent, J. A. Hartley, et al. Phase I Study of Sequence-Selective Minor Groove DNA Binding Agent SJG-136 in Patients with Advanced Solid Tumors Clin. Cancer Res., March 15, 2009; 15(6): 2140 - 2147. [Abstract] [Full Text] [PDF]

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