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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-06-1899. This Article Full Text (PDF) All Versions of this Article: 2002-06-1899v1 101/2/425    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 Marcucci, G. Articles by Caligiuri, M. A Search for Related Content PubMed PubMed Citation Articles by Marcucci, G. Articles by Caligiuri, M. A Social Bookmarking                   What's this? Submitted June 28, 2002 Accepted August 13, 2002 PHASE I AND PHARMACODYNAMIC STUDIES OF G3139, A BCL-2 ANTISENSE OLIGONUCLEOTIDE, IN COMBINATION WITH CHEMOTHERAPY IN REFRACTORY OR RELAPSED ACUTE LEUKEMIA Guido Marcucci*, John C Byrd, Guowei Dai, Marko I Klisovic, Donn C Young, Spero R Cataland, Diane B Fisher, David Lucas, Kenneth K Chan, Pierluigi Porcu, Zhong Pin Lin, Sherif F Farag, Stanley R Frankel, James A Zweibel, Eric H Kraut, Stanley P Balcerzak, Clara D Bloomfield, Michael R Grever, and Michael A Caligiuri Hematology-Oncology, Ohio State University, Columbus, OH, USA Genta, Inc., Berkely Heights, NJ, USA National Cancer Institute, Bethesda, MD, USA * Corresponding author; email: marcucci{at}medctr.osu.edu. Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia, and has been associated with unfavorable clinical outcome. We hypothesized that downregulation of Bcl-2 would restore chemosensitivity of leukemic cells. To test this hypothesis, we performed a phase I study of G3139 (GenasenseTM, Genta, Inc.), an 18-mer phosphorothioate Bcl-2 anti-sense, with fludarabine, cytarabine (ARA-C), and G-CSF [FLAG] salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid (AML) or lymphoblastic (ALL) leukemia were enrolled. G3139 was delivered by continuous infusion days 1-10. FLAG chemotherapy was administered days 5-10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance and fluid retention that were not dose-limiting. Plasma pharmacokinetics of G3139 demonstrated steady state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts, or to remain in remission for 30 days (incomplete remission). Bcl-2 mRNA levels were downregulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and downregulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase III study in previously untreated high-risk AML (i.e., age 60 years). CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Laubach and A. V. Rao Current and Emerging Strategies for the Management of Acute Myeloid Leukemia in the Elderly Oncologist, October 1, 2008; 13(10): 1097 - 1108. [Abstract] [Full Text] [PDF] R. B. Klisovic, W. Blum, X. Wei, S. Liu, Z. Liu, Z. Xie, T. Vukosavljevic, C. Kefauver, L. Huynh, J. Pang, et al. Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase, in Combination with High-Dose Cytarabine in Patients with Acute Myeloid Leukemia Clin. 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