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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 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 Citation Map 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. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 January 2003, Vol. 101, No. 2, pp. 425-432 CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Phase 1 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, Peter J. Kourlas, 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. Zwiebel, Eric H. Kraut, Stanley P. Balcerzak, Clara D. Bloomfield, Michael R. Grever, and Michael A. Caligiuri From the Division of Hematology-Oncology, Department of Medicine, and the Comprehensive Cancer Center, Ohio State University, Columbus; Genta, Berkeley Heights, NJ; and National Cancer Institute, Bethesda, MD. Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 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 at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years). © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. B. Klisovic, W. Blum, X. Wei, S. Liu, Z. Liu, Z. Xie, T. Vukosavljevic, C. 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