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Blood, 1 January 2007, Vol. 109, No. 1, pp. 52-57. Prepublished online as a Blood First Edition Paper on August 1, 2006; DOI 10.1182/blood-2006-05-021162. This Article Full Text (PDF) All Versions of this Article: blood-2006-05-021162v1 109/1/52    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 Kantarjian, H. Articles by Issa, J.-P. J Search for Related Content PubMed PubMed Citation Articles by Kantarjian, H. Articles by Issa, J.-P. J Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 11, 2006 Accepted July 12, 2006 Results of a randomized study of three schedules of low-dose decitabine in higher risk myelodysplastic syndrome and chronic myelomonocytic leukemia Hagop Kantarjian*, Yasuhiro Oki, Guillermo Garcia-Manero, Xuelin Huang, Susan O'Brien, Jorge Cortes, Stefan Faderl, Carlos Bueso-Ramos, Farhad Ravandi, Zeev Estrov, Alessandra Ferrajoli, William Wierda, Jianqin Shan, Jan Davis, Francis Giles, Hussain I Saba, and Jean-Pierre J Issa University of Texas M. D. Anderson Cancer Center The University of Texas M . D. Anderson Cancer Center University of Texas M.D. Anderson Cancer Center The University of Texas M.D. Anderson Cancer Center M. D. Anderson Cancer Center, Houston, Texas University of Texas - M. D. Anderson Cancer Center UT M. D. Anderson Cancer Center, Houston, Texas James A. Haley Veterans Hospital, H. Lee Moffitt Cancer Center and the University of South Florida M * Corresponding author; email: hkantarj{at}mdanderson.org. Epigenetic therapy with hypomethylating drugs is now standard of care for patients with myelodysplastic syndrome (MDS), though response rates remain low, and mechanism-based dose optimization has not been reported. We have investigated the clinical and pharmacodynamic results of different dose-schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to one of 3 decitabine schedules: 1) 20 mg/m2 IV daily x 5; 2) 20 mg/m2 SQ daily x 5; and 3) 10 mg/m2 IV daily x 10. Randomization followed a Bayesian adaptive design favoring the arm associated with higher complete response (CR) rates. Global methylation was measured by bisulfite pyrosequencing of LINE1 repeats and P15 expression was measured by qPCR. Ninety-five patients were treated (77 with MDS, all with IPSS score >1.0, 18 with CMML). Median age was 65 years and median MDS duration was 3.2 months. Overall 32 patients (34%) achieved CR, and 69 patients (72%) had an objective response by the new modified International Working Group criteria. The 5-day IV schedule, which had the highest dose-intensity, was selected as optimal after the 65th patient; the CR rate in that arm was 39%, compared to 21% in the 5-day SQ arm and 24% in the 10 day IV arm (p<0.05). The high dose-intensity arm was also superior at inducing hypomethylation at day 5 and at activating P15 expression at days 12 or 28 after therapy. We conclude that a low-dose, high dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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