Originally published as JCO Early Release 10.1200/JCO.2006.09.4169 on August 6 2007

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Phase I Study of Decitabine Alone or in Combination With Valproic Acid in Acute Myeloid Leukemia

William Blum, Rebecca B. Klisovic, Bjoern Hackanson, Zhongfa Liu, Shujun Liu, Hollie Devine, Tamara Vukosavljevic, Lenguyen Huynh, Gerard Lozanski, Cheryl Kefauver, Christoph Plass, Steven M. Devine, Nyla A. Heerema, Anthony Murgo, Kenneth K. Chan, Michael R. Grever, John C. Byrd, Guido Marcucci

From the Department of Medicine, Division of Hematology and Oncology; Department of Molecular Virology, Immunology, and Medical Genetics, Division of Human Cancer Genetics, The Ohio State University Comprehensive Cancer Center and Solove Research Institute; College of Pharmacy, and Department of Pathology, The Ohio State University, Columbus, OH; Cancer Therapy Evaluation Program, National Institutes of Health, Bethesda, MD; and the Department of Hematology, University of Freiburg Medical Center, Freiburg, Germany

Address reprint requests to William Blum, MD, Division of Hematology and Oncology and the Comprehensive Cancer Center, The Ohio State University, B310 Starling-Loving Hall, 320 W 10th Ave, Columbus, OH 43210; e-mail: william.blum{at}osumc.edu

Purpose To determine an optimal biologic dose (OBD) of decitabine as a single agent and then the maximum-tolerated dose (MTD) of valproic acid (VA) combined with decitabine in acute myeloid leukemia (AML).

Patients and Methods Twenty-five patients (median age, 70 years) were enrolled; 12 were untreated and 13 had relapsed AML. To determine an OBD (based on a gene re-expression end point), 14 patients received decitabine alone for 10 days. To determine the MTD, 11 patients received decitabine (at OBD, days 1 through 10) plus dose-escalating VA (days 5 through 21).

Results The OBD of decitabine was 20 mg/m²/d intravenously, with limited nonhematologic toxicity. In patients treated with decitabine plus VA, dose-limiting encephalopathy occurred in two of two patients at VA 25 mg/kg/d and one of six patients at VA 20 mg/kg/d. Drug-induced re-expression of estrogen receptor (ER) was associated with clinical response (P .05). ER promoter demethylation, global DNA hypomethylation, depletion of DNA methyltransferase enzyme, and histone hyperacetylation were also observed. In an intent-to-treat analysis, the response rate was 44% (11 of 25). Of 21 assessable patients, 11 (52%) responded: four with morphologic and cytogenetic complete remission (CR; each had complex karyotype), four with incomplete CR, and three with partial remission. In untreated AML, four of nine assessable patients achieved CR. Clinical responses appeared similar for decitabine alone or with VA.

Conclusion Low-dose decitabine was safe and showed encouraging clinical and biologic activity in AML, but the addition of VA led to encephalopathy at relatively low doses. On the basis of these results, additional studies of decitabine (20 mg/m²/d for 10 days) alone or with an alternative deacetylating agent are warranted.

published online ahead of print at www.jco.org on August 6, 2007.

Supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) Grants No. K23CA120708 (principal investigator, W.B.); NIH/NCI R01 CA102031 (principal investigator, G.M.); NCI U01 CA 76576 (principal investigator, M.R.G.); Leukemia and Lymphoma Society (J.C.B. and C.P.), Dr Mildred Scheel Foundation for Cancer Research postdoctoral Fellowship Grant (B.H.), and D. Warren Brown Foundation (J.C.B.).

Presented in part at American Society of Hematology, Orlando, FL, December 9-12, 2006; and the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 3-6, 2006.

NCI Clinical Trials Network registration: NCT00079378.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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