Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study.
Hagop Kantarjian,J. Issa,Craig S. Rosenfeld,John M. Bennett,Maher Albitar,John DiPersio,Virginia Klimek,James Slack,Carlos de Castro,Farhad Ravandi,Richard Helmer,Lanlan Shen,Stephen D. Nimer,Richard Leavitt,Azra Raza,Hussain Saba +15 more
TLDR
Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy.Abstract:
BACKGROUND
Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters.
METHODS
A total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks, or best supportive care. Response was assessed using the International Working Group criteria and required that response criteria be met for at least 8 weeks.
RESULTS
Patients who were treated with decitabine achieved a significantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (P < .001). An additional 12 patients who were treated with decitabine (13%) achieved hematologic improvement. Responses were durable (median, 10.3 mos) and were associated with transfusion independence. Patients treated with decitabine had a trend toward a longer median time to acute myelogenous leukemia (AML) progression or death compared with patients who received supportive care alone (all patients, 12.1 mos vs. 7.8 mos [P = 0.16]; those with International Prognostic Scoring System intermediate-2/high-risk disease, 12.0 mos vs. 6.8 mos [P = 0.03]; those with de novo disease, 12.6 mos vs. 9.4 mos [P = 0.04]; and treatment-naive patients, 12.3 mos vs. 7.3 mos [P = 0.08]).
CONCLUSIONS
Decitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death. The duration of decitabine therapy may improve these results further. Cancer 2006. © 2006 American Cancer Society.read more
Citations
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Clinical practice guidelines in oncology
William J. Gradishar,Benjamin O. Anderson,Ron Balassanian,Sarah L. Blair,Harold J. Burstein,Amy E. Cyr,Anthony D. Elias,William B. Farrar,Andres Forero,Sharon H. Giordano,Matthew P. Goetz,Lori J. Goldstein,Steven J. Isakoff,Janice A. Lyons,P. Kelly Marcom,Ingrid A. Mayer,Beryl McCormick,Meena S. Moran,Ruth O'Regan,Sameer A. Patel,Lori J. Pierce,Elizabeth C. Reed,Kilian E. Salerno,Lee S. Schwartzberg,Amy Sitapati,Karen L. Smith,Mary Lou Smith,Hatem Soliman,George Somlo,Melinda L. Telli,John H. Ward,Rashmi Kumar,Dorothy A. Shead +32 more
TL;DR: This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
Journal ArticleDOI
Gene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer
Xiaojing Yang,Han Han,Daniel D. De Carvalho,Daniel D. De Carvalho,Fides D. Lay,Peter A. Jones,Gangning Liang +6 more
TL;DR: It is shown that 5-aza-2'-deoxycytidine treatment not only reactivates genes but decreases the overexpression of genes, many of which are involved in metabolic processes regulated by c-MYC.
Journal ArticleDOI
Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine
Carlo Stresemann,Frank Lyko +1 more
TL;DR: The pharmacological properties of azanucleosides and their interactions with various cellular pathways are examined and an understanding of the cellular mechanisms mediating transmembrane transport and metabolic activation will be critically important for optimizing patient responses.
Journal ArticleDOI
Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia
Hagop M. Kantarjian,Yasuhiro Oki,Guillermo Garcia-Manero,Xuelin Huang,Susan O'Brien,Jorge E. Cortes,Stefan Faderl,Carlos E. Bueso-Ramos,Farhad Ravandi,Zeev Estrov,Alessandra Ferrajoli,William G. Wierda,Jianqin Shan,Jan Davis,Francis J. Giles,Hussain I. Saba,Jean Pierre J. Issa +16 more
TL;DR: It is concluded that a low-dose, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.
Journal ArticleDOI
Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents
Hui Yang,Carlos Bueso-Ramos,Courtney D. DiNardo,Marcos R. Estecio,Masoud Davanlou,Qi-Rong Geng,Zhihong Fang,Martin Nguyen,Sherry Pierce,Yue Wei,Simrit Parmar,Jorge E. Cortes,Hagop M. Kantarjian,Guillermo Garcia-Manero +13 more
TL;DR: It is suggested that PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to hypomethylating agents and blockade of this pathway can be a potential therapy in M DS and AML.
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