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Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study [see comment]

Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer (Impact Factor: 4.9). 05/2006; 106(8):1794-803. DOI: 10.1002/cncr.21792
Source: PubMed

ABSTRACT 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.
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.
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]).
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.

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    • "FDA-approved for myelodysplastic syndromes; incorporated into DNA and blocks DNMT1 [78] Azacytidine (Vidaza Ò ) FDA-approved for myelodysplastic syndromes; incorporated into DNA (and RNA) and blocks DNMT1 [90] SG-110 5-aza-2 0 -deoxycytidine pro-drug [153] Natural Curcumin From curcuma; decreases DNMT1 expression [101] EGCG From green tea; decreases DNMT expression [41] Genistein From soy; decreases DNMT activity and expression [1] Luteolin From parsley, celery; DNMT inhibitor [40] Small molecule Hydralazine Initially used in the treatment of hypertension, DNMT inhibitor [31] HAT Natural Curcumin From curcuma; inhibits HAT (p300) [28] Quercetin From onion, broccoli, berries; sirtuin activator [71] HDAC Benzamides CI-994 (Tacedinaline) Inhibits HDAC1 and 2 [92] MGCD0103 (Mocetinostat) Inhibits HDAC1, 2, 3 and 11 [52] MS-275 (Entinostat) Inhibits class I HDACs [134] Cyclic peptides None in clinical trial Depsipepides FK228 (Romidepsin) FDA-approved; from the bacteria Chromobacterium Violaceum; inhibits class I HDACs [54] Hydroxamates CHR-3996 Inhibits class I HDACs [8] ITF2357 (Givinostat) Inhibits class I and II HDACs [53] JNJ-16241199 (R306465) Inhibits class I HDACs [6] JNJ-26481585 (Quisinostat) Inhibits class I and II HDACs [158] LBH-589 (Panobinostat) Inhibits non-sirtuin HDACs [129] NVP-LAQ824 (Dacinostat) Inhibits class I and II HDACs [21] PCI-24781 (CRA-024781) Inhibits class I and IIb HDACs [20] PXD101 (Belinostat) Inhibits non-sirtuin HDACs [126] SAHA (Vorinostat) FDA-approved, inhibits non-sirtuin HDACs [128] SB939 Inhibits non-sirtuin HDACs [131] Short-chain fatty acids AN-9 (Pivanex, pivaloyloxymethyl butyrate) Inhibits Class I, IIa and IV [38] Butyrate From gut fermentation of dietary fibers; inhibits Class I, IIa and IV [33] Sodium 4-phenylbutyrate Inhibits HDACs [123] VPA Inhibits Class I and IIa [65] Others 3,3-Diindolylmethane Digestive product of indole-3-carbinol found in cruciferous vegetables; inhibits total HDAC activity, downregulation of class I HDACs [13] CUDC-101 Inhibits HDACs [93] Genistein From soy; inhibits non-sirtuin HDACs and increases HAT activity [103] Phenethyl isothiocyanate From cruciferous vegetables; inhibits non-sirtuin HDACs [162] Resveratrol From grape; sirtuin activator [42] Suramin Inhibits SIRT1, 2 and 5 [154] HMT E7438 Inhibits EZH2 [88] DNMT: DNA methyltransferase, EGCG: epigallocatechin gallate, HAT: histone acetyltransferase, HDAC: histone deacetylase, SAHA: suberoylanilide hydroxamic acid, SIRT: sirtuin, VPA: valproic acid. "
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    • "Hypomethylating agents (HMAs), such as azsacitidine (AZA), are considered the standard of care for patients with International Prognostic Scoring System (IPSS) Intermediate- 2 (Int-2) or High-risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukaemia (CMML) who are not candidates for allogeneic stem cell transplantation (alloSCT) (Kantarjian et al, 2006; Silverman et al, 2006; Fenaux et al, 2009 "
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