Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J et al.. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106: 1794-1803

Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer (Impact Factor: 4.89). 05/2006; 106(8):1794-803. DOI: 10.1002/cncr.21792
Source: PubMed


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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Available from: Farhad Ravandi
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    • "The following is the summary of options and recommendations for specific subsets of patients [20]. Patients with low risk MDS are treated with low intensity therapy including blood transfusions, hematopoietic growth factors [21], and low intensity chemotherapy using Azacitidine, Decitabine [22], and Lenalidomide [23]. Patients with high risk MDS are treated with either high risk chemotherapy similar to treatment of acute myeloid leukemia [24] or bone marrow transplantation [25]. "
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    ABSTRACT: A 20 year old male was initially diagnosed suffering from Primary ciliary dyskinesia with symptoms of bronchiectasis, severe frontal, maxillary and ethmoid sinus disease. At the age of 20, the patient was also diagnosed with Myelodysplastic syndrome requiring Bone marrow transplant due to the advanced stage at time of presentation. Primary ciliary dyskinesia and Myelodsyplastic syndrome are both rare clinical conditions found in the general population, especially in young adults. This rare combination of disorders has never been reported in literature to the best of the author's knowledge. The presence of an advanced cancer and a genetic abnormality due to two deletions occurring in two arms of the same chromosome can be explained on the base of chromothripsis. A number of evidences have been published in the literature, about multiple deletions in chromosome 5 and advanced stages of MDS being associated with chromothripsis however this is the first case report on two deletions in chromosome 7 giving rise to two different clinical entities requiring multiple modes of management.
    Full-text · Article · Sep 2014
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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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    ABSTRACT: Cancer remains a major public health problem in our society. The development of potent novel anti-cancer drugs selective for tumor cells is therefore still required. Deregulation of the epigenetic machinery including DNA methylation, histone modifications and non-coding RNAs is a hallmark of cancer, which provides potential new therapeutic targets. Natural products or their derivatives represent a major class of anti-cancer drugs in the arsenal available to the clinician. However, regarding epigenetically active anti-cancer agents for clinics, the oceans represent a largely untapped resource. This review focuses on marine natural compounds with epigenetic activities and their synthetic derivatives displaying anti-cancer properties including largazole, psammaplins, trichostatins and azumamides.
    Full-text · Article · Sep 2014 · Cancer Letters
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    • "Recently, DAC monotherapy was associated with a relatively low rate of complete remission rates in AML and MDS [6-8]. Kantarjianet al. reported in a phase III randomized study of DAC in treatment of 170 MDS patients, the overall response rate (OR) was 17%, including 9% complete responses [7]. Furthermore, Issa et al. conducted a Phase I study of 37 patients with AML receiving DAC in which the OR was 17% [8]. "
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    ABSTRACT: Background The methylation inhibitor 5-Aza-2′-deoxycytidine (decitabine, DAC) has a great therapeutic value for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). But decitabine monotherapy was associated with a relatively low rate of complete remission in AML and MDS. We aimed to investigate the effect of several anti-leukemia drugs in combination with decitabine on the proliferation of myeloid leukemia cells, to select the most efficient combination group and explore the associated mechanisms of these combination therapies. Methods Cell proliferation was tested by MTT assay and CFU-GM assay. Cell apoptosis was evaluated by Annexin V and PI staining in cell culture, TUNEL assay and transmission electron microscopy in animal study. MicroPET was used to imaging the tumor in mouse model. Molecular studies were conducted using microarray expression analysis, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry, used to assess regulation of Wnt/β-catenin pathway. Statistical significance among groups was determined by one-way ANOVA analysis followed by post hoc Bonferroni’s multiple comparison test. Results Among five anti-leukemia agents in combining with decitabine, the sequential combination of decitabine and idarubicin induced synergistic cell death in U937 cells, and this effect was verified in HEL, SKM-1 cells and AML cells isolated from AML patients. Importantly, tumor growth inhibition in this sequential combination was found to be higher than in single agent or controls in vivo. Moreover, sequential combination of the two agents induced apoptosis and depression of the Wnt/β-catenin pathway in both AML cell culture and animal studies. Conclusions The findings demonstrated that sequentially combination of decitabine and idarubicin had synergistic anti-leukemia effects. These effects were mainly attributed to demethylation of Wnt/β-catenin pathway inhibitors and downregulation of Wnt/β-catenin pathway nuclear targets.
    Full-text · Article · Jun 2014 · Journal of Translational Medicine
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