Kantarjian H, Oki Y, Garcia-Manero G et al.Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109:52-57

Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030, USA.
Blood (Impact Factor: 10.45). 01/2007; 109(1):52-7. DOI: 10.1182/blood-2006-05-021162
Source: PubMed


Epigenetic therapy with hypomethylating drugs is now the standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to 1 of 3 decitabine schedules: (1) 20 mg/m2 intravenously daily for 5 days; (2) 20 mg/m2 subcutaneously daily for 5 days; and (3) 10 mg/m2 intravenously daily for 10 days. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, and 18 with CMML). Overall, 32 patients (34%) achieved a complete response (CR), and 69 (73%) had an objective response by the new modified International Working Group criteria. The 5-day intravenous schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared with 21% in the 5-day subcutaneous arm and 24% in the 10-day intravenous arm (P < .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, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.

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Available from: Farhad Ravandi, Mar 17, 2014
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    • "Clinical studies have demonstrated that high dose DAC treatment regimens result in some clinical benefits in patients with malignancies; however, these regimens have been shown to be extremely toxic due to the poor hematologic status of these patients and may even cause death [15]. Lowdose DAC minimizes toxicity while potentially retaining the inhibition of the activities of DNA methyltransferases via incorporation into the DNA [16]. The lowest reported total dose of decitabine that has been used to treat a solid tumor is 50 mg/m 2 , but this dose was accompanied by various adverse events [17]. "
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    ABSTRACT: Aberrant DNA methylation is one of the main drivers of tumor initiation and progression. The reversibility of methylation modulation makes it an attractive target for novel anticancer therapies. Clinical studies have demonstrated that high-dose decitabine, a hypomethylating agent, results in some clinical benefits in patients with refractory advanced tumors; however, they are extremely toxic. Low doses of decitabine minimize toxicity while potentially improving the targeted effects of DNA hypomethylation. Based on these mechanisms, low-dose decitabine combined with chemoimmunotherapy may be a new treatment option for patients with refractory advanced tumors. We proposed the regimen of low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors. A favorable adverse event profile was observed in our trial that was highlighted by the finding that most of these adverse events were grades 1-2. Besides, the activity of our cohort was optimistic and the clinical benefit rate was up to 60%, and the median PFS was prolonged compared with PFS to previous treatment. We also identified a significant correlation between the PFS to previous treatment and clinical response. The low-dose DAC decitabine-based chemoimmunotherapy might be a promising protocol for improving the specificity and efficiency of patients with refractory advanced solid tumors. This trial is registered in the ClinicalTrials.gov database (identifier NCT01799083).
    Research Journal of Immunology 05/2014; 2014:371087. DOI:10.1155/2014/371087
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    • "In the US, it is indicated for treatment of previously treated and untreated de novo and secondary myelodysplastic syndrome (MDS) of all French-American-British subtypes and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups [5]. In patients with MDS [6], chronic myelomonocytic leukemia [6], or AML, intravenous (IV) decitabine 20 mg/m2 administered daily for 5 consecutive days every 4 weeks was well tolerated [7]. "
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    ABSTRACT: Compared with younger patients, older adults with acute myeloid leukemia (AML) generally have poorer survival outcomes and less benefit from clinical trials. A recent phase 3 trial demonstrated a trend toward improved overall survival (OS) with decitabine, a hypomethylating agent, compared with treatment choice of either cytarabine or supportive care (7.7 months, 95% CI: 6.2-9.2 vs 5.0 months, 95% CI: 4.3-6.3, respectively) in older adults with newly diagnosed AML. The current analyses investigated prognostic factors for outcomes in this trial and examined OS and responses in prespecified subgroups. A multivariate Cox proportional hazards model was used to investigate effects of demographic and baseline characteristics, including age, sex, cytogenetic risk, AML type, ECOG Performance Status, geographic region, bone marrow blasts, platelets, and white blood cells on OS, based on mature data. Similar analyses were conducted with a logistic regression model to predict response rates. Prespecified subgroup analyses were performed for OS and response rates, also using mature data. ClinicalTrials.gov identifier is NCT00260832. Patient characteristics that appeared to negatively influence OS included more advanced age (hazard ratio [HR] 1.560 for >=75 vs <70 years; p = 0.0010), poorer performance status at baseline (HR 0.771 for 0 or 1 vs 2; p = 0.0321), poor cytogenetics (HR 0.699 for intermediate vs poor; p = 0.0010), higher bone marrow blast counts (HR 1.355 for >50% vs <=50%; p = 0.0045), low baseline platelet counts (HR 0.775 for each additional 100 x 109/L; p = 0.0015), and high white blood cell counts (HR 1.256 for each additional 25 x 109/L; p = 0.0151). Regarding geographic regions, patients from Western Europe had the longest median OS. Response rates favored decitabine for all subgroups investigated, including patients >=75 years (odds ratio 5.94, p = 0.0006). Response to decitabine in AML is associated with known prognostic factors related to both patient demographics and disease characteristics.Trial registration: ClinicalTrials.gov identifier NCT00260832.
    BMC Cancer 02/2014; 14(1):69. DOI:10.1186/1471-2407-14-69 · 3.36 Impact Factor
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    • "Low-dose administration days 1 to 5 +/− days 8 to 12 of a cycle may be most effective [36-39]. Low-dose regimens are also particularly likely to induce DNA demethylation [38,39]. "
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    ABSTRACT: In 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed. Pre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores <=150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P <0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19). In conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation.
    01/2014; 6(1):2. DOI:10.1186/1868-7083-6-2
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