The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

Abstract

On September 20, 2012, a marketing authorization valid throughout the European Union (EU) was issued for decitabine for the treatment of adult patients aged 65 years and older with newly diagnosed de novo or secondary acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy. Decitabine is a pyrimidine analog incorporated into DNA, where it irreversibly inhibits DNA methyltransferases through covalent adduct formation with the enzyme.The use of decitabine was studied in an open-label, randomized, multicenter phase III study (DACO-016) in patients with newly diagnosed de novo or secondary AML. Decitabine (n 5 242) was compared with patient's choice with physician's advice (n 5 243) of low-dose cytarabine or supportive care alone. The primary endpoint of the study was overall survival. The median overall survival in the intent-to-treat (ITT) population was 7.7 months among patients treated with decitabine compared with 5.0 months for those in the control arm (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.04; p 5 .1079). Mature survival data after an additional year of follow-up were consistent with these results, with a median overall survival of 7.7 months in patients treated with decitabine and 5.0 months in the control arm (HR, 0.82; 95% CI, 0.68-0.99; p 5 .0373). Secondary endpoints, including response rates, progressionfree survival, and event-free survival, were increased in favor of decitabine when compared with control treatment. The most common adverse drug reactions reported during treatment with decitabine are pyrexia, anemia, thrombocytopenia, febrile neutropenia, neutropenia, nausea, and diarrhea. This paper summarizes the scientific review of the application leading to approval of decitabine in the EU. The detailed scientific assessment report and product information (including the summary of product characteristics) for this product are available on the EMA website (http://www.ema.europa.eu). The Oncologist 2016;21:692-700

Development and in vitro evaluations of new decitabine nanocarriers for the treatment of acute myeloid leukemia

“…Contrary to EMA, FDA has not approved decitabine for AML treatment due to its lack of efficacy (the drug was only approved for myelodysplasic syndrome). 6 This limitation may be due to its short half-life. Incorporation of decitabine in an Figure 6 cell viability following exposure of hel (A) and hl-60 (B) cells to various concentrations of free-decitabine, blank ThP-T80-lNcs, or decitabine-loaded ThP-T80-lNcs.…”

“…The increase of median survival (2.7 months) is modest, but was considered to be meaningful by the EMA in the context of AML in older patients without alternative treatment. 6 A Phase II clinical trial (NCT01786343) is ongoing with modified dosing schedules to increase the cytotoxic activity of the drug.…”

MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia

“…Decitabine is approved by the European Medicines Agency, but not by the US FDA, for the treatment of adult patients with AML [41]. In this respect, decitabine is active in inducing complete remissions in patients with AML, but has a modest effect on overall survival, highlighting the need to improve the outcome of decitabine treatment [42, 43].…”

DNA hypermethylation enhanced telomerase reverse transcriptase expression in human-induced pluripotent stem cells

“…In this study, we focused on the distal promoter region of the TERT gene and identified the TERT-DMR, which provides additional information for the human TERT gene. Of note, the demethylating reagent 5-aza-dC (also known as decitabine) has been used clinically for treating acute myeloid leukemia (AML) in patients whose malignant cells express TERT gene [34]. In addition, treatment with decitabine has been reported to suppress expression and inhibit malignant cell proliferation [35,36].…”