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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In the UK, decitabine is approved for the treatment of newly diagnosed acute myeloid leukemia in patients over the age of 65 who are not candidates for standard induction chemotherapy. Side effects include bone marrow suppression, leading to thrombocytopenia and anemia, diarrhea, epistaxis, and headaches.
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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Mistry B, Gibiansky L, Hussein Z. Pharmacokinetic modelling of decitabine in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). J Clin Oncol. 29: 2011 (suppl; abstr 6551).
DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jesus Duque, Michael Lübbert, Mark Kirschbaum
Inhibitors of DNA methylation have been shown to reactivate the expression of genes that have undergone epigenetic silencing, particularly if this silencing has occurred in a pathological situation. 5-azacytidine (Vidaza®) and 5-aza-2′deoxycytidine (Dacogen®, decitabine, DAC), which were initially developed as cytotoxic antineoplasic agents when used at maximally tolerated doses as with standard chemotherapeutic agents, were found to have the clinically more important DNA demethylating activity when used at very low doses (106) leading to the recognition of its clinical activity in MDS and AML (107). Both compounds are cytosine analogs that inhibit DNMT, reverse methylation, and reactivate genes. When used at these doses, these agents were shown to differentiate cells in tissues cultures (106) and to induce gene re-expression. These agents do not have direct demethylation activity, rather, 5-azacytidine and decitabine have to be incorporated in the DNA in the S-phase of the cell cycle, covalently binding DNMTs, and thus depleting the nucleus of their enymatic activity (108,109). DNA replication in the absence of DNMTs leads to global and gene-specific hypomethylation (110). In vitro and in vivo, these compounds are able to demethylate the promoter of hypermethylated genes, as was shown for p15INK4B promoter in MDS patients, leading to a reactivation of silenced genes (25,111). At the cytotoxic doses of these compounds, cell death may be due to DNA damage and apoptosis (108). While decitabine at cytotoxic doses demonstrated significant antitumor activity in hematological malignancies in clinical trials, severe and prolonged myelosuppression was frequently observed (112).
Non-intensive acute myeloid leukemia therapies for older patients
Published in Expert Review of Hematology, 2023
Rodrick Babakhanlou, Farhad Ravandi-Kashani
The ASTRAL-1 trial, a randomized phase 3 trial intended to compare Guadecitabine against treatment of choice, which included azacitidine, decitabine, or LDAC for the management of newly diagnosed AML in elderly unfit patients ineligible for intensive chemotherapy [55]. This led to an indirect comparison of azacitidine and decitabine. Azacitidine was given intravenously or subcutaneously at 75 mg/m2 per day on days 1 to 7. Decitabine was given intravenously at 20 mg/m2 per day on days 1 to 5. There were no significant differences in the CR rate and OS between both groups. Serious adverse events leading to death seemed to be more frequent in the azacitidine group. Data of this trial suggested that azacitidine and decitabine can be used interchangeably among older and unfit AML patients [55].
Efficacy of azacitidine in preventing relapse after hematopoietic stem cell transplantation for advanced myeloid malignancies: a systematic review and meta-analysis
Published in Expert Review of Hematology, 2022
Tingting Pan, Shiyu Han, Meng Zhou, Jiaqian Qi, Hong Wang, Xiaoyan Xu, Xueqian Li, Yifang Yao, Yue Han
Aberrant methylation is involved in the initiation of MDS/AML, and administration of demethylating drugs may improve outcomes in patients with advanced MDS and AML. A recent meta-analysis of patients treated with decitabine for refractory or relapsed disease included 20 studies and 310 patients and reported a median survival of 7.2 months [7]. The 3-year overall survival rate after relapse of advanced myeloid malignancies was 19% [8]. Considering the almost equal effectiveness with decitabine, AZA appears to be less myelosuppressive. Although there have been many studies implementing AZA to prophylaxis of relapse post HSCT [9], the outcomes vary among different reports. To obtain comprehensive data on the efficacy of AZA for the prevention of relapse in malignant hematologic diseases, we performed a systematic review and meta-analysis on administering AZA for the prevention of relapse after HSCT.
Therapeutic strategies, including allogeneic stem cell transplantation, to overcome relapsed/refractory adult T-cell acute lymphoblastic leukemia
Published in Expert Review of Hematology, 2021
Dong Won Baek, Jung Min Lee, Juhyung Kim, Hee Jeong Cho, Joon Ho Moon, Sang Kyun Sohn
An increasing amount of evidence implicates epigenetic dysregulation, particularly aberrant DNA methylation, as an important contributor to carcinogenesis, including hematologic malignancies, by silencing tumor suppressor genes [76,77]. DNA methyltransferases (DNMTs) inhibitors, such as azacitidine and decitabine, are known to reverse promoter hypermethylation in cancer cells, leading to reexpression of aberrantly silenced genes [78]. As hypomethylating agents, azacitidine and decitabine have shown significant antileukemic effects in myelodysplatic syndrome (MDS) and acute myeloblastic leukemia (AML) [79]. A genomic analysis was conducted using matched diagnosis/relapse BM samples in the study with relapsed pediatric B-ALL. In this study, Carroll and colleagues identified a characteristic relapse-specific gene expression and DNA methylation signature, which was increased in the relapsed samples [80]. Furthermore, they found that DNMT inhibitors could reverse relapse-specific promoter hypermethylation and reexpress aberrantly silenced genes in the decitabine pretreated ALL cell lines [81]. In a clinical trial with refractory ALL patients (NCT00349596), low-dose decitabine (10 mg/m2) every other week for five consecutive days alone or in combination with hyper-CVAD regimen showed feasibility and a clinical effect in patients with advanced ALL [82].