DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
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).
Antimetabolites
David E. Thurston, Ilona Pysz in 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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Caroline Ashley, Aileen Dunleavy, John Cunningham in The Renal Drug Handbook, 2018
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).
Emerging DNA methylation inhibitors for cancer therapy: challenges and prospects
Published in Expert Review of Precision Medicine and Drug Development, 2019
Aurora Gonzalez-Fierro, Alfonso Dueñas-González
The second randomized trial was done in 233 patients, and the primary endpoint was overall survival. Decitabine was administered at the same dose and schedule but infused over 4 h and the control arm was BSC. Again, responses favored the decitabine arm. These were CR (13% v 0%), PR (6% v 0%), hematologic improvement (15% v 2%), stable disease (14% v 22%), progressive disease (29% v 68%), hypoplasia (14% v 0%), and unevaluable (8% v 8%) for decitabine and BSC, respectively. There was no increase in overall survival with decitabine (median OS, 10.1 vs 8.5 months, [HR], 0.88; 95% CI, 0.66 to 1.17; two-sided, log-rank p = 0.38). Progression-free survival (PFS), but not AML-free survival (AMLFS), was significantly prolonged with decitabine versus BSC (median PFS, 6.6 versus 3.0 months, respectively; HR, 0.68; 95% CI, 0.52 to 0.88; p = 0.004; median AMLFS, 8.8 versus 6.1 months, respectively; HR, 0.85; 95% CI, 0.64 to 1.12; p = 0.24). Nevertheless, the rate of transformation to AML at 1 year was statistically significantly reduced, 33% in BSC and 22% with decitabine. The most common toxicity for decitabine is myelosuppression and infection which are also observed in untreated patients. In this study, 47.4% of decitabine patients had grade 3–4 infection with neutropenia versus 35% in BSC arm, likewise, grade 3–4 febrile neutropenia was most frequent (25.4% vs 7.1%) in decitabine and BSC groups, respectively. Both randomized decitabine trials formally assessed QOL which was significantly improved in patients of decitabine arms [87].
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].
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].
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