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Hypomethylating Agents

Overview

Hypermethylation of DNA in the regulatory area of selected genes has been shown to be common in neoplasia and is associated with tumor resistance or progression.

Both 5-azacytidine (Pfizer’s Vidaza/Mylosar) and decitabine (Supergen and MGI Pharma’s Dacogen) are potent DNA methylation inhibitors and have shown significant antileukemic activity in myeloid malignancies, including acute myelogenous leukemia and myelodysplastic syndrome. In chronic myelogenous leukemia, these agents have been used mostly in the accelerated and blastic phases.

Mechanism Of Action

DecitabineThe Pa promoter of abl and several other genes that are central to the development of chronic myelogenous leukemia are hypermethylated in a significant proportion of patients, and methylation increases with disease progression. The p15 gene is hypermethylated with chronic myelogenous leukemia progression, and different patterns of hypermethylation for myeloid and lymphoid blastic phases have been reported. Therefore, hypomethylating agents may play a role in treating chronic myelogenous leukemia. Decitabine

Decitabine is a DNA methyltransferase inhibitor under development by Supergen and MGI Pharma for the potential treatment of a range of hematologic malignancies, solid tumors, and sickle cell disease. Decitabine has shown activity in accelerated-phase and blastic-phase chronic myelogenous leukemia as a single agent and is now being investigated in combination with other chemotherapeutic agents and imatinib. The agent is in Phase II trials for the treatment of chronic myelogenous leukemia.

Decitabine is a cytidine analogue that exerts potent DNA hypomethylating effects through its covalent binding to DNA methyltransferase. Decitabine is cytotoxic at high doses, hypomethylating at low doses, and has clinical activity in myeloid malignancies that appears to be optimal at low doses.

In a Phase II study, the activity of decitabine mono therapy (at 15 mg/m2 intravenously [IV] over one hour daily, five days a week for two weeks) in patients who were either imatinib-intolerant or had chronic myelogenous leukemia that was refractory to imatinib was evaluated. Thirty-five patients were enrolled (12 in the chronic phase, 17 in the accelerated phase, and 6 in the blastic phase). CHRs were seen in 12 patients (34%), partial hematologic responses were seen in 7 patients (20%), and hematologic improvement was seen in 4 patients (11%); there was an overall hematologic response rate of 65% (83% in the chronic phase, 59% in the accelerated phase, and 50% in the blastic phase). MCRs were observed in 7 patients (20%), and minor cytogenetic responses were seen in 9 patients (26%), with an overall cytogenetic response rate of 46%. Median response duration was three months. The only common grade 3 or 4 toxicities observed were related to myelosuppression. There were two deaths in the study, both related to thrombocytopenia and hemorrhage.

Another study showed synergy between imatinib and decitabine. Ten patients who presented with untreated accelerated or blastic-phase chronic myelogenous leukemia were treated with a combination of decitabine (15 mg/m2, IV, for 10 days) and imatinib (600 mg po daily). Of the ten patients enrolled, six were evaluable; two patients achieved CHR, and one patient achieved a minor cytogenetic response.

If approved for the treatment of chronic myelogenous leukemia, decitabine will likely be used in accelerated-phase and blastic-phase disease that is unresponsive to imatinib therapy. The agent is unlikely to be used alone and will be used in combination with imatinib and other therapies.

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