The history of oral decitabine/cedazuridine and its potential role in acute myeloid leukemia

Abstract

Decitabine, a member of the 5-azanucleosides, has a dose-dependent mechanism of action in vitro: termination of DNA replication at high doses, and inhibition of DNA methyltransferase at low doses. The alteration of DNA methylation patterns by low-dose decitabine is hypothesized to upregulate genes, which promote myeloblast differentiation. In a phase III clinical trial, low-dose decitabine achieved a superior overall response rate (ORR) when compared with 'treatment choice' [consisting of low-dose cytarabine (80%) and supportive care (20%)] as a frontline treatment for elderly patients with acute myeloid leukemia (AML). Despite an improved ORR, the median overall survival (OS) for elderly patients with AML was poor, <1 year. In turn, venetoclax was added to low-dose decitabine, the combination of which significantly improved the ORR and median OS in elderly patients with AML. Currently, hypomethylating agents are being combined with other novel therapies as investigational strategies for elderly and unfit patients with AML. They are also being evaluated as components of maintenance therapy in patients achieving remission. An oral formulation of decitabine has been developed which relies on the concomitant use of oral cedazuridine to protect against first pass metabolism. This oral formulation, which has been approved in myelodysplastic syndrome, is intended to increase convenience of use and therefore compliance in patients. This review characterizes the evolution of decitabine, its oral formulation, and its future in the treatment of AML.

Keywords: 5-azanucleosides decitabine; acute myeloid leukemia; decitabine/cedazuridine; epigenetics; hypomethylating agents; hypomethylation; novel combination therapy for AML; oral decitabine; oral therapy for AML; therapy for elderly and unfit patients with AML.

Figure 1.

Timeline of decitabine discovery. Events leading to the discovery of decitabine, and the application of decitabine in clinical trials. Source: Created using biorender.com

Figure 2.

(a) The chemical structure of the DNA nucleoside deoxycytidine (there are four potential locations for chemical modification: the phosphate group, the sugar, the glycosidic bond, and the heterocyclic base). (b) The chemical structure of cytarabine (it differs from the RNA nucleoside cytidine by the conformation of the 2′ hydroxyl group in the sugar). (c) Azacytidine (differs from cytidine by the presence of a nitrogen atom in the 5′ position of the heterocyclic ring). (d) Decitabine (differs from deoxycytidine by the presence of a nitrogen atom in the 5′ position of the heterocyclic ring). (e) Methylated deoxycytidine. Source: Created using biorender.com

Figure 3.

Patient serum decitabine concentration by time following infusion. Area under the curve for the combination of oral decitabine/cedazuridine versus oral decitabine alone versus IV decitabine. The dose of decitabine/cedazuridine 35 mg/100 mg was not directly tested. However, based on the areas under the curve for decitabine/cedazuridine 40 mg/100 mg and 30 mg/100 mg, it was determined that 35 mg/100 mg would be the most comparable to 20 mg decitabine IV. Source: Reprinted from Savona et al., with permission from Elsevier.