The History of Oral Decitabine/Cedazuridine and Its Potential Role in Acute Myeloid Leukemia

Authors

Robert Briski
Guillermo Garcia-Manero
Hagop Kantarjian
Farhad Ravandi

Publication Date

1-1-2023

Journal

Therapeutic Advances in Hematology

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,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

acute myeloid leukemia, 5-azanucleosides decitabine, 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

DOI

10.1177/20406207231205429

PMID

37854355

PMCID

PMC10580721

PubMedCentral® Posted Date

10-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes