TY - JOUR
T1 - The history of oral decitabine/cedazuridine and its potential role in acute myeloid leukemia
AU - Briski, Robert
AU - Garcia-Manero, Guillermo
AU - Kantarjian, Hagop
AU - Ravandi, Farhad
N1 - Publisher Copyright:
© The Author(s), 2023.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - 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.
AB - 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.
KW - 5-azanucleosides decitabine
KW - acute myeloid leukemia
KW - decitabine/cedazuridine
KW - epigenetics
KW - hypomethylating agents
KW - hypomethylation
KW - novel combination therapy for AML
KW - oral decitabine
KW - oral therapy for AML
KW - therapy for elderly and unfit patients with AML
UR - http://www.scopus.com/inward/record.url?scp=85174605068&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85174605068&partnerID=8YFLogxK
U2 - 10.1177/20406207231205429
DO - 10.1177/20406207231205429
M3 - Review article
C2 - 37854355
AN - SCOPUS:85174605068
SN - 2040-6207
VL - 14
JO - Therapeutic Advances in Hematology
JF - Therapeutic Advances in Hematology
ER -