Azacitidine and its role in the upfront treatment of acute myeloid leukemia

ABSTRACT

Introduction

Acute myeloid leukemia (AML) predominantly affects elderly population. This poses challenges in management, as patients are frequently not candidates for intensive therapy given comorbidities or frailty. Currently, azacitidine (AZA), either as monotherapy or in combination regimens, is the backbone treatment in this group of patients.

Areas covered

We review the mechanism of action, pharmacology, clinical efficacy, and safety of AZA. It reviews current combination therapies of AZA with other targeted therapies for the treatment of newly diagnosed AML.

Expert opinion

AZA is a cornerstone for the treatment of patients considered ineligible for intensive chemotherapy induction, but better results and therapies are required for these patients. AZA has shown synergistic properties when combined with other medications. Its safety profile and few drug interactions make it a suitable medication to use as backbone. Newer therapies are being combined with AZA, demonstrating safety and in cases, improved responses, and survival. AZA/venetoclax has emerged as the standard of care for patients who are ineligible for intensive chemotherapy. Doublet and triplet combinations are increasingly being studied. With the results observed in elderly patients, the intensive chemotherapy paradigm might be put to test in younger populations, with AZA combinations being at the forefront.

KEYWORDS:

• Azacitidine
• acute myeloid leukemia
• AML
• de novo
• venetoclax
• gilteritinib

Abbrivations

2HG – 2-hydroxyglutatate

Allo-SCT – allogeneic stem cell transplant

AML – Acute myeloid leukemia

AZA – Azacitidine

BCL-2 – B-cell lymphoma 2

BSC – best supportive care

CMML – chronic myelomonocytic leukemia

CR – complete remission

CRc – composite complete response

CRi – complete remission with incomplete hematologic recovery

CYP3A – cytochrome P450, family 3, subfamily A

CYP450 – cytochrome P450

DFS – disease-free survival

DNA – deoxyribonucleic acid

ECOG – eastern cooperative oncology group

EFS – event-free survival

EHA – European Hematology Association

EMA – European Medicines agency

FAB – French American British

FDA – the US food and drug administration

FL – FLT3 ligand

FLT-3 – FMS-like tyrosine kinase 3

HMA – hypomethylating agent

HR – hazard ratio

IDH1 – Isocitrate dehydrogenase 1

IDH2 – Isocitrate dehydrogenase 2

IPSS – International prognostic scoring system

ITD – Internal tandem duplication

ITT – Intention to treat

JM – Juxtamembrane

LDAC – low-dose ara-C

MDS – myelodysplastic syndrome

mOS – median overall survival

NCCN – national comprehensive cancer network

ORR – overall response rate

OS – Overall survival

R/R – relapsed/refractory

RFS – relapse-free survival

RNA – ribonucleic acid

SC – subcutaneous

TKD – tyrosine kinase domain

WHO – world health organization

αKG – alpha ketoglutarate

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.