The development and clinical use of oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes: dawn of the total oral therapy era

ABSTRACT

Introduction

Intravenous and subcutaneous hypomethylating agents have held a key role in myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia treatment. Following the approval of the cedazuridine/decitabine combination, ASTX727, as well as development of an oral formulation of azacitidine, CC-486, in the USA in 2020, these agents could gradually replace their injectable counterparts.

Areas covered

ASTX727 is approved for the treatment of adult patients with intermediate 1 or high-risk MDS as well as those with chronic myelomonocytic leukemia based on the findings from the ASTX727-01-B and ASCERTAIN trials. Oral azacitidine (CC-486) is approved for maintenance treatment of acute myeloid leukemia after induction chemotherapy for patients unfit for allogeneic hematopoietic cell transplant based on the findings from the QUAZAR AML-001 trial.

Expert opinion

Oral hypomethylating agent formulations have the potential to offer a convenient alternative to injectable hypomethylating agent. However, their current FDA-approved indications are narrow and efficacy needs to be shown in clinical trials before considering use beyond the approved indications. Areas of special interest include: identification of predictive biomarkers for clinical benefit, post-transplant maintenance therapy, and potential combination therapies with other oral agents such as venetoclax, IDH and FLT3 inhibitors.

KEYWORDS:

• Azacitidine
• cedazuridine
• decitabine
• oral hypomethylating agent

Article highlights

• Intravenous (IV) and subcutaneous (SC) hypomethylating agents (HMAs) have played a large role in MDS, CMML, and AML treatment for over 15 years however impose significant treatment burden on patients and family members due to its daily administration for 5 to 7 days every month, administration-related pain and local reactions, and potential need for indwelling catheters.

• The oral HMAs, decitabine/cedazuridine and oral formulation of azacitidine, CC-486, have been approved for use in MDS and AML, respectively.

• While pharmacokinetic (PK) and pharmacodynamics (PD) analyses show similar results when comparing oral decitabine and cedazuridine to IV decitabine, oral azacitidine have variable PK/PD based on route of administration and should not be used as a replacement for injectable azacitidine.

• The ASTX727-01-B and ASTX727-02 trials evaluated MDS or CMML patients randomized in a crossover design to oral decitabine/cedazuridine or IV. In both trials, complete response was observed in 18% and 21% of patients, respectively, with a comparable duration of response. Long-term outcomes such as survival are still being evaluated.

• The phase III, QUAZAR AML-001 trial evaluated AML patients whom were not candidates for allogeneic hematopoietic stem cell transplantation or more intensive chemotherapy and were randomized to oral azacitidine or placebo. Findings of this trial showed significantly longer overall (24.7 months vs. 14.8 months) and relapse-free survival (10.2 months vs. 4.8 months) in patients receiving oral azacitidine.

• The most common adverse events seen in both oral agents are similar to the injectable counterparts with gastrointestinal events and hematologic toxicity.

Declaration of interest

A Zeidan is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a NCI’s Cancer Clinical Investigator Team Leadership Award (CCITLA). A Zeidan has received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics, participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Trovagene, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, and Tyme. A Zeidan has also served on steering and independent data review committees for clinical trials for Novartis, Abbvie, Geron, and Janssen, received travel support for meetings from Pfizer, Novartis, and Trovagene. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

Research reported in this publication was in part supported by the National Cancer Institute of the National Institutes of Health under Award Number P30 CA016359.