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Improving Cancer Care: The Role of Oral Hypomethylating Agents and Education

Investigators say oral formulations of hypomethylating agents could be a significant advancement for people with myelodysplastic syndromes and acute myeloid leukemia.

Oral hypomethylating agents (HMAs) can be an important tool to improve the quality of life of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML), according to a new review. But the authors caution that benefits can only be realized if multidisciplinary teams have sufficient knowledge of how they are similar to and different from their intravenous (IV) counterparts.

The review was published in Journal of Oncology Pharmacy Practice.

The study authors noted that both MDS and AML are marked by epigenetic dysregulation that leads to aberrant DNA hypermethylation, which makes both candidates for therapy with HMAs.

“Considering the inherent reversibility of epigenetic modifications, the possibility of restoring normal DNA methylation has led to the pursuit of targeted epigenetic agents with hypomethylating potential,” they explained.

At present, patients have 2 approved options for HMAs. IV decitabine (Dacogen; MGI Pharma) and subcutaneous or IV azacitidine (Vidaza; Bristol Myers Squibb) are approved to treat MDS in the US. In the European Union, both drugs are available to treat AML, and the latter is also approved to treat MDS.

Decitabine and azacitidine work differently, the study authors said. Decitabine is incorporated exclusively into te DNA, they said, and azacitidine is mostly incorporated in the RNA.

“However, both are cytidine analogs that bind to and inhibit the activity of DNA methyltransferase 1 (DNMT1), which catalyzes the process of DNA methylation,” they wrote. “Inhibition of DNMT1 results in global DNA hypomethylation and the reactivation of previously silenced genes, including critical tumor suppressor genes, which can be detected by the HMA-induced demethylation of long interspersed nuclear element 1 (LINE-1).”

Biomarker discovery | Image Credit: artemisDiana - stock.adobe.com

There are 2 approved hypomethylating agents: intravenous (IV) decitabine and subcutaneous or IV azacitidine | Image Credit: artemisDiana - stock.adobe.com

Yet, the investigators said there is a gap between the benefits of HMAs in clinical trials and those seen in real-world outcomes. One reason, they said, is that the therapies appear to be underutilized and patients who are prescribed the therapies often do not stay on track with their recommended usage.

“In the Surveillance, Epidemiology and End Results–Medicare study, 44% of HMA users were nonpersistent with therapy and received less than 4 cycles or had a gap of ≥ 90 days between consecutive cycles,” they wrote.

Recently, oral formulations of HMAs have been approved. Oral decitabine-cedazuridine combination therapy (DEC-C; sold under the brand name Invoqi; Astex Pharmaceuticals) has been approved for certain patients with MDS, and oral azacitidine (Onureg; Bristol Myers Squibb) has been approved for a subgroup of patients with AML.

In the review, the investigators looked at the pharmacokinetics (PK) and pharmacodynamics (PD) of oral HMAs. They found the combination of 35-mg decitabine and 100-mg cedazuridine had an equivalent systemic area under the concentration-time curve (AUC) to a 5-day regimen of IV decitabine (20 mg/m2 and had no significant PD difference.

“The AUC equivalence of oral DEC-C and IV decitabine means that these regimens can be treated interchangeably (but must not be substituted within a cycle),” they said.

Oral azacitidine, on the other hand, “has a distinct PK-PD profile vs IV or subcutaneous azacitidine, and the formulations are not bioequivalent or interchangeable owing to differences in plasma time-course kinetics and exposures.”

In addition to those 2 currently available therapies, the authors said novel oral HMAs and HMA combination therapies are also under investigation.

They added that clinicians, pharmacists, and nurse practitioners will need to consider several factors when deciding which HMAs to use with which patients, and in order to understand those considerations, multidisciplinary teams need better education on topics like the differences between oral HMAs and the implications of treatment persistence and toxicities. The authors said pharmacists are likely best positioned to provide such education.

Reference

Haumschild R, Kennerly-Shah J, Barbarotta L, Zeidan AM. Clinical activity, pharmacokinetics, and pharmacodynamics of oral hypomethylating agents for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: a multidisciplinary review. J Oncol Pharm Pract. Published online March 21, 2024. doi:10.1177/10781552241238979

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