Oral hypomethylating agents: beyond convenience in MDS

Abstract

Oral hypomethylating agents (HMAs) represent a substantial potential boon for patients with myelodysplastic syndrome (MDS) who have previously required between 5 and 7 visits per month to an infusion clinic to receive therapy. For patients who respond to treatment, ongoing monthly maintenance visits represent a considerable burden to quality of life, and for those who are early in therapy, these sequential visits may tax transportation and financial resources that would be optimally distributed over the treatment cycle to facilitate transfusion support. The availability of oral HMAs may support the optimal application of these agents by contributing to adherence and lessening the burden of therapy, potentially encouraging patients to stay on longer-term treatment. Distinct pharmacokinetic profiles for the recently approved oral HMAs (oral azacitidine and decitabine-cedazuridine) result in differential toxicity profiles and have prompted their clinical trial development in lower- and higher-risk MDS, respectively.

Clinical activity, pharmacokinetics, and pharmacodynamics of oral hypomethylating agents for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: A multidisciplinary review

“…7,8,19 The oral (CC-486) and parenteral formulations of azacitidine have distinct PK profiles (Table 1) and should therefore be considered different drugs; in contrast to oral DEC-C and IV decitabine, the oral and parenteral formulations of azacitidine are not bioequivalent or interchangeable and should not be substituted. 13,39 In a pilot study in four patients with AML, MDS, and solid tumors, oral azacitidine (CC-486) displayed rapid absorption following a single dose, and C max was reached within 1 h after dosing. Oral azacitidine was well tolerated at the 80-mg dose level and mean bioavailability was 17% relative to SC administration.…”

“…43 These characteristics can be largely attributed to the rapid degradation of decitabine by CDA, which itself has high inter- and intraindividual variability in expression. 39,44 To counteract this, oral decitabine was combined with the CDA inhibitor cedazuridine.…”

“…38 Thus, oral HMAs have the potential to reduce the treatment burden and decrease rates of early discontinuation, resulting in improved QoL, efficacy, and survival for patients with MDS and AML. 39 Differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of oral versus parenteral HMA formulations (Table 1) have implications for their potential toxicities, mechanisms of action, and planned use. Moreover, oral DEC-C and oral azacitidine (CC-486) have distinct PK, PD, and safety profiles, resulting in differences in their approved indications.…”

“…38 Thus, oral HMAs have the potential to reduce the treatment burden and decrease rates of early discontinuation, resulting in improved QoL, efficacy, and survival for patients with MDS and AML. 39…”

Maintenance therapy for AML after allogeneic HCT

“…The recent development of effective oral azacitidine (CC-486) and decitabine (oral decitabine/cedazuridine) formulations has made this class of agents significantly more attractive and feasible as a post allo-HCT maintenance regimen ( 24 ). There are currently several ongoing clinical studies examining the safety and efficacy of oral azacitidine (CC-486) as maintenance therapy.…”