Therapeutic Options in Myelodysplastic Syndromes Following Hypomethylating Agent Failure

Background
Hypomethylating agents (HMA) azacitidine and decitabine are standard of care for the treatment of myelodysplastic syndromes (MDS). Although HMA have revolutionized the treatment of MDS, only approximately half of patients respond to these agents with variable duration of effect, known as primary and secondary HMA failure, respectively.

Methods
Therapeutic options following HMA failure remain limited; however, growing understanding of the pathogenesis underlying MDS has resulted in the development of multiple targeted therapies showing varying degrees of success in clinical trials.

Results
Drugs that target molecular alterations (such as abnormal histone regulation, IDH mutations, and spliceosome gene mutations), abnormal signaling pathways (such as the multikinase inhibitor rigosertib), cellular apoptosis (such as the Bcl2 inhibitor venetoclax), and immune checkpoint inhibition are under development (Table 1). Agents recently approved for use in higher-risk acute myeloid leukemia, such as FLT3-inhibitors and CPX-351, are also being studied in MDS. Several more agents, including two first in class agents, a novel immune regulator targeting CD47, and pevonedistat, a NEDD8-activating enzyme inhibitor, are under investigation.

Conclusions
In the absence of established therapeutic approaches following HMA failure, decisions in therapy should be based on the type of HMA resistance as well as the patient’s clinical and molecular characteristics. As targeted therapies continue to be developed, a comprehensive re-evaluation of the patient including the mutational profile at the time of HMA failure may reveal new treatment options. Here, emerging therapeutic approaches to HMA failure in MDS are reviewed.