Management of patients with higher-risk myelodysplastic syndromes after failure of hypomethylating agents: What is on the horizon?

The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) are the standard of care for frontline treatment of patients with higher-risk myelodysplastic syndromes (MDS). As complete responses to HMAs are rare and typically not durable, HMA failure is a common clinical dilemma and associated with very short survival in most patients. Salvage therapies with various agents such as novel HMAs (guadecitabine, CC-486), and CTLA-4/PD1-type immune checkpoint inhibitors (ICPIs) have yielded mixed and only modest results at best in MDS patients with HMA failure. Thanks to advances in the understanding of the molecular and biologic pathogenesis of MDS, several novel targeted agents such as the BCL-2 inhibitor venetoclax, TP-53 refolding agent APR-246, IDH1/2 inhibitors, and novel ICPIs such as magrolimab and sabatolimab have been developed and demonstrated activity in combination with HMA in the frontline setting. However, clinical testing of these agents post HMA failure has been limited to date. Furthermore, the biology of HMA failure remains poorly defined which significantly limits rationale drug development. This highlights the importance of optimization of frontline therapy to avoid/delay HMA failure in addition to development of more effective salvage therapies.

Automated summary

Hypomethylating agents AZA and DAC are standard frontline treatments for high-risk MDS, but often lead to unsatisfactory responses and short survival durations, known as HMA failure. While salvage therapies like novel HMAs and ICPIs have shown mixed results in MDS patients with HMA failure, the development of targeted agents like venetoclax and ICPIs has demonstrated activity in combination with HMA in frontline treatment. However, limited clinical testing of these agents post HMA failure and poorly defined biology of HMA failure highlight the need for optimization of frontline therapy and development of more effective salvage therapies.