Hypomethylating agents (HMA) treatment for myelodysplastic syndromes: alternatives in the frontline and relapse settings

ABSTRACT

Introduction: Hypomethylating agents (HMA) have played a pivotal role for treating myelodysplastic syndromes (MDS) over the past decade, inducing sustained hematological responses and delaying progression to leukemia. However, a vast majority of patients will experience treatment failure within 2 years, with poor prognoses and limited options, and management of this growing patient population remains unclear.

Areas covered: With the introduction of new agents in the MDS field, a better understanding of the biology of MDS, and updated information on standard of care options (including allogeneic transplantation), we re-evaluate the global treatment strategy in MDS via novel agents, focusing in particular on investigational approaches for patients who fail to respond to HMA when applicable. This review aims to address two questions: what are reasonable alternatives to HMA in MDS, and what strategies can be used for patients experiencing HMA failure.

Expert opinion/commentary: HMA therapy remains a mainstay of treatment, even if additional research is still warranted to maximize its benefits for the different groups of patients. The outcome of patients experiencing HMA failure remains grim, without standard of care, but several new approaches seem promising, as there is an increasing focus on studying treatments for patients refractory to HMA treatment.

KEYWORDS:

• Disease management
• epigenetic modification
• hypomethylating agents
• hypomethylating agent failure
• IPSS
• investigational agents
• myelodysplastic syndrome
• treatment failure

Article highlights

• HMA therapy has been a major breakthrough for MDS management; however, the majority of patients eventually relapse over the course of 2 years, with poor prognosis and limited options

• With better understanding of the biologic mechanism of MDS and improved standard of care options, including transplant, along with the development of novel agents, the current approach for low and high risk MDS patients is being re-evaluated as seen with new scoring systems.

• HMA alternatives for lower and higher risk MDS patients include current therapy, such as transplantation, chemotherapy, immunosuppression, and alternative HMA agents, as well as a growing number of both targeted and non-targeted investigational approaches.

• Recent years have shown exciting developments as we optimize dosage, sequence of agents, and combination therapies with current and emerging drugs that, in the future, may serve as frontline alternatives to HMA or second-line line therapy after HMA failure.

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Declaration of interest

S Gore has received consultancy fees from Celgene. T Prebet has received consultancy fees from Celgene and Novartis. 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.

Additional information

Funding

S Gore has received support from the National Cancer Institute (K24CA111717).