Advances in the management of higher-risk myelodysplastic syndromes: future prospects

Abstract

Higher-risk myelodysplastic syndromes (HR-MDS) are defined using a number of prognostic scoring systems that include the degree of cytopenias, percentage of blasts, cytogenetic alterations, and more recently genomic data. HR-MDS encompasses characteristics such as progressive cytopenias, increased bone marrow blasts, unfavorable cytogenetics, and an adverse mutational profile. Survival is generally poor, and patients require therapy to improve outcomes. Hypomethylating agents (HMAs), such as azacitidine, decitabine, and more recently, oral decitabine/cedazuridine, are the only approved therapies for HR-MDS. These are often continued until loss of response, progression, or unacceptable toxicity. Combinations including an HMA plus other drugs have been investigated but have not demonstrated better outcomes compared to single-agent HMA. Moreover, in a disease of high genomic complexity such as HR-MDS, therapy targeting specific genomic abnormalities is of interest. This review will examine the biological underpinnings of HR-MDS, its therapeutic landscape in the frontline and relapsed settings, as well as the impact of hematopoietic stem cell transplantation, the only known curative intervention for this disease.

Keywords:

• Higher-risk myelodysplastic syndromes
• hypomethylating agents
• targeted therapies
• allogeneic stem cell transplant

Future directions

HR-MDS constitutes a complex group of myeloid disorders with significant cytogenetic and molecular heterogeneity. As we await the results of the Verona trial, no therapy or combination has been shown to improve the results achieved with single-agent HMA. That said, results of trials using targeted approaches and the recent experience with stem cell transplantation, suggest that the incorporation of total therapy approaches may be associated with better outcomes.

Authorship contributions

All authors contributed equally to the writing of the manuscript.

Disclosure statement

Garcia-Manero: declares research funding from Astex Pharmaceuticals, Novartis, Abbvie, BMS, Genentech, Aprea Therapeutics, Curis,Gilead Sciences, consultancy from Astex Pharmaceuticals, AcceleronPharma, BMS, and honoraria from Astex Pharmaceuticals, Acceleron Pharma, Abbvie, Novartis, Gilead Sciences, Curis, Genentech, BMS. All other authors declare no conflicts of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.