PURPOSE OF REVIEW: Hypomethylating agents (HMAs) are the standard of care for 
patients with myelodysplastic syndromes (MDS). Although these agents induce 
responses in up to 40% of patients, most patients ultimately experience loss of 
response. The purpose of this review is to provide an overview of the different 
therapies under development for MDS after HMA therapy.
RECENT FINDINGS: Recent advances in the understanding of MDS pathogenesis have 
led to the development of new potential therapies after HMA failure. Newer HMAs, 
less susceptible to in-vivo deamination, such as guadecitabine or ASTX727 have 
shown activity. Alterations of immune checkpoints in MDS have led to multiple 
clinical trials evaluating the activity of monoclonal antibodies targeting these 
proteins (pembrolizumab, nivolumab, ipilimumab). Different combinations and new 
formulations of cytotoxic agents, such as clofarabine or CPX-351, are newer 
options for specific subsets of patients. Finally, targeted agents inhibiting 
multiple kinases (rigosertib), BCL2 (venetoclax) or mutant IDH1 (ivosidenib), 
IDH2 (enasidenib), FLT3 (sorafenib, midostaurin) or spliceosome components 
(H3B-8800) are other novel options.
SUMMARY: Despite the poor prognosis associated with HMA failure, clinical 
trials, new cytotoxic agents and allogeneic stem-cell transplantation, can offer 
therapeutic opportunities for these patients for whom there is no standard of 
care.