LAUSR

Simple Summary The hypomethylating agents (HMA) azacitidine and decitabine are among the standard treatment options for myeloid neoplasms. However, the treatment of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) who progress after treatment with HMA is challenging in the absence of standardized guidelines. Many potential novel therapeutics are under development, some of which have demonstrated promising outcomes in early clinical trials. Here we review the mechanisms and factors that predict resistance to HMA in MDS/AML patients while highlighting the latest findings in the search for therapies with significant potential in this specific setting. Abstract Hypomethylating agents (HMA) such as azacitidine and decitabine are a mainstay in the current management of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) as either single agents or in multidrug combinations. Resistance to HMA is not uncommon, and it can result due to several tumor cellular adaptations. Several clinical and genomic factors have been identified as predictors of HMA resistance. However, the management of MDS/AML patients after the failure of HMA remains challenging in the absence of standardized guidelines. Indeed, this is an area of active research with several potential therapeutic agents currently under development, some of which have demonstrated therapeutic potential in early clinical trials, especially in cases with particular mutational characteristics. Here, we review the latest findings and give a rational approach for such a challenging scenario.