What’s Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach

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.

Resistance of Leukemia Cells to 5-Azacytidine: Different Responses to the Same Induction Protocol

“…The variability of the response of our AZA-resistant cell variants to HMAs, specifically highlighting differences between them, is summarized in Table 2. Since there is still no treatment approved for MDS and AML patients after HMA treatment failure [55], the possibility of including TFN or other de novo pyrimidine synthesis inhibitors in combination with AZA in the treatment protocol should be further investigated and validated. In a specific group of MDS or AML patients with AZA resistance, this combination of drugs could restore the sensitivity of leukemic cells to AZA.…”