Beyond initial response: acquired resistance to hypomethylating agents in myeloid malignancies

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are haematological malignancies characterized by the uncontrolled proliferation of immature, dysplastic myeloid stem and progenitor cells. These diseases exist on a biological continuum, with many MDS patients eventually progressing to AML. Both conditions predominantly affect older adults, who are often ineligible for intensive chemotherapy and stem cell transplantation due to comorbidities and frailty. For such patients, hypomethylating agents (HMAs) represent a critical therapeutic option, offering lower-intensity treatment that can induce temporary remission and extend survival. However, HMA responses are transient, with inevitable resistance leading to fatal relapse. Despite the clinical significance of HMA resistance, the underlying mechanisms remain poorly understood, and effective treatment strategies for HMA-relapsed disease are lacking. This review provides a comprehensive update on the current clinical use of HMA-based therapies in AML and MDS, and highlights the significant challenge of relapse. We then summarise available data on the molecular features of acquired HMA resistance, revealing complex and inter-connected drivers of disease recurrence. • Acquired HMA resistance remains poorly understood relative to refractory resistance • Poor outcomes demand greater mechanistic understanding of acquired HMA resistance • Genetic changes at relapse are insufficient to explain acquired HMA resistance. • Leukemic stem cells increase fatty acid metabolism to fuel relapse. • Pyrimidine metabolism adaptations at relapse may be therapeutically exploitable. • Acquired HMA resistance occurs despite sustained DNA hypomethylation.