Myelodysplastic syndromes (MDS) is a heterogeneous group of pre-leukemic diseases characterized by peripheral blood cytopenia, morphologic dysplasia, and an increased risk of transformation to leukemia. MDS develop from genetically mutant clonal hematopoietic stem and progenitor cells (HSPCs) which have defects in generating mature functional blood cells due to impaired differentiation and/or survival activities. In addition, mutant HSPCs also inhibit the generation of new blood cells from remaining healthy HSPCs. Thus, the complete elimination of mutant HSPCs is the optimal goal for MDS treatment. However, most current therapies for MDS are little more than palliative, primarily addressing cytopenia-related symptoms and improving the quality of life. Only the hypomethylating agents (HMA) lenalidomide and imetelstat reduced the mutational burden, and then only in a small subset of cases. Many HMA-based combination therapies failed to show benefits superior to single-agent HMA treatment in clinical trials. At the present time, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only cure for the minority of qualified patients who have HLA-matched donors. Novel effective treatments are urgently needed. Here we summarize the current standard therapeutic approaches for MDS patients and discuss major advances in MDS research and treatments. We also discuss major challenges and potential solutions to overcome these challenges for future MDS research and drug development.
