Figure 1.

Novel therapies for myelodysplastic syndromes: immunologic, epigenetic and molecular targets. The physiopathology of myelodysplasia implies several pathogenic mechanisms, including epigenetic alterations, the disruption of intracellular molecular pathways, and the derangement of immunosurveillance that favors leukemic immune escape. All these pathogenic mechanisms may represent a target for novel drugs. For instance, immune checkpoint inhibitors, such as nivolumab, atezolizumab, durvalumab, ipilimumab, magrolimab, are able to restore T cells and adaptive and innate immunity to target dysplastic hematopoietic stem cells. Other immunotherapies include bispecific antibodies, such as flotetuzumab, and in the future, CART cells. Drugs that target intracellular pathways include luspatercept, galunisertib, sabatolimab, pevonedistat, imetelstat, pexmetinib, venetoclax, tomaralimab, roxadustat, and rigosertib and these act on various levels in cell maturation, survival/apoptosis, ineffective erythropoiesis, response to hypoxia, and telomeres elongation. Targeting epigenetic alteration by hypomethylating agents such as azacytidine, decitabine and novel agents (guadecitabine, decitabine/cedazuridine) restores MDS maturation. Finally, specific mutation inhibitors include H3B-8800, ivosidenib, enasidenib and eprenetapopt, which restore hematopoietic differentiation. Novel drugs for low-risk MDS are represented in blue boxes, drugs for high-risk MDS in green boxes and drugs for low-risk and high-risk MDS in red boxes.