Abstract Body

Profound immune dysregulation is an increasingly recognized feature of myelodysplastic neoplasms (MDS), contributing to ineffective hematopoiesis and driving disease progression. Immune dysregulation in MDS is highly complex and composed of many interdependent factors, including clonal hematopoietic cells with somatic mutations providing faulty signals to the immune system and altered cells of the bone marrow microenvironment contributing to inflammation and immunosuppression. IST with antithymocyte globulin (ATG, either horse or rabbit), with or without addition of cyclosporine (CSA), has been evaluated for treatment of low-risk MDS in a number of phase II clinical trials with small numbers of patients and response rates ranging from 16% to 67%. Several novel agents are under investigation that target cell-intrinsic innate immune pathways, such as the TLR axis. Blocking NLRP3 inflammasome signaling is another appealing cell-intrinsic approach, given its importance in MDS pathogenesis. Immunotherapeutic approaches have also been tried in MDS (eg, checkpoint inhibitors), with disappointing overall response rates. However, targeting macrophage activity with an anti-CD47 antibody (magrolimab) and 5-azacitidine is promising. Immune modulatory approaches show therefore high promise in the treatment of MDS. Given the heterogeneity of the disease, both in terms of risk stratification as well as highly variable genetic traits and the type of immune dysregulation present, it will be of utmost importance to correctly identify which patients will most likely benefit from which approach.