Targeting inflammation in lower-risk MDS

The myelodysplastic syndromes (MDS) are a heterogeneous group of malignant hematopoietic stem cell disorders characterized by ineffective growth and differentiation of hematopoietic progenitors leading to peripheral blood cytopenias, dysplasia, and a variable risk of transformation to acute myelogenous leukemia. As most patients present with lower-risk disease, understanding the pathogenesis of ineffective hematopoiesis is important for developing therapies that will increase blood counts in patients with MDS. Various inflammatory cytokines are elevated in MDS and contribute to dysplastic differentiation. Inflammatory pathways mediated by interleukin (IL) 1b, IL-6, IL-1RAP, IL-8, and others lead to growth of aberrant MDS stem and progenitors while inhibiting healthy hematopoiesis. Spliceosome mutations can lead to missplicing of genes such as IRAK4, CASP8, and MAP3K, which lead to activation of proinflammatory nuclear factor κB-driven pathways. Therapeutically, targeting of ligands of the transforming growth factor β (TGF-β) pathway has led to approval of luspatercept in transfusion-dependent patients with MDS. Presently, various clinical trials are evaluating inhibitors of cytokines and their receptors in low-risk MDS. Taken together, an inflammatory microenvironment can support the pathogenesis of clonal hematopoiesis and low-risk MDS, and clinical trials are evaluating anti-inflammatory strategies in these diseases.