Ineffective erythropoiesis and its treatment

The erythroid marrow and circulating red blood cells (RBCs) are the key components of the human erythron. Abnormalities of the erythron that are responsible for anemia can be separated into 3 major categories: erythroid hypoproliferation, ineffective erythropoiesis, and peripheral hemolysis. Ineffective erythropoiesis is characterized by erythropoietin-driven expansion of early-stage erythroid precursors, associated with apoptosis of late-stage precursors. This mechanism is primarily responsible for anemia in inherited disorders like β-thalassemia, inherited sideroblastic anemias, and congenital dyserythropoietic anemias, as well as in acquired conditions like some subtypes of myelodysplastic syndrome (MDS). The inherited anemias that are due to ineffective erythropoiesis are also defined as iron-loading anemias because of the associated parenchymal iron loading caused by the release of erythroid factors that suppress hepcidin production. Novel treatments specifically targeting ineffective erythropoiesis are being developed. Iron restriction through enhancement of hepcidin activity or inhibition of ferroportin function has been shown to reduce ineffective erythropoiesis in murine models of β-thalassemia. Luspatercept is a transforming growth factor-β ligand trap that inhibits SMAD2/3 signaling. Based on preclinical and clinical studies, this compound is now approved for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. Luspatercept is also approved for the treatment of transfusion-dependent anemia in patients with MDS with ring sideroblasts, most of whom carry a somatic SF3B1 mutation. While the long-term effectiveness and safety of luspatercept need to be evaluated in β-thalassemia and MDS, defining the molecular mechanisms of ineffective erythropoiesis in different disorders might allow the discovery of new effective compounds.