ace-011 and Iron-Overload

Distinct subtypes of lower risk myelodysplastic syndromes display ring sideroblasts in the bone marrow, i. e., erythroid progenitors characterized by excessive iron deposited in the mitochondria. This morphological feature is frequently associated with somatic mutations in components of the splicing machinery that constitutes the underlying molecular principle of the disease. Conventional treatment regimen with erythropoiesis-stimulating agents often fails to induce sustained erythroid improvement in these patients that harbor defects in late-stage erythroblasts downstream of erythropoietin action. In the present review, we will discuss activin receptor ligand traps as novel therapeutic strategies particularly for sideroblastic subgroups of myelodysplastic syndromes that were recently shown to alleviate anemia by specifically inhibiting aberrant TGF-β signaling and thereby promoting erythroid differentiation.

Topics: Activin Receptors, Type II; Activins; Humans; Immunoglobulin Fc Fragments; Iron Overload; Myelodysplastic Syndromes; Phosphoproteins; Recombinant Fusion Proteins; RNA Splicing Factors; Transforming Growth Factor beta

Thalassemia intermedia is a clinical entity where anemia is mild or moderate, requiring no or occasional transfusion. Non-transfusion-dependent thalassemia encompasses 3 main clinical forms: beta-thalassemia intermedia, hemoglobin E/beta-thalassemia and alpha-thalassemia intermedia (HbH disease). Clinical severity of thalassemia intermedia increases with age, with more severe anemia and more frequent complications such as extramedullary hematopoiesis and iron overload mainly related to increased intestinal absorption. Numerous adverse events including pulmonary hypertension and hypercoagulability have been associated with splenectomy, often performed in thalassemia intermedia patients. The potential preventive benefit of transfusion and chelation therapies on the occurrence of numerous complications supports the strategy of an earlier therapeutic intervention. Increasing knowledge about pathophysiological mechanisms involved in thalassemia erythropoiesis and related iron overload is currently translating in novel therapeutic approaches.

Topics: Allografts; alpha-Thalassemia; beta-Thalassemia; Blood Transfusion; Chelation Therapy; Combined Modality Therapy; Disease Management; Disease Progression; Erythropoiesis; Hematopoiesis, Extramedullary; Hematopoietic Stem Cell Transplantation; Hemoglobinuria; Hepcidins; Humans; Hydroxyurea; Iron Chelating Agents; Iron Overload; Janus Kinase 2; Recombinant Fusion Proteins; Splenectomy; Thrombophilia