EPIDEMIOLOGY, CLINICAL PATHOPHYSIOLOGY AND THERAPEUTIC APPROACH TO TRANSFUSION-DEPENDENT AND NON-TRANSFUSION-DEPENDENT THALASSEMIA

Thalassemia is among the most prevalent monogenic disorders worldwide. It comprises several clinical forms of α- and β-thalassemia, caused by mutations in globin genes that impair hemoglobin synthesis. The disease is characterized by unbalanced globin chain production, ineffective erythropoiesis, chronic anemia, increased intestinal iron absorption, and multi-organ morbidity. Based on anemia severity and transfusion requirements, β-thalassemia is classified as transfusion-dependent (TDT) or non-transfusion-dependent (NTDT). Epidemiological data on hemoglobinopathies are largely based on carrier frequency models and may not reflect the actual burden of clinically significant disease. Survival data are often derived from selected cohorts and may not represent the broader population. The life expectancy and geographical distribution of the thalassemias in Italy has changed considerably due to advances in management, patient mobility, and migration fluxes. A recent national survey showed that the age distribution of patients increasingly resembles that of the general population in the first five decades, indicating improved survival. Adult patients benefit from regular transfusions and iron chelation. Advances in transfusion safety, iron overload monitoring, and comorbidity management have significantly prolonged life expectancy. In Italy, the presence of a specialized care network supported by the Italian Scientific Society for Thalassemia and Hemoglobinopathies ensures standardized multidisciplinary care. As a result, a growing number of patients are aging. However, older patients are at higher risk of disease-related complications such as endocrine disorders, osteoporosis, liver and renal dysfunction, and malignancies. Increased mortality compared to the general population underscores the need for optimized therapeutic strategies. Quality of life of patients has not improved totally. New pharmacological agents are emerging: Luspatercept, which enhances erythropoiesis, has been integrated into standard care. Mitapivat, targeting erythroid metabolism, has shown favorable results in phase 3 trials. Conversely, agents targeting iron homeostasis such as hepcidin mimetics and ferroportin inhibitors have not confirmed preclinical efficacy in clinical studies. Patient quality of life should become a central endpoint in future clinical trial design. Developing new therapies will require a holistic and multidisciplinary approach. References: 1. Taher AT, Musallam KM, Cappellini MD. β-Thalassemias. N Engl J Med. 2021 Feb 25;384(8):727-743. doi: 10.1056/NEJMra2021838. PMID: 33626255. 2. Tuo Y, Li Y, Li Y, Ma J, Yang X, Wu S, Jin J, He Z. Global, regional, and national burden of thalassemia, 1990-2021: a systematic analysis for the global burden of disease study 2021. EClinicalMedicine. 2024 May 6;72:102619. doi: 10.1016/j.eclinm.2024.102619. 3. 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