Thalassemia major is a severe hereditary hemoglobinopathy characterized by ineffective erythropoiesis and transfusion-dependent anemia. Regular red blood cell transfusions remain the cornerstone of supportive treatment; however, they inevitably result in progressive iron overload due to the absence of physiological mechanisms for iron excretion. Iron accumulation predominantly affects the liver, heart, and endocrine organs, leading to cirrhosis, cardiomyopathy, arrhythmias, and multiple endocrinopathies. Consequently, iron chelation therapy constitutes a fundamental component of long-term management in patients with thalassemia major.

The first clinically available chelating agent was deferoxamine (DFO) promotes urinary and fecal iron excretion. Long-term use of DFO has significantly improved survival by reducing iron-related cardiac mortality. Nevertheless, its administration—via subcutaneous or intravenous infusion for 8–12 hours on most days of the week—poses substantial challenges to adherence, particularly in pediatric and adolescent populations.

To address these limitations, oral chelators were developed. Deferiprone (DFP) is effective in reducing myocardial iron burden and preventing cardiac dysfunction, although it carries the risk of agranulocytosis, requiring strict hematological monitoring. Deferasirox (DFX) has demonstrated efficacy in maintaining negative iron balance and reducing hepatic iron concentration, thereby improving adherence and overall patient satisfaction.

In cases of severe or refractory iron overload, combination therapy has been employed. The concurrent use of DFO and DFP exhibits synergistic effects, particularly in the clearance of cardiac iron. Emerging data also support the potential benefits of combining DFO with DFX in select clinical scenarios. These strategies allow for individualized treatment based on iron burden, organ involvement, and patient tolerance.

Monitoring of chelation efficacy is essential. Serum ferritin is widely utilized as a surrogate marker of body iron, though it may be confounded by inflammation or hepatic injury. T2-star magnetic resonance imaging provides a more reliable and non-invasive quantification of cardiac and hepatic iron, enabling timely therapeutic adjustments and prevention of irreversible organ damage.

Chelation therapy has transformed the prognosis of thalassemia major, shifting the natural history from early mortality to survival into adulthood with improved quality of life. Nevertheless, challenges persist, including variability in drug availability, treatment adherence, and adverse event profiles. Future perspectives include optimization of chelation regimens, development of safer agents, and curative approaches such as gene therapy and hematopoietic stem cell transplantation, which may ultimately reduce or eliminate the lifelong requirement for transfusion and chelation.