Beta-thalassemia and related disorders

Beta-thalassemia and related disorders encompass a group of inherited blood conditions caused by mutations in the HBB gene on chromosome 11, which encodes the beta-globin chain of hemoglobin. These mutations lead to reduced (beta-plus) or absent (beta-zero) production of beta-globin chains, resulting in an imbalance of alpha- and beta-globin chains, ineffective erythropoiesis, and chronic hemolytic anemia. The spectrum of beta-thalassemia ranges from the clinically silent carrier state (beta-thalassemia minor or trait) to the moderately severe form (beta-thalassemia intermedia, also known as non-transfusion-dependent thalassemia) and the most severe form (beta-thalassemia major, historically called Cooley's anemia), which requires regular blood transfusions. Related disorders within this group include hemoglobin E/beta-thalassemia and other compound heterozygous states. The disease primarily affects the hematologic system, but its consequences are multisystemic. Patients with severe forms may develop pallor, jaundice, failure to thrive, hepatosplenomegaly, skeletal deformities due to bone marrow expansion, growth retardation, and iron overload affecting the heart, liver, and endocrine organs. Iron overload — resulting from both increased intestinal iron absorption and chronic transfusion therapy — is a major cause of morbidity and mortality, leading to cardiomyopathy, liver fibrosis, diabetes mellitus, hypogonadism, and hypothyroidism. Patients with beta-thalassemia intermedia may present later in life with variable severity and may not require regular transfusions but can still develop significant complications including pulmonary hypertension, thromboembolic events, and extramedullary hematopoiesis. The current treatment landscape includes regular red blood cell transfusions combined with iron chelation therapy (using agents such as deferoxamine, deferasirox, or deferiprone) as the mainstay for transfusion-dependent patients. Allogeneic hematopoietic stem cell transplantation remains the only established curative therapy and is most successful when performed in childhood with an HLA-matched sibling donor. Gene therapy has emerged as a transformative treatment option, with betibeglogene autotemcel (Zynteglo) approved for transfusion-dependent beta-thalassemia, and exagamglogene autotemcel (Casgevy), a CRISPR-based gene editing therapy, also receiving regulatory approval. Luspatercept, a modified activin receptor ligand trap, has been approved to reduce transfusion burden. Supportive care includes monitoring and management of endocrine complications, cardiac surveillance, bone health optimization, and psychosocial support. Beta-thalassemia is most prevalent in populations from the Mediterranean region, the Middle East, Central Asia, India, and Southeast Asia, where carrier rates can be very high due to the selective advantage conferred against malaria.

Common questions about Beta-thalassemia and related disorders