Clinical Pearls & Morning Reports
The thalassemias are a group of recessively inherited disorders characterized by reduced or no production of hemoglobin and chronic anemia of varying severity. Read the NEJM Review Article here.
Q: Does the degree of imbalance between α-globin and β-globin chains affect the severity of β-thalassemia?
A: The severity of anemia, need for transfusions, and clinical morbidity in β-thalassemia are closely tied to the degree of imbalance between α-globin and β-globin chains. Deficient production of β-globin chains leads to the accumulation of excess, unstable α-globin tetramers in erythroid cells. Free α-globin protein is unstable and generates cytotoxic reactive oxidant species and cellular precipitates that impair the maturation and viability of red-cell precursors, resulting in ineffective erythropoiesis and premature hemolysis of circulating red cells. Thus, patients who have severe β-thalassemia mutations in the homozygous or compound heterozygous state tend to have more severe clinical manifestations, whereas patients who coinherit α-thalassemia tend to have a milder disease.
Q: Does iron overload develop solely in patients with transfusion-dependent β-thalassemia?
A: Although it has traditionally been assumed that, for patients with non–transfusion-dependent β-thalassemia, iron overload does not develop in the absence of transfusions, a bidirectional relationship between ineffective erythropoiesis and primary iron overload has been revealed in such patients. Ineffective erythropoiesis and hypoxia lead to decreased production of the hepatic hormone hepcidin, which in turn results in increased intestinal iron absorption and its release from macrophages in the reticuloendothelial system.
A: Luspatercept is the most recently approved agent (in the United States and Europe) for the treatment of adults with transfusion-dependent β-thalassemia. It is a recombinant fusion protein comprising a modified extracellular domain of the human activin receptor type IIB fused to the Fc domain of human IgG1. Together, the domains bind to select transforming growth factor β superfamily ligands, block SMAD2/3 signaling, and enhance erythroid maturation. A recent phase 3, double-blind trial (BELIEVE) involving adults with transfusion-dependent β-thalassemia who were randomly assigned to receive subcutaneous luspatercept at a dose of 1.00 to 1.25 mg per kilogram of body weight (224 patients) or placebo (112 patients) every 3 weeks showed that luspatercept reduced the transfusion burden by at least 33% (in 21.4% of the luspatercept group vs. 4.5% of the placebo group) over a fixed 12-week period. Luspatercept is now gradually being integrated in local management protocols for transfusion-dependent β-thalassemia. Data on long-term use and use in children are awaited.