Medication Summary
Medical therapy for beta thalassemia primarily involves iron chelation. Each unit of transfused red blood cells (RBCs) contains approximately 200 mg of elemental iron. Additionally, anemia and ineffective erythropoiesis down-regulates the synthesis of hepcidin. [31, 32]
The objective of iron chelation is to avoid the complications of iron overload such as cardiac and hepatic dysfunction. Chelation therapy significantly improves myocardial T2* (a magnetic resonance technique for assessing tissue iron concentration) and left ventricular function. [33, 34]
The following chelation agents are approved for use in the United States:
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Deferoxamine – Intravenously administered
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Deferiprone [35] – Orally administered; indicated for adults and children aged 3 years and older with iron overload due to transfusions for thalassemia syndromes, sickle cell disease, or other anemias
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Deferasirox [36] – Orally administered; approved for treatment of chronic iron overload due to multiple blood transfusions and non–transfusion-dependent thalassemia
A study in 197 beta thalassemia major patients who had evidence of myocardial siderosis (T2* 6-20 ms) but no sign of cardiac dysfunction reported that deferasirox was noninferior to subcutaneous deferoxamine for myocardial iron removal (assessed by improvement in myocardial T2*). [37]
Deferiprone is particularly effective for cardiac iron removal and is therefore recommended for use in patients with significant cardiac iron loading or iron-related cardiac disease. The adverse effects of most concern are agranulocytosis and milder forms of neutropenia. [38] In clinical trials, agranulocytosis has occurred in 1.5% of patients taking deferiprone, most often during the first year of therapy. Weekly monitoring of the absolute neutrophil count allows early detection of granulocytosis, so that therapy can be interrupted. [39]
A comparison study by Poggi et al in 165 adults with beta thalassemia major found benefits of deferasirox compared with other iron chelation regimens (deferoxamine, deferiprone, alone or in combination). After 5 consecutive years of therapy, patients on deferasirox had the highest decrease in the prevalence of any endocrinopathy (diabetes mellitus, hypothyroidism, or hypogonadism) A significant increase in mean bone mineral density T-score (P < 0.001) and a considerable decrease in osteoporosis prevalence were observed in patients receiving deferasirox but not other chelators. [40]
Combinations of deferasirox with other chelating agents have also been evaluated. The combination of deferasirox and deferiprone produced a higher reduction in serum ferritin, greater improvement in cardiac T2* and quality of life indices, and better compliance compared with the combination of deferoxamine and deferiprone. [41]
Guidelines on chelation treatment in thalassemia major have been published. [42, 43] In general, iron chelation is started at age 2-4 years after 20-25 RBC units have been transfused, in patients with a serum ferritin level of greater than 1000 μg/dL and a liver iron concentration (LIC) of greater than 3 mg iron/g dry weight as measured by liver biopsy or by hepatic T2* on magnetic resonance imaging. [12]
Starting iron chelation therapy earlier had been avoided because of concerns over toxicity from deferoxamine; however, this may increase the risk of toxicity from iron accumulation. However, Elalfy et al reported that chelation with deferiprone, which has a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. [44]
In their study, 61 patients with transfusion-dependent thalassemia, aged 10 to 18 (median 12) months, with serum ferritin levels between 400 and 1000 ng/mL, were randomized to early chelation with low-dose (50 mg/kg/day) of deferiprone or to delayed chelation. By approximately 6 months after randomization, none of the patients in the early-chelation arm, but all of those in the delayed-chelation arm, had serum ferritin levels >1000 ng/mL and transferrin saturation levels > 70%. None of the patients in the early-chelation arm experienced unexpected, serious, or severe adverse events. [44]
Luspatercept, an erythroid maturation agent, is approved for anemia in adults with beta thalassemia who require regular red blood cell transfusions. The drug is a recombinant fusion protein that diminishes Smad2/3 signaling by binding several endogenous transforming growth factor–beta (TGF-beta) superfamily ligands. In a model of beta thalassemia, luspatercept decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis.
Approval of luspatercept was based on the BELIEVE phase 3 clinical trial that included adults with beta thalassemia who require regular RBC transfusions (defined as 6-20 RBC units per 24 weeks, with no transfusion-free period greater than 35 days during that period). Patients (n=336) were randomized 2:1 to receive luspatercept (n=224) or placebo (n=112) at a starting dose of 1 mg/kg SC every 21 days for up to 48 weeks. In the patients who received luspatercept, 21.4% achieved a 33% or greater reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) during weeks 13-24 after randomization, compared with 4.5% (n=5) in the placebo arm (risk difference [95% CI]: 17.0 [10.4, 23.6], P< 0.0001). [45]
In 2019, the European Union conditionally approved the use of betibeglogene autotemcel (Zynteglo), the first gene therapy for the treatment of transfusion-dependent beta thalassemia. The FDA approved the betibeglogene autotemcel in August 2022.
Chelating Agents
Class Summary
These agents bind iron and promote excretion.
Deferoxamine (Desferal)
Deferoxamine is usually administered as a slow, subcutaneous infusion through a portable pump. It is freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. This agent is excreted in bile and urine, resulting in red discoloration. It readily chelates iron from ferritin and hemosiderin, but not from transferrin. Deferoxamine is most effective when it is administered as a continuous infusion.
Deferasirox (Exjade)
Deferasirox is available as a tablet for oral suspension. It is an oral iron-chelating agent that reduces liver iron concentration and serum ferritin levels. Deferasirox binds iron with high affinity in a 2:1 ratio. It is approved for treatment of chronic iron overload due to multiple blood transfusions and non–transfusion-dependent thalassemia.
Deferiprone (Ferriprox)
Updated information for deferiprone (Ferriprox). Now approved for transfusional iron overload caused by thalassemia syndromes, sickle cell disease, or other anemias in adults and children aged 3 years and older. It is available as tablets and oral solution.
Gene Therapy, Hematologics
Class Summary
One-time IV infusion that adds functional copies of a modified beta-globin gene into the patients’ hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells using a lentiviral vector, thereby addressing the underlying genetic cause of β-thalassemia.
Betibeglogene autotemcel (Zynteglo)
Indicated for beta-thalassemia in patients who required regular red blood cell transfusions. After IV infusion, transduced CD34+ HSCs engraft in bone marrow and differentiate to produce RBCs containing biologically active beta A-T87Q-globin (a modified beta-globin protein) that combines with alpha-globin to produce functional hemoglobin containing beta A-T87Q-globin (HbA-T87Q).
Erythroid Maturation Agents
Class Summary
In November 2019, the first erythroid maturation agent was approved for anemia in adults with beta thalassemia who require regular red blood cell (RBC) transfusions.
Luspatercept (Reblozyl, luspatercept-aamt)
Recombinant fusion protein that diminishes Smad2/3 signaling by binding several endogenous TGF-beta superfamily ligands. In a model of beta thalassemia, luspatercept decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis. It is indicated for anemia in adults with beta thalassemia who require regular red blood cell transfusions.
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Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.
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Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.
