What is the role of medications in the treatment of beta thalassemia?

Updated: May 07, 2021
  • Author: Pooja Advani, MD; Chief Editor: Emmanuel C Besa, MD  more...
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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:

  • Deferoxamine – Intravenously administered
  • 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 
  • 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]

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