Beta Thalassemia 

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


Practice Essentials

Beta thalassemia syndromes are a group of hereditary disorders characterized by a genetic deficiency in the synthesis of beta-globin chains. In the homozygous state, beta thalassemia (ie, thalassemia major) causes severe, transfusion-dependent anemia. In the heterozygous state, the beta thalassemia trait (ie, thalassemia minor) causes mild to moderate microcytic anemia. (See Etiology.)

Patients in whom the clinical severity of the disease lies between that of thalassemia major and thalassemia minor are categorized as having thalassemia intermedia. Several different genotypes are associated with thalassemia intermedia.

Hemoglobin (Hb) E, a common Hb variant found in Southeast Asia, is associated with a beta thalassemia phenotype, and this variant is included in the beta thalassemia category of diseases.

Patients with thalassemia minor usually do not require any specific treatment. Treatment for patients with thalassemia major includes long-term transfusion therapy, iron chelation, splenectomy, allogeneic hematopoietic stem cell transplantation, and supportive measures. See Treatment.

Complications associated with beta thalassemia

Complications associated with beta thalassemia, aside from the aforementioned anemia, are as follows (see Prognosis, Presentation, Workup, Treatment, and Medication):

  • Extramedullary hematopoiesis

  • Asplenia secondary to splenectomy

  • Medical complications from long-term transfusional therapy - Iron overload and transfusion-associated infections (eg, hepatitis); iron overload cardiomyopathy accounts for the majority of deaths in thalassemia patients[1]

  • Increased risk for infections resulting from asplenia (eg, encapsulated organisms such as pneumococcus) or from iron overload (eg, Yersinia species)

  • Cholelithiasis (eg, bilirubin stones)


Beta-globin gene mutations

Mutations in globin genes cause thalassemias. Beta thalassemia affects one or both of the beta-globin genes. More than 200 beta-globin gene mutations have been identified in these patients; this underlies the wide genotypic and phenotypic variability of the disease.[2]  (Alpha thalassemia affects the alpha-globin gene[s].) These mutations, by causing impaired synthesis of the beta-globin protein component of Hb, result in anemia.[3, 4]

Beta thalassemia is inherited as an autosomal recessive disorder. The defect can be a complete absence of the beta-globin protein (ie, beta-zero thalassemia) or a severely reduced synthesis of the beta-globin protein (ie, beta-plus thalassemia). (See the image below.)

Peripheral smear in beta-zero thalassemia minor sh Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.

Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.The genetic defect usually is a missense or nonsense mutation in the beta-globin gene, although occasional defects due to gene deletions of the beta-globin gene and surrounding regions also have been reported.

In beta thalassemia minor (ie, beta thalassemia trait or heterozygous carrier-type), one of the beta-globin genes is defective, resulting in an approximately 50% decrease in the synthesis of the beta-globin protein.

In beta thalassemia major (ie, homozygous beta thalassemia), the production of the beta-globin chains is severely impaired because both beta-globin genes are mutated. The severe imbalance of globin chain synthesis (alpha >> beta) results in ineffective erythropoiesis and severe microcytic hypochromic anemia. (See the image below.)

Peripheral smear from a patient with beta-zero tha 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.

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. The excess unpaired alpha-globin chains aggregate to form precipitates that damage red cell membranes, resulting in intravascular hemolysis. Premature destruction of erythroid precursors results in intramedullary death and ineffective erythropoiesis. The profound anemia typically is associated with erythroid hyperplasia and extramedullary hematopoiesis.

Although beta thalassemia is caused by a genetic mutation in the beta-globin gene (which is located on chromosome 11), many additional factors influence the clinical manifestations of the disease. That is, the same mutations may have different clinical manifestations in different patients. The factors below are known to influence the clinical phenotype.

Intracellular fetal Hb concentrations

The level of expression of fetal Hb (ie, the expression level of the gamma-globin gene) in red blood cells determines, in part, the severity of the disease. Patients with high fetal Hb have milder disease.

Coinheritance of alpha thalassemia

Patients with coinheritance of alpha thalassemia have a milder clinical course because they have a less severe alpha-beta chain imbalance.

Coexistence of sickle cell trait

The coexistence of sickle cell trait and beta thalassemia is a major and symptomatic hemoglobinopathy with most of the symptoms and complications of sickle cell disease. Unlike sickle cell trait, in which most Hb-on-Hb electrophoresis is Hb A (AS), S is the dominant Hb (SA) and usually constitutes about 60% or more of the circulating Hb, depending on the transfusion status of the patient and the nature of the coexisting beta-thalassemia mutation (ie, beta-zero vs beta-plus).


Occurrence in the United States

The frequency of beta thalassemia varies widely, depending on the ethnic population. The disease is reported most commonly in Mediterranean, African, and Southeast Asian populations.

International occurrence

The disease is found most commonly in the Mediterranean region, Africa, and Southeast Asia, presumably as an adaptive association to endemic malaria. The prevalence may be as high as 10% in these areas.

Race-related demographics

Beta thalassemia genes are reported throughout the world, although more frequently in Mediterranean, African, and Southeast Asian populations. Patients of Mediterranean extraction are more likely than Africans to be anemic with thalassemia trait, because they tend to have beta-zero thalassemia rather than beta-plus thalassemia.

The genetic defect in Mediterranean populations is caused most commonly by either (1) a mutation creating an abnormal splicing site or (2) a mutation creating a premature translation termination codon. Southeast Asian populations also have a significant prevalence of Hb E and alpha thalassemia. African populations more commonly have genetic defects leading to alpha thalassemia.

Age-related demographics

The manifestations of the disease may not be apparent until a complete switch from fetal to adult Hb synthesis occurs. This switch typically is completed by the sixth month after birth.


Individuals with thalassemia minor (thalassemia trait) usually have mild, asymptomatic microcytic anemia. This state does not result in mortality or significant morbidity.

The prognosis of patients with thalassemia major is highly dependent on the patient's adherence to long-term treatment programs, namely the hypertransfusion program and lifelong iron chelation. Allogeneic bone marrow transplantation may be curative.

Morbidity and mortality

The major causes of morbidity and mortality in beta thalassemia are anemia and iron overload. The severe anemia resulting from this disease, if untreated, can result in high-output cardiac failure; the intramedullary erythroid expansion may result in associated skeletal changes such as cortical bone thinning. The long-term increase in red-cell turnover causes hyperbilirubinemia and bilirubin-containing gallstones.

Increased iron deposition resulting from lifelong transfusions and enhanced iron absorption results in secondary iron overload. This overload causes clinical problems similar to those observed with primary hemochromatosis (eg, endocrine dysfunction, liver dysfunction, cardiac dysfunction).

A broad spectrum of neurological complications has also been reported in beta thalassemia complications, although most were subclinical. These have included the following[5] :

  • Cognitive impairment
  • Abnormal findings on evoked potentials
  • Cerebrovascular disease
  • Peripheral neuropathy

Patient Education

Educate patients with thalassemia minor about the genetic (hereditary) nature of their disease, and inform them that their immediate family members (ie, parents, siblings, children) may be affected. The presence of beta-thalassemia minor in both parents implies that there is about a one fourth chance that a child will have thalassemia major. Careful genetic counseling is also appropriate for patients in whom one parent has beta-thalassemia minor and the other parent has some form of beta-globin–related disease, such as sickle cell carriage.

Inform patients with thalassemia minor that they do not have iron deficiency and that iron supplementation will not improve their anemia.

For patient education information, see the Thalassemia Directory.



History and Physical Examination

Patients with the beta thalassemia trait generally have no unusual physical findings. In patients with beta thalassemia major, the physical findings are related to severe anemia, ineffective erythropoiesis, extramedullary hematopoiesis, and iron overload resulting from transfusion and increased iron absorption.

The skin may show pallor from anemia and jaundice from hyperbilirubinemia, and the skull and other bones may be deformed secondary to erythroid hyperplasia with intramedullary expansion and cortical bone thinning. Skin ulceration may be present on the extremities.

Thalassemia can result in maxillary enlargement, leading to an appearance known as chipmunk face, along with increased spaces between teeth, overbite, and malocclusion. Painful swelling of salivary glands and a dry mouth may occur, which leads to reduced salivary protection and an increased rate of tooth decay.[6]

Cardiac examination may reveal heart failure and arrhythmia (eg, atrial fibrillation[7] ), related to either severe anemia or iron overload.

Abdominal examination may reveal changes in the liver, gallbladder, and spleen. Hepatomegaly related to significant extramedullary hematopoiesis is typically found. Patients who have received blood transfusions may have hepatomegaly or chronic hepatitis due to iron overload.

The gallbladder may contain bilirubin stones formed as a result of the patient's lifelong hemolytic state. Splenomegaly typically is observed as part of the extramedullary hematopoiesis or as a hypertrophic response related to the extravascular hemolysis.

In addition to cardiac dysfunction, hepatomegaly, and hepatitis, iron overload can also cause endocrine dysfunction, especially affecting the pancreas, testes, and thyroid. Transfusion-associated viral hepatitis resulting in cirrhosis or portal hypertension also may occur.



Diagnostic Considerations

A major diagnostic consideration is to distinguish mild microcytic anemia due to beta-thalassemia carrier state from microcytic anemia due to other causes. Iron studies (iron, transferrin, ferritin) are useful in excluding iron deficiency and the anemia of chronic disorders as the cause of the patient's anemia.

Calculation of the Mentzer index (mean corpuscular volume per red cell count) may be helpful. A Mentzer index of less than 13 suggests that the patient has the thalassemia trait, and an index of more than 13 suggests that the patient has iron deficiency.[8]

Alpha thalassemia, which is characterized by genetic defects in the alpha-globin gene, is another known cause of mild microcytic anemia and has features similar to those of beta thalassemia. However, in contrast to beta-thalassemia minor (carrier) patients who have elevated levels of Hb A2 (2 alpha-globin chains complexed with 2 delta-globin chains), patients with alpha-thalassemia have normal levels of Hb.

Establishing the diagnosis of the alpha-thalassemia trait is often a diagnosis of exclusion. Definitive diagnosis requires measuring either the alpha-beta chain synthesis ratio or performing genetic tests of the alpha-globin cluster (using Southern blot or polymerase chain reaction [PCR] assay tests).

Unstable Hb levels and some types of red cell membrane disorders are other conditions to consider in the differential diagnosis of beta-thalassemia.

Differential Diagnoses



Approach Considerations

Thalassemia major is a severe anemia that presents during the first few months after birth, when the patient’s level of fetal hemoglobin decreases. The diagnosis is usually obvious in the clinical setting of appropriate age and ethnic background. In some cases, the brisk erythropoiesis with increased erythroblasts may be mistaken for clonal proliferative disorders such as leukemia or myelodysplasia.

Skeletal abnormalities in patients with longstanding beta thalassemia major include an expanded bone marrow space, resulting in thinning of the bone cortex. These changes are particularly dramatic in the skull, which may show the characteristic “hair-on-end” appearance.[9] Bone changes can also be observed in the long bones, vertebrae, and pelvis.

The liver and biliary tract of patients with thalassemia major may show evidence of extramedullary hematopoiesis and damage secondary to iron overload from multiple transfusion therapy. Transfusion also may result in infection with the hepatitis virus, which leads to cirrhosis and portal hypertension. Gallbladder imaging may show the presence of bilirubin stones.

The heart is a major organ affected by iron overload and anemia. Cardiac dysfunction in patients with thalassemia major includes conduction system defects, decreased myocardial function, and fibrosis. Some patients also develop pericarditis. Cardiac magnetic resonance imaging (MRI) is considered the criterion standard for measuring cardiac indices, as well as for evaluating cardiac overload by measurement of T2* (relaxation parameter), with a cardiac T2* of less than 10 ms being the most important predictor of development of heart failure.[10]

Thalassemia minor usually presents as a mild, asymptomatic microcytic anemia and is detected through routine blood tests in adults and in older children. These laboratory findings should be evaluated as indicated.

Laboratory Studies

The diagnosis of beta thalassemia minor usually is suggested by the presence of the following:

  • Mild, isolated microcytic anemia

  • Target cells on the peripheral blood smear (see the images below)

  • A normal red blood cell (RBC) count

    Peripheral smear in beta-zero thalassemia minor sh Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.
    Peripheral smear from a patient with beta-zero tha 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.

Heinz bodies, which represent inclusions within RBCs consisting of denatured hemoglobin (Hb), may also be seen in the peripheral blood.[11]

Elevation of the Hb A2 level, demonstrated by electrophoresis or column chromatography, confirms the diagnosis of beta thalassemia trait. The Hb A2 level in these patients usually is approximately 4-6%. In rare cases of concurrent severe iron deficiency, an increased Hb A2 level may not be observed, although it becomes evident with iron repletion. The increased Hb A2 level also is not observed in patients with the rare delta-beta thalassemia trait. An elevated Hb F level is not specific to patients with the beta thalassemia trait.

Free erythrocyte porphyrin (FEP) tests may be useful in situations in which the diagnosis of beta thalassemia minor is unclear. The FEP level is normal in patients with the beta thalassemia trait, but it is elevated in patients with iron deficiency or lead poisoning.

Alpha thalassemia is characterized by genetic defects in the alpha-globin gene, and this variant has features similar to beta thalassemia (see Diagnostic Considerations). Patients with this disorder have normal Hb A2 levels. Establishing the diagnosis of the alpha thalassemia trait requires measuring either the alpha-beta chain synthesis ratio or performing genetic tests of the alpha-globin cluster (using Southern blot or polymerase chain reaction [PCR] assay tests).

Iron studies (iron, transferrin, ferritin) are useful in excluding iron deficiency and the anemia of chronic disorders as the cause of the patient's anemia.

Evidence of hemolysis in the form of indirect hyperbilirubinemia, low haptoglobin, and elevated lactate dehydrogenase may be seen as a result of ineffective erythropoiesis and consequent destruction of these RBCs.

Patients may require a bone marrow examination to exclude certain other causes of microcytic anemia. Physicians must perform an iron stain (Prussian blue stain) to diagnose sideroblastic anemia (ringed sideroblasts).

The Mentzer index is defined as mean corpuscular volume per red blood cell count. An index of less than 13 suggests that the patient has the thalassemia trait, and an index of more than 13 suggests that the patient has iron deficiency.[8]

Prenatal Diagnosis

Prenatal diagnosis is possible through analysis of DNA obtained via chorionic villi sampling at 8-10 weeks’ fetal gestation or by amniocentesis at 14-20 weeks’ gestation. In most laboratories, the DNA is amplified using PCR and then is analyzed for the presence of the thalassemia mutation using a panel of oligonucleotide probes corresponding to known thalassemia mutations.

Since the genetic defects are quite variable, family genotyping usually must be completed for diagnostic linkage (segregation) analysis. With the anticipated availability of large-scale mutation screening by DNA chip technology, extensive pedigree analyses may be obviated.

Physicians can perform fetal blood sampling for Hb chain synthesis at 18-22 weeks’ gestation, but this procedure is not as reliable as DNA analysis sampling methods. Genetic therapy strategies are currently in the early stages of development.



Approach Considerations

The therapeutic approach to thalassemia varies between thalassemia minor and thalassemia major.

Thalassemia minor

Patients with thalassemia minor usually do not require any specific treatment. Inform patients that their condition is hereditary and that physicians sometimes mistake the disorder for iron deficiency. Some pregnant patients with the beta thalassemia trait may develop concurrent iron deficiency and severe anemia; they may require transfusional support if they are not responsive to iron repletion modalities.

Thalassemia major

Treatment for patients with thalassemia major includes the following:

  • Long-term transfusion therapy
  • Erythroid maturation agents (eg, luspatercept)
  • Iron chelation
  • Splenectomy
  • Allogeneic hematopoietic transplantation
  • Supportive measures

Supportive measures include folic acid replacement and monitoring for the development of complications such as pulmonary hypertension, osteoporosis, and bone fractures, poor dentition, heart failure, and aplastic crisis with parvovirus B-19 infection.

Long-term transfusion therapy

The goal of long-term hypertransfusional support is to maintain the patient's hemoglobin level at 9-10 g/dL, thus improving his or her sense of well being while simultaneously suppressing enhanced erythropoiesis. This strategy treats the anemia and suppresses endogenous erythropoiesis so that extramedullary hematopoiesis and skeletal changes are suppressed. Patients receiving long-term transfusion therapy also require iron chelation. (See Medication.)

Blood banking considerations for these patients include completely typing their erythrocytes for Rh and ABO antigens prior to the first transfusion. This procedure helps future cross-matching processes and minimizes the chances of alloimmunization. Transfusion of washed, leukocyte-poor red blood cells (RBCs) at approximately 8-15 mL RBCs per kilogram (kg) of body weight over 1-2 hours is recommended.[12]

Hapgood et al suggest that current recommendations lead to undertransfusion in males. As a result, males may be more likely to have extramedullary hematopoiesis and thus more likely to require splenectomy or to develop spinal cord compression, an uncommon but serious complication of paraspinal extramedullary hematopoiesis.[13]

In their study of 116 patients (51 males and 65 females) with thalassemia major, males were receiving more units of RBCs per transfusion and had a higher annual transfusion volume, but with correction for weight, females were receiving a higher transfused volume per kg: 225 versus 202 mL/kg in males (P=0.028). Erythropoietin (EPO) levels were higher in males: 72 versus 52 mIU/mL (P=0.006). The incidence of splenectomy was higher in males (61%, vs 40% in females; P=0.031).[13]

Hematopoietic stem cell transplantation

Allogeneic hematopoietic transplantation may be curative in some patients with thalassemia major.[14] The first successful allogeneic stem cell transplant from an HLA-identical sibling donor was reported in 1982.[15] An Italian group led by Lucarelli has the most experience with this procedure.[16] This group's research documented a 90% long-term survival rate in patients with favorable characteristics (young age, HLA match, no organ dysfunction).

Transplantation-related issues such as graft versus host disease, graft failure, chronic immunosuppressive therapy, and transplantation-related mortality should be carefully considered prior to proceeding with this approach.

Diet and activity

Drinking tea may help to reduce iron absorption through the intestinal tract. Vitamin C may improve iron excretion in patients receiving iron chelation, especially with deferoxamine.[17] However, anecdotal reports suggest that large doses of vitamin C can cause fatal arrhythmias when administered without concomitant infusion of deferoxamine.

Patient activity may be limited secondary to severe anemia.

Gene therapy

Since the first successful gene therapy for thalassemia major, in 2007, researchers have worked to improve the efficacy and safety of the procedure.[14, 18, 19] In this process, autologous hematopoietic stem cells (HSCs) are harvested from the patient and then genetically modified with a lentiviral vector expressing a normal globin gene. After the patient has undergone appropriate conditioning therapy to destroy existing HSCs, the modified HSCTs are reinfused into the patient. Clinical trials of gene therapy for thalassemia are currently recruiting participants.[20, 21]

A newer approach employs genome editing techniques, such as zinc finger nucleases (ZFN), transcription activator–like effectors with Fokl nuclease (TALEN), or the clustered regularly interspaced short palindromic repeats (CRISPR) with Cas9 nuclease system. These can specifically target single-mutation sites and replace them with the normal sequence, restoring the wild-type functional configuration of the gene. Producing a sufficiently large number of corrected genes is the major challenge with this approach.[14, 22]

Surgical Treatment


Physicians often use splenectomy to decrease transfusion requirements in patients with thalassemia major. (Patients with thalassemia minor only rarely require splenectomy.) Splenectomy is recommended when the calculated annual transfusion requirement is greater than 200-220 mL RBCs/kg/y with a hematocrit value of 70%.[12] In addition to reducing transfusion requirements and the resultant iron overload, splenectomy also prevents extramedullary hematopoiesis.

Because postsplenectomy sepsis is possible, defer this procedure until the patient is older than 6-7 years. In addition, to minimize the risk of postsplenectomy sepsis, vaccinate the patient against Pneumococcus species, Meningococcus species, and Haemophilus influenzae. Administer penicillin prophylaxis to children after splenectomy. Postsplenectomy thrombocytosis can increase the risk of thrombotic events. The risk-to-benefit ratio for this procedure should be cautiously evaluated.


Patients with thalassemia minor may have bilirubin stones in their gallbladder and, if symptomatic, may require treatment. Perform a cholecystectomy using a laparoscope or carry out the procedure at the same time as the splenectomy.

Investigational Therapy

Emerging therapies include pharmacologic agents that induce fetal hemoglobin, Jak2 inhibitors to reverse splenomegaly, hepcidin-related compounds to improve iron metabolism, and gene therapy aimed at delivering the beta globin gene into cells by a viral vector.[23]

Because fetal globin gene expression is associated with a milder phenotype, approaches to enhance intracellular Hb F levels (through drugs that activate gamma-globin gene expression) are under investigation. The two most widely studied drugs in this area are butyrates and hydroxyurea.[24] More recently, new therapeutic targets have been reported, such as BCL11A, which regulates fetal hemoglobin expression.[25, 26]

Other therapeutic approaches currently being investigated include the following[27, 28] :

  • Demethylating agents (eg, decitabine, 5-azacytidine)
  • Histone deacetylase (HDAC) inhibitors (eg, vorinostat, panobinostat)
  • Immunomodulating agents (eg, pomalidomide)
  • Short-chain fatty acid derivatives (eg, arginine butyrate, sodium phenylbutyrate)

Sotatercept (ACE-011) is a promising activin type IIA receptor fusion protein that has been recently reported to improve anemia in patients with non–transfusion-dependent thalassemia intermedia.[29]

Improvement in anemia has been reported with administration of erythropoietin in several studies; however, well-controlled clinical trials have not been performed. The postulated mechanism of action of erythropoietin is that increasing the erythroid mass (pathologic and less pathologic RBCs) and, thus hemoglobin, stimulates fetal hemoglobin, increases iron use, and reduces oxidative stress.[30]

Gene therapy

Gene therapy for beta thalassemia is being pursued by several research groups. In one case report, an adult patient with severe, transfusion-dependent beta thalassemia became transfusion independent for 21 months, 33 months after lentiviral beta-globin gene transfer, with peripheral blood hemoglobin being maintained at 9-10 g/dL.[31]

Obstacles to gene therapy include an inability to express high levels of the beta-globin gene in erythroid cells and an inability to transduce hematopoietic pluripotent stem cells at high efficiency. Additionally, the quest for a safe and specific target gene–delivering vector has been challenging.

A phase I clinical trial using autologous CD34+ hematopoietic progenitor cells transduced with a lentiviral vector encoding the normal human beta-globin gene for treatment of beta thalassemia major is currently under way (NCT01639690).



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.[32, 33]

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.[34, 35]

The following chelation agents are approved for use in the United States:

  • Deferoxamine – Intravenously administered
  • Deferiprone [36] – 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 [37]  – 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*).[38]  

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.[39]  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.[40]  

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.[41]  

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.[42]

 Guidelines on chelation treatment in thalassemia major have been published.[43, 44]  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.[45]  

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.[45]

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).[46]

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.

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. 


Questions & Answers


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What is the focus of investigational treatments for beta thalassemia?


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

Which medications in the drug class Chelating Agents are used in the treatment of Beta Thalassemia?

Which medications in the drug class Erythroid Maturation Agents are used in the treatment of Beta Thalassemia?