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Beta Thalassemia Medication

  • Author: Pooja Advani, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Dec 24, 2015
 

Medication Summary

Medical therapy for beta thalassemia primarily involves iron chelation. Each unit of transfused RBCs contains approximately 200 mg of elemental iron. Additionally, anemia and ineffective erythropoiesis down-regulates the synthesis of hepcidin.[12]

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* and left ventricular function.[13, 14]

Deferoxamine is an intravenously administered chelation agent currently approved for use in the United States. Deferiprone, an oral chelation agent, has been approved for use in Europe and received approval in the United States in October 2011 for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Deferasirox (Exjade), another orally administered chelation agent, was approved for use in the United States by the US Food and Drug Administration (FDA) in 2005. Guidelines on chelation treatment in thalassemia major have been published.[15, 16]

In general, iron chelation is started at age 2-4 years after 20-25 RBC units are transfused, 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 noninvasive hepatic T2*MRI.[7]

In January 2013, the FDA approved deferasirox for treatment of chronic iron overload caused by nontransfusion-dependent thalassemia. Deferasirox is a selective trivalent iron chelator that reduces LIC and serum ferritin levels. Approval was based on two clinical trials that measured the number of patients whose LIC was reduced to < 5 mg/g dry weight after 52 weeks of treatment. In the first trial, 166 patients received 5 mg/kg or 10 mg/kg of deferasirox, or a placebo daily. Results showed 15% and 27% of deferasirox-treated patients, respectively, achieved the target LIC compared with 4% of placebo-treated patients.[17] The second trial included 133 patients from the first study who received an additional year of deferasirox treatment or switched from placebo. Of the evaluable patients in this group, 35% achieved the target LIC.[18]

Recently, deferasirox was reported to be noninferior to subcutaneous deferoxamine for myocardial iron removal (assessed by improvement in myocardial T2*) in 197 beta thalassemia major patients who had evidence of myocardial siderosis (T2* 6-20 ms) but no sign of cardiac dysfunction.[19]

A combination of the above-mentioned chelating agents has also been evaluated. For example, the combination of deferiprone and deferasirox demonstrated a higher reduction in serum ferritin, greater improvement in cardiac T2* and quality of life indices, and better compliance compared with the combination of deferiprone and deferoxamine.[20] Similarly, the combination of deferasirox and deferoxamine was also shown to improve cardiac T2* and LIC in patients with severe transfusional body iron burden.[21]

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 2 most widely studied drugs in this area are butyrates and hydroxyurea.[22] More recently, new therapeutic targets have been reported, such as BCL11A (regulates fetal hemoglobin expression).[23, 24]

Demethylating agents such as decitabine and 5-azacytidine, histone deacetylase (HDAC) inhibitors such as vorinostat and panobinostat, immunomodulating agents such as pomalidomide, and short-chain fatty acid derivatives such as arginine butyrate and sodium phenylbutyrate are currently being investigated.[25]

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.[26]

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 by increasing the erythroid mass (pathologic and less pathologic RBCs) and, thus hemoglobin, stimulating fetal hemoglobin, increasing iron use, and reducing oxidative stress.[27]

Gene therapy for beta thalassemia is being pursued by several research groups. 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. In one study, 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.[28]

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 underway (NCT01639690).

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.

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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 treat chronic iron overload due to multiple blood transfusions and nontransfusion-dependent thalassemia.

Deferiprone (Ferriprox)

 

Deferiprone is an iron chelator indicated for patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Approval is based on a reduction in serum ferritin levels. No controlled trials have demonstrated a direct treatment benefit, such as improvement in disease-related symptoms, functioning, or increased survival. It is available as 500-mg, film-coated tablets.

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Contributor Information and Disclosures
Author

Pooja Advani, MD Clinical Fellow, Department of Hematology/Oncology, Mayo Clinic

Pooja Advani, MD is a member of the following medical societies: American Society of Hematology, American Society of Clinical Oncology, Florida Society of Clinical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Kenichi Takeshita, MD Adjunct Associate Professor, Department of Medicine, Division of Hematology, New York University School of Medicine; Medical Director, Clinical Research and Development, Celgene

Kenichi Takeshita, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

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