Beta Thalassemia Medication
- Author: Pooja Advani, MD; Chief Editor: Emmanuel C Besa, MD more...
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.
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.
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. 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.
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.
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. Similarly, the combination of deferasirox and deferoxamine was also shown to improve cardiac T2* and LIC in patients with severe transfusional body iron burden.
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. 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.
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.
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.
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.
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.
These agents bind iron and promote excretion.
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 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 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.
Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood. 2011 Sep 29. 118(13):3479-88. [Medline].
Nemtsas P, Arnaoutoglou M, Perifanis V, Koutsouraki E, Orologas A. Neurological complications of beta-thalassemia. Ann Hematol. 2015 Aug. 94 (8):1261-5. [Medline].
Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R. Cardiovascular function and treatment in ß-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013 Jul 16. 128(3):281-308. [Medline].
Jacob HS, Winterhalter KH. The role of hemoglobin heme loss in Heinz body formation: studies with a partially heme-deficient hemoglobin and with genetically unstable hemoglobins. J Clin Invest. 1970 Nov. 49 (11):2008-16. [Medline]. [Full Text].
Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood. 2011 Sep 29. 118(13):3479-88. [Medline].
Hapgood G, Walsh T, Cukierman R, Paul E, Cheng K, Bowden DK. Erythropoiesis is not equally suppressed in transfused males and females with β-thalassemia major: are there clinical implications?. Haematologica. 2015 Aug. 100 (8):e292-4. [Medline]. [Full Text].
Thomas ED, Buckner CD, Sanders JE, Papayannopoulou T, Borgna-Pignatti C, De Stefano P. Marrow transplantation for thalassaemia. Lancet. 1982 Jul 31. 2(8292):227-9. [Medline].
Elalfy MS, Saber MM, Adly AA, Ismail EA, Tarif M, Ibrahim F, et al. Role of vitamin C as an adjuvant therapy to different iron chelators in young β-thalassemia major patients: efficacy and safety in relation to tissue iron overload. Eur J Haematol. 2015 May 28. [Medline].
Maggio A, Vitrano A, Lucania G, Capra M, Cuccia L, Gagliardotto F, et al. Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients. Am J Hematol. 2012 Jul. 87(7):732-3. [Medline].
Cassinerio E, Roghi A, Pedrotti P, Brevi F, Zanaboni L, Graziadei G, et al. Cardiac iron removal and functional cardiac improvement by different iron chelation regimens in thalassemia major patients. Ann Hematol. 2012 May 10. [Medline].
Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med. 1998 Aug 13. 339(7):417-23. [Medline]. [Full Text].
[Guideline] Angelucci E, Barosi G, Camaschella C, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica. 2008 May. 93(5):741-52. [Medline].
Taher AT, Porter J, Viprakasit V, Kattamis A, Chuncharunee S, Sutcharitchan P, et al. Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood. 2012 Aug 2. 120(5):970-7. [Medline].
Taher AT, Porter JB, Viprakasit V et al. Deferasirox continues to reduce iron overload in non-transfusion-dependent thalassemia: a one-year, open-label extension to a one-year, randomized double-blind, placebo-controlled study (THALASSA). Poster presented at the 54th American Society of Hematology Annual Meeting and Exposition in Atlanta, GA (8-11 December 2012). Abstract #3258.
Pennell DJ, Porter JB, Piga A, Lai Y, El-Beshlawy A, Belhoul KM, et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in ß-thalassemia major (CORDELIA). Blood. 2014 Mar 6. 123(10):1447-54. [Medline]. [Full Text].
Elalfy M et al, 55th Annual ASH Annual Meeting abstracts, 2013, abstract# 559.
Yesim A et al, 55th ASH Annual Meeting abstracts, 2013, abstract # 2257.
Italia KY, Jijina FJ, Merchant R, et al. Response to hydroxyurea in beta thalassemia major and intermedia: experience in western India. Clin Chim Acta. 2009 Sep. 407(1-2):10-5. [Medline].
Raechel P et al, 55th Annual ASH Meeting abstracts, 2013, abstract # 1022.
Perrine SP, Pace BS, Faller DV. Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am. 2014 Apr. 28(2):233-48. [Medline].
Maria-Domenica C, 55th Annual ASH Meeting abstracts, 2013, abstract # 3448.
Fibach E, Rachmilewitz EA. Does erythropoietin have a role in the treatment of ß-hemoglobinopathies?. Hematol Oncol Clin North Am. 2014 Apr. 28(2):249-63. [Medline].
Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human ß-thalassaemia. Nature. 2010 Sep 16. 467(7313):318-22. [Medline].