Thalassemia medical therapy: Difference between revisions

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{{Thalassemia}}
{{Thalassemia}}


{{CMG}} {{shyam}}
{{CMG}} {{shyam}} {{NP}}


==Overview==
==Overview==
The treatment of thalassemia ranges from conservative treatments like supportive measures to intensive approaches like bone marrow transplant and gene therapy. Supportive measures include [[red blood cell]] transfusions. However, this can be complicated by iron overload, with iron deposition in various organs. This can sometimes require iron chelation therapy. [[Stem cell transplant]] has been done for thalassemia, with the goal of eliminating the cells with defective globin chains and substituting them for cells with normal globin chains. Gene therapy involves ''in vitro'' or ''ex vivo'' manipulation of the beta-globin gene such that normal gene function can be restored. Other therapies that have been tried with limited success include [[hydroxyurea]] and anti-oxidant therapy. Overall, these therapies have low efficacy.


==Treatment==
==Treatment==


Anyone with thalassemia should consult a properly qualified [[hematologist]].  
===Consultation with a Hematologist===
The first and most important step in management of a patient with thalassemia is consultation with a hematologist. Thalassemia is a relatively rare condition with intricacies such that a specialist should be involved.  


Thalassemias may co-exist with other deficiencies such as [[folic acid]] (or folate, a B-complex vitamin) and [[iron deficiency]] (only in Thalassemia Minor).
===Correction of Nutritional Deficiencies===
Concurrent nutritional deficiencies can exacerbate anemia and contribute towards worsening clinical status. Treatment or correction of the underlying deficiencies is highly important to optimize the therapy plan for thalassemia. Such deficiencies include:


===Thalassemia Major and Intermedia===
*Vitamin B6: This deficiency can be corrected via supplementation with pyridoxine at 100 mg daily. Vitamin B6 is needed for heme synthesis.
Thalassemia Major patients receive frequent [[blood transfusions]] that lead to [[iron overload]]. In recent years, bone marrow transplant has shown promise with some patients of thalassemia major. Successful [[transplant]] can eliminate the patients dependencies in transfusions.  Thalassemia Intermedia patients vary a lot in their treatment needs depending on the severity of their anemia.
*Vitamin B12: This deficiency can be corrected via supplementation with cyanocobalamin at 1000 micrograms daily.
*Folate: This deficiency can be corrected via supplementation with folic acid 1 mg daily. Folate is needed for nucleotide synthesis and [[red blood cell]] production.


====Complications of Treatment====
===Transfusion Support===
Iron overload.
Red blood cell transfusions is a mainstay of therapy for thalassemia. Red blood cell transfusion restores hemoglobin toward a normal range. On average, one unit of packed red blood cells will increase a patient's hemoglobin by 1 gram per deciliter. One unit of packed red blood cells contains 200mg of iron. Iron chelation therapies should be started shortly after transfusion of 10 packed RBC units or ferritin level>1000 ng/dl. Of note, packed red blood cell transfusion is a supportive measure and does not alter the course of the disease. However, given that there are no known effective disease-modifying therapies for thalassemia, red blood cell transfusions are frequently considered as the main type of therapy. Splenectomy can be done in patients who are unable to get transfusion and chelation therapy or those with splenomegaly.
=====Treatment=====
Iron [[chelation treatment]] is necessary to prevent iron overload damage to the internal organs in patients with Thalassemia Major. Because of recent advances in iron chelation treatments, patients with Thalassemia Major can live long lives if they have access to proper treatment. Popular chelators include [[deferoxamine]] and [[deferiprone]]. Of the two, deferoxamine is preferred; it is associated with fewer [[Adverse effect (medicine)|side-effects]].<ref>{{cite journal | author=Maggio A, D'Amico G, ''et al.''
| title=Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial
| journal=Blood Cells Mol Dis
| year=2002
| volume=28
| issue=2
| pages=196&ndash;208
| id=PMID 12064916 }}</ref>


The most common complaint by patients is that it is difficult to comply with the intravenous chelation treatments because they are painful and inconvenient. The oral chelator [[deferasirox]] (marketed as Exjade) was recently approved for use in some countries and may offer some hope with compliance.
===[[Bone Marrow Transplant]]===
Bone marrow transplant for thalassemia is administered with curative intent, similar to the intent of therapy for hematologic malignancies like leukemia. Bone marrow transplant has shown promise with some patients of thalassemia major. Successful [[transplant]] can eliminate the patients dependencies on transfusions. Allogeneic transplant should be considered if a human leukocyte antigen (HLA)-matched sibling donor can be identified.<ref name="pmid26886832">{{cite journal| author=Negre O, Eggimann AV, Beuzard Y, Ribeil JA, Bourget P, Borwornpinyo S et al.| title=Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the β(A(T87Q))-Globin Gene. | journal=Hum Gene Ther | year= 2016 | volume= 27 | issue= 2 | pages= 148-65 | pmid=26886832 | doi=10.1089/hum.2016.007 | pmc=4779296 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26886832  }} </ref> If an HLA-matched sibling cannot be identified, an unrelated donor or haploidentical donor can be used as the source of stem cells. However, the efficacy of this is limited. The disease-free survival rate in adults after transplant is approximately 65%, and the disease-free survival after transplant in children is 88%. Thalassemia intermedia patients vary a lot in their treatment needs depending on the severity of their anemia. It has been proposed that even a small degree of correction of the impaired globin chain can help to reconstitute normal erythrocyte production. Bone marrow transplant for thalassemia involves either autologous or allogeneic donors.


===Thalassemia Minor===
*'''Autologous transplant''': This involves the introduction of genetically engineered [[hematopoietic stem cells]] with normal globin genes from oneself rather than from another human.<ref name="pmid20665635">{{cite journal| author=Roselli EA, Mezzadra R, Frittoli MC, Maruggi G, Biral E, Mavilio F et al.| title=Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients. | journal=EMBO Mol Med | year= 2010 | volume= 2 | issue= 8 | pages= 315-28 | pmid=20665635 | doi=10.1002/emmm.201000083 | pmc=3377331 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20665635  }} </ref> The benefit is that this bypassed histocompatibility barriers.
Contrary to popular belief, Thalassemia Minor patients should not avoid iron-rich foods by default. A serum [[ferritin]] test can determine what their iron levels are and guide them to further treatment if necessary. Thalassemia Minor, although not life threatening on its own, can affect quality of life due to the effects of a mild to moderate [[anemia]]. Studies have shown that Thalassemia Minor often coexists with other diseases such as [[asthma]]<ref>{{cite journal | author=Palma-Carlos AG, Palma-Carlos ML, Costa AC
*'''Allogeneic transplant''': This involves introduction of another person's normal [[hematopoietic stem cells]] containing normal globin chains, rather than cells from oneself. The rate of cure with allogeneic transplant is high, but there are many considerations prior to proceeding with transplant. For example, histocompatibility matching must be done. There can be many complications of transplant such as graft rejection and infections, which can lead to significant morbidity and mortality. [[Graft-versus-host disease]] is a major complication of allogeneic transplant. This is a very significant condition that leads to immune-mediated damage to the skin, liver, and gastrointestinal tract.
| title="Minor" hemoglobinopathies: a risk factor for asthma
| journal=Allerg Immunol (Paris)
| year=2005
| volume=37
| issue=5
| pages=177&ndash;82 }}</ref>, and [[mood disorders]]<ref>{{cite journal | author=Brodie BB
| title=Heterozygous β-thalassaemia as a susceptibility factor in mood disorders: excessive prevalence in bipolar patients
| journal=Clin Pract Epidemiol Mental Health
| year=2005
| volume=1
| pages=6
| id={{doi|10.1186/1745-0179-1-6}} }}</ref>.


===Anti-Oxidant Therapy===
===Anti-oxidant Therapy===
The antioxidant indicaxanthin, found in beets, in a [[spectrophotometric]] study showed that indicaxanthin can reduce perferryl-Hb generated in solution from met-Hb and hydrogen peroxide, more effectively than either Trolox or [[Vitamin C]]. Collectively our results demonstrate that indicaxanthin can be incorporated into the redox machinery of β-thalassemic RBC and defend the cell from oxidation, possibly interfering with perferryl-Hb, a reactive intermediate in the hydroperoxide-dependent Hb degradation.<ref>[http://www.ingentaconnect.com/content/tandf/gfrr/2006/00000040/00000007/art00010;jsessionid=7uvcai88gfora.alexandra?format=print Cytoprotective effects of the antioxidant phytochemical indicaxanthin in β-thalassemia red blood cells]</ref>
The anti-oxidant [[indicaxanthin]], found in beets, has been shown in [[spectrophotometric]] studies to reduce [[perferryl]]-Hb generated in solution from met-Hb and [[hydrogen peroxide]], more effectively than either Trolox or [[Vitamin C]]. Collectively our results demonstrate that indicaxanthin can be incorporated into the redox machinery of beta-thalassemia [[red blood cells]] and defend the cell from oxidation, possibly interfering with perferryl-Hb, a reactive intermediate in the hydroperoxide-dependent hemoglobin degradation.<ref>[http://www.ingentaconnect.com/content/tandf/gfrr/2006/00000040/00000007/art00010;jsessionid=7uvcai88gfora.alexandra?format=print Cytoprotective effects of the antioxidant phytochemical indicaxanthin in β-thalassemia red blood cells]</ref> However, there is no strong supportive evidence for the efficacy of anti-oxidants in thalassemia, given that this is not a disease characterized by oxidative stress.


===Hydroxyurea===
===[[Hydroxyurea]]===
Recently, increasing reports suggest that up to 5% of patients with beta-thalassemias produce fetal hemoglobin (HbF), and use of hydroxyurea also has a tendency to increase the production of HbF, by as yet unexplained mechanisms.
Data from a few observational studies suggest there were lower rates of complications such as leg ulcers, extramedualary hematopoietic pseudotumors, pulmonary hypertension and endocrinopathy in patients treated with Hydroxyurea.  Recently, increasing reports suggest that up to 5% of patients with beta-thalassemias produce fetal hemoglobin (HbF), and use of hydroxyurea also has a tendency to increase the production of fetal hemoglobin, or HbF, by as yet unexplained mechanisms. Hydroyurea is also used in [[sickle cell anemia]] to help increase fetal hemoglobin production. This improves the oxygen carrying capacity of blood. This medication is also used to achieve cytoreduction given that it inhibits ribonucleotide reductase.


===Gene therapy===
===[[Gene Therapy]]===
Beta-globin gene therapy has been proposed for treatment of thalassemias. This concept is based on the idea that restoration of normal globin gene function can treat the disease.<ref name="pmid25737641">{{cite journal| author=Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M et al.| title=Recent trends in the gene therapy of β-thalassemia. | journal=J Blood Med | year= 2015 | volume= 6 | issue=  | pages= 69-85 | pmid=25737641 | doi=10.2147/JBM.S46256 | pmc=4342371 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25737641  }} </ref> The proposed ''in vitro'' systems include [[embryonic stem cells]] (ESCs) and [[induced pluripotent stem cells]] (iPS cells), as these cells can give rise to daughter cells that propagate the normal globin gene.<ref name="pmid25737641">{{cite journal| author=Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M et al.| title=Recent trends in the gene therapy of β-thalassemia. | journal=J Blood Med | year= 2015 | volume= 6 | issue=  | pages= 69-85 | pmid=25737641 | doi=10.2147/JBM.S46256 | pmc=4342371 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25737641  }} </ref>
Beta-globin gene therapy has been proposed for treatment of thalassemias. This concept is based on the idea that restoration of normal globin gene function can treat the disease.<ref name="pmid25737641">{{cite journal| author=Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M et al.| title=Recent trends in the gene therapy of β-thalassemia. | journal=J Blood Med | year= 2015 | volume= 6 | issue=  | pages= 69-85 | pmid=25737641 | doi=10.2147/JBM.S46256 | pmc=4342371 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25737641  }} </ref> The proposed ''in vitro'' systems include [[embryonic stem cells]] (ESCs) and [[induced pluripotent stem cells]] (iPS cells), as these cells can give rise to daughter cells that propagate the normal globin gene.<ref name="pmid25737641">{{cite journal| author=Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M et al.| title=Recent trends in the gene therapy of β-thalassemia. | journal=J Blood Med | year= 2015 | volume= 6 | issue=  | pages= 69-85 | pmid=25737641 | doi=10.2147/JBM.S46256 | pmc=4342371 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25737641  }} </ref> Alternatively, ''ex vivo'' lentiviral transduction of hematopoietic stem cells can be done.<ref name="pmid26886832">{{cite journal| author=Negre O, Eggimann AV, Beuzard Y, Ribeil JA, Bourget P, Borwornpinyo S et al.| title=Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the β(A(T87Q))-Globin Gene. | journal=Hum Gene Ther | year= 2016 | volume= 27 | issue= 2 | pages= 148-65 | pmid=26886832 | doi=10.1089/hum.2016.007 | pmc=4779296 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26886832 }} </ref>  
*'''[[Embryonic stem cells]]''': Early phase of hematopoiesis have been studies in ESCs. These are totipotent cells, meaning that they can give rise to all tissue types within the body. In order to generate this model system, a [[blastocyst]] is generated, and ESCs are isolated from the [[inner cell mass]]. After formation of [[embryoid bodies]], these cells can be used for tissue generation. Each resulting tissue contains cells with the normal globin gene, without the thalassemia mutation.
*'''[[Inducible pluripotent stem cells]]''': The discovery of iPS cells by Yamanaka's group paved the way for downstream scientific applications for stem cell therapy for diseases. iPS cells are generated by retroviral transduction of stem cell transcription factors such as Oct4, Sox2, c-Myc, and KLF4 into differentiated cell types. The factors allow for the differentiated cell types to become reprogrammed into stem cells, which then have the ability to give rise to all cells of the body. iPS cells from patients may thus be therapeutic for patients with thalassemias, as alpha-globin and beta-globin production can be restored.<ref name="pmid25737641">{{cite journal| author=Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M et al.| title=Recent trends in the gene therapy of β-thalassemia. | journal=J Blood Med | year= 2015 | volume= 6 | issue= | pages= 69-85 | pmid=25737641 | doi=10.2147/JBM.S46256 | pmc=4342371 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25737641 }} </ref>


====Contraindicated medications====
*'''[[Embryonic stem cells]]''': Early phase of hematopoiesis have been studies in [[embryonic stem cells]]. These are totipotent cells, meaning that they can give rise to all tissue types within the body. In order to generate this model system, a [[blastocyst]] is generated, and [[embryonic stem cells]] are isolated from the [[inner cell mass]]. After formation of [[embryoid bodies]], these cells can be used for tissue generation. Each resulting tissue contains cells with the normal globin gene, without the thalassemia mutation.
*'''[[Inducible pluripotent stem cells]] (iPS cells)''': The discovery of iPS cells by Yamanaka's group paved the way for downstream scientific applications for stem cell therapy for diseases. iPS cells are generated by retroviral transduction of stem cell transcription factors such as Oct4, Sox2, c-Myc, and KLF4 into differentiated cell types. The factors allow for the differentiated cell types to become reprogrammed into stem cells, which then have the ability to give rise to all cells of the body. iPS cells from patients may thus be therapeutic for patients with thalassemias, as alpha-globin and beta-globin production can be restored.<ref name="pmid25737641">{{cite journal| author=Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M et al.| title=Recent trends in the gene therapy of β-thalassemia. | journal=J Blood Med | year= 2015 | volume= 6 | issue=  | pages= 69-85 | pmid=25737641 | doi=10.2147/JBM.S46256 | pmc=4342371 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25737641  }} </ref>
*'''[[Retroviral vectors]]''': Gamma-retroviral vectors and lentiviral vectors have been used to introduce normal globin genes into cells.<ref name="pmid25737641">{{cite journal| author=Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M et al.| title=Recent trends in the gene therapy of β-thalassemia. | journal=J Blood Med | year= 2015 | volume= 6 | issue=  | pages= 69-85 | pmid=25737641 | doi=10.2147/JBM.S46256 | pmc=4342371 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25737641  }} </ref> An exogenous globin gene is encoded in these viruses, and the viruses are then used to transfect cells. Rapamycin can be used to increase the lentiviral transduction efficiency. Additional methods can be used to prevent silencing of the transgenes. These methods include use of chromatin accessibility elements and insulators in the viral vectors.<ref name="pmid25737641">{{cite journal| author=Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M et al.| title=Recent trends in the gene therapy of β-thalassemia. | journal=J Blood Med | year= 2015 | volume= 6 | issue=  | pages= 69-85 | pmid=25737641 | doi=10.2147/JBM.S46256 | pmc=4342371 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25737641  }} </ref>
*'''[[Hemoglobin F]] inducers''': These are chemical agents that can increase HbF production. These work in synergy with gene therapy for thalassemias. Epigenetic therapies that induce HbF include microRNAs.<ref name="pmid26862517">{{cite journal| author=Saki N, Abroun S, Soleimani M, Kavianpour M, Shahjahani M, Mohammadi-Asl J et al.| title=MicroRNA Expression in β-Thalassemia and Sickle Cell Disease: A Role in The Induction of Fetal Hemoglobin. | journal=Cell J | year= 2016 | volume= 17 | issue= 4 | pages= 583-92 | pmid=26862517 | doi= | pmc=4746408 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26862517  }} </ref> Such epigenetic strategies include inhibition of methylation of the globin gene promoter, allowing for enhanced gene expression of the globin chains.
 
===Treatment of Complications===
 
*Iron overload: The frequent use of blood transfusions poses a significant problem to the treatment of thalassemia. Iron intake from transfusion can saturate the capacity of serum transferrin and leads to formation of non transferrin bound iron species that can accumulate in various organs (liver, heart, endocrine glands). Advancing age is an important risk factor for the complications. Beginning at the age of 10, iron levels should be monitored.<ref name="pmid23475638">{{cite journal| author=Taher AT, Viprakasit V, Musallam KM, Cappellini MD| title=Treating iron overload in patients with non-transfusion-dependent thalassemia. | journal=Am J Hematol | year= 2013 | volume= 88 | issue= 5 | pages= 409-15 | pmid=23475638 | doi=10.1002/ajh.23405 | pmc=3652024 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23475638  }} </ref> Ferritin levels above 2500 ng/ml are associated with increased risk of heart disease and death. Liver concentrations above 7 mg per gram are associated with liver disease. myocardial and hepatic MRI can also be done to monitor patients for iron overload. 
**Limitation to the number of transfusions: Cautious use of blood transfusions is an important initial step to combat iron overload. The typical hemoglobin threshold for transfusion is 7 g/dl. Below this threshold, it is reasonable to administer a blood transfusion.
**Deferasirox: This is an iron chelator that binds to iron in a 2:1 ratio. The mode of excretion is the feces. The frequency of administration is typically once daily or twice weekly, given its long half-life. This medication is not as effective in reducing cardiac iron stores. Adverse effects include renal dysfunction, gastrointestinal symptoms, rash, anaphylactic reactions. This was introduced in 2006.
**Deferoxamine: This is an iron chelator that binds to iron in a 1:1 ratio.<ref name="pmid23112580">{{cite journal| author=Berdoukas V, Farmaki K, Carson S, Wood J, Coates T| title=Treating thalassemia major-related iron overload: the role of deferiprone. | journal=J Blood Med | year= 2012 | volume= 3 | issue=  | pages= 119-29 | pmid=23112580 | doi=10.2147/JBM.S27400 | pmc=3480237 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23112580  }} </ref> It is not given orally due to poor absorption. A slow infusion is the optimal way to administer this agent. It is given daily for 7 days each week. A major complication of deferoxamine is cardiotoxicity.
**Deferiprone: This is an iron chelator that was FDA-approved in October 2011. It binds to iron is a 3:1 ratio. This medication is given orally three times daily, given its short half-life. It works well with regards to chelation of cardiac iron.<ref name="pmid23112580">{{cite journal| author=Berdoukas V, Farmaki K, Carson S, Wood J, Coates T| title=Treating thalassemia major-related iron overload: the role of deferiprone. | journal=J Blood Med | year= 2012 | volume= 3 | issue=  | pages= 119-29 | pmid=23112580 | doi=10.2147/JBM.S27400 | pmc=3480237 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23112580  }} </ref> Urinary excretion is the major method of elimination. This medication was first introduced in 1999 in Europe. Compared to deferoxamine, it can remove iron from the liver equally well. This medication also has efficacy in the central nervous system as it can cross the blood-brain barrier.<ref name="pmid23868464">{{cite journal| author=Bentley A, Gillard S, Spino M, Connelly J, Tricta F| title=Cost-utility analysis of deferiprone for the treatment of β-thalassaemia patients with chronic iron overload: a UK perspective. | journal=Pharmacoeconomics | year= 2013 | volume= 31 | issue= 9 | pages= 807-22 | pmid=23868464 | doi=10.1007/s40273-013-0076-z | pmc=3757270 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23868464  }} </ref>
**Combination deferoxamine and deferiprone: This combination has been studied and has been shown to reduce ferritin and achieve a negative iron balance. However, the combination is not typically used in clinical practice.
*'''Tmprss6 silencing''': Tmprss6 is an enzyme that functions to inhibit hepcidin, which is a liver protein that induces iron deficiency. Silencing of Tmprss6 via RNA interference has been proposed to treat iron overload via regulation of hepcidin.<ref name="pmid23223430">{{cite journal| author=Schmidt PJ, Toudjarska I, Sendamarai AK, Racie T, Milstein S, Bettencourt BR et al.| title=An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia. | journal=Blood | year= 2013 | volume= 121 | issue= 7 | pages= 1200-8 | pmid=23223430 | doi=10.1182/blood-2012-09-453977 | pmc=3655736 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23223430  }} </ref> Preclinical studies in mice have shown efficacy for Tmprss6 silencing for treatment of iron overload via upregulation of hepcidin. This strategy has also been shown to be efficacious in mice with [[hemochromatosis]], a state of iron overload.
*'''Dietary modifications''': Patients with thalassemia who develop iron overload should be counseled about dietary measures that can be taken to prevent the risk of iron overload. Certain foods, such as red meats, should be avoided given their high iron content. Vitamin C should be limited, as vitamin C enhanced iron absorption.
 
===Precision Therapy for Thalassemias===
There are hundreds of beta-thalassemia mutations and thus the molecular phenotype can be quite complex. A targeted therapeutic approach, or precision medicine approach, may be required for proper treatment of thalassemias that occur with rare frequencies.
 
===Contraindicated medications===


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Latest revision as of 13:19, 26 April 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Neel Patel, M.B.B.S[3]

Overview

The treatment of thalassemia ranges from conservative treatments like supportive measures to intensive approaches like bone marrow transplant and gene therapy. Supportive measures include red blood cell transfusions. However, this can be complicated by iron overload, with iron deposition in various organs. This can sometimes require iron chelation therapy. Stem cell transplant has been done for thalassemia, with the goal of eliminating the cells with defective globin chains and substituting them for cells with normal globin chains. Gene therapy involves in vitro or ex vivo manipulation of the beta-globin gene such that normal gene function can be restored. Other therapies that have been tried with limited success include hydroxyurea and anti-oxidant therapy. Overall, these therapies have low efficacy.

Treatment

Consultation with a Hematologist

The first and most important step in management of a patient with thalassemia is consultation with a hematologist. Thalassemia is a relatively rare condition with intricacies such that a specialist should be involved.

Correction of Nutritional Deficiencies

Concurrent nutritional deficiencies can exacerbate anemia and contribute towards worsening clinical status. Treatment or correction of the underlying deficiencies is highly important to optimize the therapy plan for thalassemia. Such deficiencies include:

  • Vitamin B6: This deficiency can be corrected via supplementation with pyridoxine at 100 mg daily. Vitamin B6 is needed for heme synthesis.
  • Vitamin B12: This deficiency can be corrected via supplementation with cyanocobalamin at 1000 micrograms daily.
  • Folate: This deficiency can be corrected via supplementation with folic acid 1 mg daily. Folate is needed for nucleotide synthesis and red blood cell production.

Transfusion Support

Red blood cell transfusions is a mainstay of therapy for thalassemia. Red blood cell transfusion restores hemoglobin toward a normal range. On average, one unit of packed red blood cells will increase a patient's hemoglobin by 1 gram per deciliter. One unit of packed red blood cells contains 200mg of iron. Iron chelation therapies should be started shortly after transfusion of 10 packed RBC units or ferritin level>1000 ng/dl. Of note, packed red blood cell transfusion is a supportive measure and does not alter the course of the disease. However, given that there are no known effective disease-modifying therapies for thalassemia, red blood cell transfusions are frequently considered as the main type of therapy. Splenectomy can be done in patients who are unable to get transfusion and chelation therapy or those with splenomegaly.

Bone Marrow Transplant

Bone marrow transplant for thalassemia is administered with curative intent, similar to the intent of therapy for hematologic malignancies like leukemia. Bone marrow transplant has shown promise with some patients of thalassemia major. Successful transplant can eliminate the patients dependencies on transfusions. Allogeneic transplant should be considered if a human leukocyte antigen (HLA)-matched sibling donor can be identified.[1] If an HLA-matched sibling cannot be identified, an unrelated donor or haploidentical donor can be used as the source of stem cells. However, the efficacy of this is limited. The disease-free survival rate in adults after transplant is approximately 65%, and the disease-free survival after transplant in children is 88%. Thalassemia intermedia patients vary a lot in their treatment needs depending on the severity of their anemia. It has been proposed that even a small degree of correction of the impaired globin chain can help to reconstitute normal erythrocyte production. Bone marrow transplant for thalassemia involves either autologous or allogeneic donors.

  • Autologous transplant: This involves the introduction of genetically engineered hematopoietic stem cells with normal globin genes from oneself rather than from another human.[2] The benefit is that this bypassed histocompatibility barriers.
  • Allogeneic transplant: This involves introduction of another person's normal hematopoietic stem cells containing normal globin chains, rather than cells from oneself. The rate of cure with allogeneic transplant is high, but there are many considerations prior to proceeding with transplant. For example, histocompatibility matching must be done. There can be many complications of transplant such as graft rejection and infections, which can lead to significant morbidity and mortality. Graft-versus-host disease is a major complication of allogeneic transplant. This is a very significant condition that leads to immune-mediated damage to the skin, liver, and gastrointestinal tract.

Anti-oxidant Therapy

The anti-oxidant indicaxanthin, found in beets, has been shown in spectrophotometric studies to reduce perferryl-Hb generated in solution from met-Hb and hydrogen peroxide, more effectively than either Trolox or Vitamin C. Collectively our results demonstrate that indicaxanthin can be incorporated into the redox machinery of beta-thalassemia red blood cells and defend the cell from oxidation, possibly interfering with perferryl-Hb, a reactive intermediate in the hydroperoxide-dependent hemoglobin degradation.[3] However, there is no strong supportive evidence for the efficacy of anti-oxidants in thalassemia, given that this is not a disease characterized by oxidative stress.

Hydroxyurea

Data from a few observational studies suggest there were lower rates of complications such as leg ulcers, extramedualary hematopoietic pseudotumors, pulmonary hypertension and endocrinopathy in patients treated with Hydroxyurea. Recently, increasing reports suggest that up to 5% of patients with beta-thalassemias produce fetal hemoglobin (HbF), and use of hydroxyurea also has a tendency to increase the production of fetal hemoglobin, or HbF, by as yet unexplained mechanisms. Hydroyurea is also used in sickle cell anemia to help increase fetal hemoglobin production. This improves the oxygen carrying capacity of blood. This medication is also used to achieve cytoreduction given that it inhibits ribonucleotide reductase.

Gene Therapy

Beta-globin gene therapy has been proposed for treatment of thalassemias. This concept is based on the idea that restoration of normal globin gene function can treat the disease.[4] The proposed in vitro systems include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS cells), as these cells can give rise to daughter cells that propagate the normal globin gene.[4] Alternatively, ex vivo lentiviral transduction of hematopoietic stem cells can be done.[1]

  • Embryonic stem cells: Early phase of hematopoiesis have been studies in embryonic stem cells. These are totipotent cells, meaning that they can give rise to all tissue types within the body. In order to generate this model system, a blastocyst is generated, and embryonic stem cells are isolated from the inner cell mass. After formation of embryoid bodies, these cells can be used for tissue generation. Each resulting tissue contains cells with the normal globin gene, without the thalassemia mutation.
  • Inducible pluripotent stem cells (iPS cells): The discovery of iPS cells by Yamanaka's group paved the way for downstream scientific applications for stem cell therapy for diseases. iPS cells are generated by retroviral transduction of stem cell transcription factors such as Oct4, Sox2, c-Myc, and KLF4 into differentiated cell types. The factors allow for the differentiated cell types to become reprogrammed into stem cells, which then have the ability to give rise to all cells of the body. iPS cells from patients may thus be therapeutic for patients with thalassemias, as alpha-globin and beta-globin production can be restored.[4]
  • Retroviral vectors: Gamma-retroviral vectors and lentiviral vectors have been used to introduce normal globin genes into cells.[4] An exogenous globin gene is encoded in these viruses, and the viruses are then used to transfect cells. Rapamycin can be used to increase the lentiviral transduction efficiency. Additional methods can be used to prevent silencing of the transgenes. These methods include use of chromatin accessibility elements and insulators in the viral vectors.[4]
  • Hemoglobin F inducers: These are chemical agents that can increase HbF production. These work in synergy with gene therapy for thalassemias. Epigenetic therapies that induce HbF include microRNAs.[5] Such epigenetic strategies include inhibition of methylation of the globin gene promoter, allowing for enhanced gene expression of the globin chains.

Treatment of Complications

  • Iron overload: The frequent use of blood transfusions poses a significant problem to the treatment of thalassemia. Iron intake from transfusion can saturate the capacity of serum transferrin and leads to formation of non transferrin bound iron species that can accumulate in various organs (liver, heart, endocrine glands). Advancing age is an important risk factor for the complications. Beginning at the age of 10, iron levels should be monitored.[6] Ferritin levels above 2500 ng/ml are associated with increased risk of heart disease and death. Liver concentrations above 7 mg per gram are associated with liver disease. myocardial and hepatic MRI can also be done to monitor patients for iron overload.
    • Limitation to the number of transfusions: Cautious use of blood transfusions is an important initial step to combat iron overload. The typical hemoglobin threshold for transfusion is 7 g/dl. Below this threshold, it is reasonable to administer a blood transfusion.
    • Deferasirox: This is an iron chelator that binds to iron in a 2:1 ratio. The mode of excretion is the feces. The frequency of administration is typically once daily or twice weekly, given its long half-life. This medication is not as effective in reducing cardiac iron stores. Adverse effects include renal dysfunction, gastrointestinal symptoms, rash, anaphylactic reactions. This was introduced in 2006.
    • Deferoxamine: This is an iron chelator that binds to iron in a 1:1 ratio.[7] It is not given orally due to poor absorption. A slow infusion is the optimal way to administer this agent. It is given daily for 7 days each week. A major complication of deferoxamine is cardiotoxicity.
    • Deferiprone: This is an iron chelator that was FDA-approved in October 2011. It binds to iron is a 3:1 ratio. This medication is given orally three times daily, given its short half-life. It works well with regards to chelation of cardiac iron.[7] Urinary excretion is the major method of elimination. This medication was first introduced in 1999 in Europe. Compared to deferoxamine, it can remove iron from the liver equally well. This medication also has efficacy in the central nervous system as it can cross the blood-brain barrier.[8]
    • Combination deferoxamine and deferiprone: This combination has been studied and has been shown to reduce ferritin and achieve a negative iron balance. However, the combination is not typically used in clinical practice.
  • Tmprss6 silencing: Tmprss6 is an enzyme that functions to inhibit hepcidin, which is a liver protein that induces iron deficiency. Silencing of Tmprss6 via RNA interference has been proposed to treat iron overload via regulation of hepcidin.[9] Preclinical studies in mice have shown efficacy for Tmprss6 silencing for treatment of iron overload via upregulation of hepcidin. This strategy has also been shown to be efficacious in mice with hemochromatosis, a state of iron overload.
  • Dietary modifications: Patients with thalassemia who develop iron overload should be counseled about dietary measures that can be taken to prevent the risk of iron overload. Certain foods, such as red meats, should be avoided given their high iron content. Vitamin C should be limited, as vitamin C enhanced iron absorption.

Precision Therapy for Thalassemias

There are hundreds of beta-thalassemia mutations and thus the molecular phenotype can be quite complex. A targeted therapeutic approach, or precision medicine approach, may be required for proper treatment of thalassemias that occur with rare frequencies.

Contraindicated medications

Thalassemia is considered an absolute contraindication to the use of the following medications:

References

  1. ↑ 1.0 1.1 Negre O, Eggimann AV, Beuzard Y, Ribeil JA, Bourget P, Borwornpinyo S; et al. (2016). "Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the β(A(T87Q))-Globin Gene". Hum Gene Ther. 27 (2): 148–65. doi:10.1089/hum.2016.007. PMC 4779296. PMID 26886832.
  2. ↑ Roselli EA, Mezzadra R, Frittoli MC, Maruggi G, Biral E, Mavilio F; et al. (2010). "Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients". EMBO Mol Med. 2 (8): 315–28. doi:10.1002/emmm.201000083. PMC 3377331. PMID 20665635.
  3. ↑ Cytoprotective effects of the antioxidant phytochemical indicaxanthin in β-thalassemia red blood cells
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M; et al. (2015). "Recent trends in the gene therapy of β-thalassemia". J Blood Med. 6: 69–85. doi:10.2147/JBM.S46256. PMC 4342371. PMID 25737641.
  5. ↑ Saki N, Abroun S, Soleimani M, Kavianpour M, Shahjahani M, Mohammadi-Asl J; et al. (2016). "MicroRNA Expression in β-Thalassemia and Sickle Cell Disease: A Role in The Induction of Fetal Hemoglobin". Cell J. 17 (4): 583–92. PMC 4746408. PMID 26862517.
  6. ↑ Taher AT, Viprakasit V, Musallam KM, Cappellini MD (2013). "Treating iron overload in patients with non-transfusion-dependent thalassemia". Am J Hematol. 88 (5): 409–15. doi:10.1002/ajh.23405. PMC 3652024. PMID 23475638.
  7. ↑ 7.0 7.1 Berdoukas V, Farmaki K, Carson S, Wood J, Coates T (2012). "Treating thalassemia major-related iron overload: the role of deferiprone". J Blood Med. 3: 119–29. doi:10.2147/JBM.S27400. PMC 3480237. PMID 23112580.
  8. ↑ Bentley A, Gillard S, Spino M, Connelly J, Tricta F (2013). "Cost-utility analysis of deferiprone for the treatment of β-thalassaemia patients with chronic iron overload: a UK perspective". Pharmacoeconomics. 31 (9): 807–22. doi:10.1007/s40273-013-0076-z. PMC 3757270. PMID 23868464.
  9. ↑ Schmidt PJ, Toudjarska I, Sendamarai AK, Racie T, Milstein S, Bettencourt BR; et al. (2013). "An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia". Blood. 121 (7): 1200–8. doi:10.1182/blood-2012-09-453977. PMC 3655736. PMID 23223430.

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