Thalassemia medical therapy

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

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. 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.

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. 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. 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. 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

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. 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. Alternatively, ex vivo lentiviral transduction of hematopoietic stem cells can be done.

• 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.
• Retroviral vectors: Gamma-retroviral vectors and lentiviral vectors have been used to introduce normal globin genes into cells. 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.
• 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. 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. Beginning at the age of 10, iron levels should be monitored.
  • 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. 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. 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.**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. 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:

• Pegylated interferon alfa-2b