**7. Treatment of thalassemia**

#### **7.1. Transfusion therapy**

In general, children with β-thalassemia major and hemoglobins of less than 6–7 g/dl should receive chronic transfusions. It is important to start early before the child has a chance to develop splenomegaly and hypersplenism and before skeletal changes and growth retardation. It is also important to establish a reliable, routine transfusion schedule that maintains hemoglobin levels of 9–10 g/dl [27].

Transfusions of washed, leukocyte-depleted RBCs are recommended for all the patients to reduce the incidence of febrile and urticarial reactions as well as infectious cytomegalovirus contamination [28]. Extended red cell antigen typing, including at least the Rh antigens, Duffy, Kidd, and Kell, is recommended before the patient is started on a transfusion regimen [27].

#### **7.2. Iron chelation therapy**

carpals, and metatarsals. Skull bones show "hair-on-end." The maxilla may overgrow, which results in maxillary overbite, prominence of the upper incisors, and separation of the orbit. These changes contribute to the classic chipmunk facies observed in patients with thalassemia major [21]. Chest radiography is used to evaluate cardiac size and shape. Left ventricular function can be quantified using MRI, MUGA (multiple gated acquisition scan) or echocar-

120 Epidemiology of Communicable and Non-Communicable Diseases - Attributes of Lifestyle and Nature on Humankind

Cardiac T2\*, a noninvasive procedure involves measuring the cardiac T2 with cardiac magnetic resonance (CMR). This procedure has shown decreased values in cardiac T2 due to iron deposit in the heart. Unlike liver MRI, CMR does not correlate well with the ferritin level, the liver iron level, or echocardiography findings. The liver is clear of iron loading much earlier than the heart, and so the decision to stop or reduce chelation treatment based on liver iron levels is

A poor correlation was noted between cardiac and hepatic iron concentrations as assessed by T2-MRI where approximately 14% of patients with cardiac iron overload were identified who

PCR-based procedures can detect the commonly occurring mutations in β-globin gene. The most commonly used methods are reverse dot blot analysis or primer-specific amplification, with a set of probes complementary to the most common mutations in each population. β-Globin gene sequence analysis is used to detect mutations in the β-globin gene in case of failure

Prenatal diagnosis is possible through analysis of DNA obtained through 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 the PCR assay test and then is analyzed for the presence of the thalassemia mutation using a panel of oligonucleotide probes corresponding to known thalassemia mutations. Prenatal diagnosis may be performed noninvasively, with the use of maternal blood samples to isolate either fetal cells or fetal DNA for analysis [26].

In general, children with β-thalassemia major and hemoglobins of less than 6–7 g/dl should receive chronic transfusions. It is important to start early before the child has a chance to develop splenomegaly and hypersplenism and before skeletal changes and growth retardation. It is also important to establish a reliable, routine transfusion schedule that maintains

had no matched degree of hepatic hemosiderosis [24].

diography [22].

misleading [23].

**6.3. Molecular genetic analysis**

of targeted mutation analysis [25].

**7. Treatment of thalassemia**

hemoglobin levels of 9–10 g/dl [27].

**7.1. Transfusion therapy**

**6.4. Prenatal diagnosis**

Children with thalassemia major should begin therapy at the earliest possible age and certainly by the time they have accumulated more than 7 g of excess iron. In young children, a serum ferritin level much greater than 1.000 μg/l or 1 year of regular transfusions (or both) can be used as surrogate indicators to initiate chelation therapy [27].

#### *7.2.1. Deferoxamine*

Deferoxamine (DFO) is a hexadentate iron chelator (deferoxamine mesylate; desferal®). DFO was introduced as parenteral therapy for iron overload associated with β-thalassemia major in 1976 [30]. Plasma half-life of DFO is short (20–30 min). Therefore, standard treatment involves the subcutaneous infusion of 40 mg DFO for 8–12 h nightly for 5–7 nights weekly using a battery-operated infusion pump. Subcutaneous administration is preferred except in patients with severe cardiac iron deposition, for whom continuous intravenous deferoxamine therapy is recommended. Iron excretion occurs through biliary and urinary routes [29].

Adverse events of DFO include growth retardation, skeletal changes, ocular and auditory disturbances, pulmonary, and renal toxicities. They are preventable if proper monitoring is practiced to detect early signs of toxicity. Susceptibility to infection with Yersinia and perhaps other Gram-negative bacilli is increased in thalassemia patients who receive DFO therapy. Painful local skin reactions at the infusion site are common. Zinc deficiency can occur [29].

#### *7.2.2. Deferiprone*

Deferiprone (DFP) is an orally administered bidentate iron chelator (Ferriprox®, Kelfer®). The usual dose of DFP is 75–100 mg/kg/day taken orally in three divided doses. Plasma half-life of DFP is 2–3 h, and iron is mainly excreted in urine [30]. Adverse effects of DFP include gastrointestinal disturbances, agranulocytosis and neutropenia, arthropathy, increased liver enzyme levels, and low plasma zinc level [29, 30].

#### *7.2.3. Deferasirox*

Deferasirox (DFX) is an orally administered tridentate iron chelator that is indicated for the treatment of transfusion iron overload in persons more than 2 years of age. The US Food and Drug Administration approves a recommended daily dose of 20–40 mg/kg body weight, taken once on an empty stomach at least 30 min before food [29]. The most common adverse events with DFX therapy include gastrointestinal disturbances, rash, and mild increases in serum creatinine [31].

#### *7.2.4. Combination therapy*

#### *1. "Shuttle hypothesis": combination of DFO and deferiprone*

Combined DFO and DFP regimens offer an alternative option for patients with severe heart disease. Deferiprone, though a weaker chelator, is a relatively small uncharged molecule that can enter the cardiac cells more easily than DFO and transfers the chelated iron from the myocardial cells to the stronger chelator, DFO in the plasma [32].

#### *2. Combination of Deferasirox and DFO*

The efficacy of combining DFO with Deferasirox has been assessed in a number of studies. This combination has an additive effect, allows decreasing the dose of both chelators and improves the compliance. The "shuttle effect" is also applicable with this combination as Deferasirox acts as an intracellular chelator and DFO as a powerful extracellular chelator [32].

#### **7.3. Splenectomy**

Splenectomy is recommended when the calculated annual transfusion requirement is >200 to 220 ml RBCs/kg per year with a hematocrit of 70%. Splenectomy may be necessary to decrease the disabling effects of abdominal pressure and to increase the life span of supplemental RBCs. After splenectomy, children generally require fewer transfusions, although the basic defect in Hb synthesis remains unaffected. Splenectomy is a therapy that should not be considered casually because susceptibility to infection with *Streptococcus pneumoniae, Haemophilus influenza*, and *Neisseria meningitids* increases after splenectomy in children, particularly in those younger than 5 years. Standard therapy for splenectomized individuals includes immunizations, prophylactic penicillin, and a high index of suspicion and aggressive antibiotic therapy for febrile illness. Thromboembolic events and pulmonary hypertension are also increased in splenectomized patients. These complications may be minimized by the routine use of aspirin or low dose anticoagulants [28].

#### **7.4. Stem cell transplantation (SCT)**

SCT or bone marrow transplantation (BMT) is the only possible, proven curative treatment for β-thalassemia major. The most important role of SCT is the high chance of cure for individuals who otherwise face a lifetime of invasive, demanding treatment and a reduced life span [33].

#### **7.5. Vitamin supplementation**

Vitamin E supplementation in thalassemia major is often suggested, but data demonstrating its efficacy are lacking. Folic acid supplements help to maintain folic acid levels in the face of increased requirements [27].

#### **7.6. Fetal hemoglobin induction**

In β-thalassemia, pharmacologically induced increase in γ-globin chains would be expected to decrease globin chain imbalance with consequent amelioration of clinical manifestation. Pharmacologically, three classes of agents have been shown to be capable of inducing HbF to therapeutic levels: erythropoietins, short-chain fatty acid derivatives, and chemotherapeutic agents. Hydroxyurea has been recommended in patients with thalassemia intermedia [28].

#### **7.7. Gene therapy**

*7.2.4. Combination therapy*

[32].

**7.3. Splenectomy**

or low dose anticoagulants [28].

**7.5. Vitamin supplementation**

increased requirements [27].

**7.4. Stem cell transplantation (SCT)**

*2. Combination of Deferasirox and DFO*

*1. "Shuttle hypothesis": combination of DFO and deferiprone*

Combined DFO and DFP regimens offer an alternative option for patients with severe heart disease. Deferiprone, though a weaker chelator, is a relatively small uncharged molecule that can enter the cardiac cells more easily than DFO and transfers the chelated iron

122 Epidemiology of Communicable and Non-Communicable Diseases - Attributes of Lifestyle and Nature on Humankind

The efficacy of combining DFO with Deferasirox has been assessed in a number of studies. This combination has an additive effect, allows decreasing the dose of both chelators and improves the compliance. The "shuttle effect" is also applicable with this combination as Deferasirox acts as an intracellular chelator and DFO as a powerful extracellular chelator

Splenectomy is recommended when the calculated annual transfusion requirement is >200 to 220 ml RBCs/kg per year with a hematocrit of 70%. Splenectomy may be necessary to decrease the disabling effects of abdominal pressure and to increase the life span of supplemental RBCs. After splenectomy, children generally require fewer transfusions, although the basic defect in Hb synthesis remains unaffected. Splenectomy is a therapy that should not be considered casually because susceptibility to infection with *Streptococcus pneumoniae, Haemophilus influenza*, and *Neisseria meningitids* increases after splenectomy in children, particularly in those younger than 5 years. Standard therapy for splenectomized individuals includes immunizations, prophylactic penicillin, and a high index of suspicion and aggressive antibiotic therapy for febrile illness. Thromboembolic events and pulmonary hypertension are also increased in splenectomized patients. These complications may be minimized by the routine use of aspirin

SCT or bone marrow transplantation (BMT) is the only possible, proven curative treatment for β-thalassemia major. The most important role of SCT is the high chance of cure for individuals who otherwise face a lifetime of invasive, demanding treatment and a reduced life span [33].

Vitamin E supplementation in thalassemia major is often suggested, but data demonstrating its efficacy are lacking. Folic acid supplements help to maintain folic acid levels in the face of

from the myocardial cells to the stronger chelator, DFO in the plasma [32].

B-Thalassemia is a potential attractive target for gene therapy. This could be a reality if a functional β-globin gene could be safely and efficiently introduced into the hematopoietic stem cells, and lineage-restricted expression of the β-globin protein exceeding 15% could be achieved in erythroid progenitor cells. Gene therapy for β-thalassemia requires gene transfer into hematopoietic stem cells (HSCs) using integrating vectors that direct the regulated expression of β-globin at therapeutic levels [34].
