Pediatric Thalassemia Treatment & Management

Splenectomy is the principal surgical procedure used for some patients with thalassemia. With reports made of venous thromboembolic events (VTEs) after splenectomy, one should carefully consider the benefits and risks before splenectomy is advocated. Splenectomy may be justified when the spleen becomes hyperactive, leading to excessive destruction of RBCs and increasing the need for transfusion to over 200-250 mL/kg of packed RBCs (PRBCs) per year to maintain an Hb concentration of more than 10 g/dL. It can also be helpful in patients with severe HbH disease, since most of the red cells with inclusion bodies are being destroyed in the spleen. ^[15]

The risks associated with splenectomy are small but not trivial. The risk of postsplenectomy infections with encapsulated organisms and malaria in endemic areas is always a concern. Although presplenectomy immunizations and postsplenectomy prophylactic antibiotics have decreased that risk, the procedure is delayed whenever possible until the child is aged 4-5 years or older. Given the risk of thrombosis, low-dose daily aspirin should be considered if the platelet count is greater than 600,000/µL postsplenectomy.

Another surgical procedure in patients with severe thalassemia on transfusion therapy is the placement of a central line for ease of venous access.

Bone marrow transplantation from a matched sibling donor is curative and can yield thalassemia-free survival rates of close to 90%. However, this procedure carries potential morbidity and is not available to the majority of affected patients. ^[4]

Red cell transfusion administration

The Thalassemia Clinical Research Network (TCRN) developed a series of guidelines for ongoing thalassemia management. These guidelines primarily refer to beta-thalassemia major but can be extrapolated to all patients with severe thalassemias. They can also be modified for low-resource countries, where the bulk of severe thalassemia patients are found. ^[7]

Patients typically receive PRBC transfusions (up to 20 mL/kg) every 3-4 weeks, with clinicians aiming for a 9-10 g/dL hemoglobin level prior to the next transfusion. In some patients, shorter intervals between transfusions may be beneficial. A record of the patient's transfusion history should be kept. Extended RBC antigen matching to include C, E, and Kell may reduce alloantibodies, but the reported benefit varies. Premedication with acetaminophen and diphenhydramine is often needed in patients with a history of febrile or urticarial reactions. ^[7]

Immune-mediated hemolytic transfusion reactions, which can be acute or may be delayed by as much as 14 days, have been found in 16.6% of patients. Cross-matching can be complicated and the safe provision of blood delayed when anti-RBC antibodies are present. The use of immunomodulation to treat allosensitization is not recommended, although some studies have employed corticosteroids, intravenous immunoglobulin (IVIG), and rituximab against autoimmune hemolysis or hemolytic transfusion reactions. ^[7]

Routine, age-appropriate immunizations, as well as annual surveillance serologic testing for hepatitis A, B, and C viruses and human immunodeficiency virus (HIV), should be performed in transfused patients with thalassemia. Annual surveillance strategies—for example, annual liver ultrasonographic evaluation and alpha-fetoprotein monitoring to assess for hepatocellular carcinoma secondary to hepatitis B or C—should be carried out according to disease-specific guidelines in patients who have seroconverted for any of these pathogens. ^[7]

Iron chelators

Routine administration of iron chelation is essential to avoid transfusion-related iron overload and multiorgan (especially cardiac and liver) toxicity. ^[7] These agents are discussed in more detail under Medication.

Gene therapy

Betibeglogene autotemcel 

β-globin gene insertion has been shown to be effective in pilot studies, and in 2019, the European Union conditionally approved the use of betibeglogene autotemcel (Zynteglo), the first gene therapy for the treatment of transfusion-dependent beta thalassemia. However, the expense of such therapy is likely to restrict its application. ^{[5, 8, 9, 24]}  The US Food and Drug Administration (FDA) approved betibeglogene autotemcel in August 2022.

The autologous, one-time IV infusion transduces autologous CD34+ cells via a lentiviral vector, thus providing a patient’s hematopoietic stem cells (HSCs) with functional copies of a modified β-globin gene. Adding the functional gene addresses the underlying genetic cause of beta thalassemia. ^{[25, 26]}

The following consultations may be indicated:

• Pediatric surgeon
• Pediatric endocrinologist
• Pediatric ophthalmologist
• Pediatric otolaryngologist
• Pediatric gastroenterologist
• Pediatric HSCT specialist

A normal diet is recommended, with emphasis on the following supplements: folic acid, small doses of ascorbic acid (vitamin C), and alpha tocopherol (vitamin E). Iron should not be given, and foods rich in iron should be avoided. Depletion of trace elements is common in older patients, and supplements containing copper and zinc should be considered. ^[27]

 

Patients with well-controlled disease are usually fully active. Patients with anemia, heart failure, or massive hepatosplenomegaly are restricted according to their tolerances.

Patients with severe thalassemia who are regularly transfused and undergo adequate chelation can live normal, healthy lives. However, chronic blood transfusion carries a risk of specific complications, including iron overload. These complications are discussed below.

Iron overload

Approximately 100 mg of elemental iron (Fe) is contained in 100 mL of PRBCs. Since the normal intake of iron into the body is only 1-2 mg/day, this results in an iatrogenic iron overload after 10-20 transfusions. Iron overload is one of the major causes of morbidity in all patients with severe thalassemia, regardless of whether they are regularly transfused. Increased iron absorption is the cause in nontransfused patients, but the reason behind this phenomenon is not clear. ^[28]

Serum ferritin level is the most commonly used test for evaluation of body iron stores, but it is important to keep in mind the following limitations of this test:

• It reflects only 1% of the total iron storage pool
• At high levels, marginal changes have little meaning
• Inflammatory conditions such as fever and infection may cause the serum ferritin level to rise

T2*-weighted magnetic resonance imaging (MRI) is a noninvasive technique to assess iron loading of the liver and heart, as well as other organs, and has largely replaced liver biopsy and other invasive techniques.

Cardiac complications

Most deaths in patients with thalassemia are due to cardiac involvement secondary to iron overload. Complications range from constrictive pericarditis to heart failure and arrhythmias. Cardiac hemosiderosis does not occur without significant accumulation of iron in other tissues; aggressive chelation therapy may help reverse some of the changes.

Cardiac T2*-weighted MRI has been used to estimate iron deposition in the myocardium. A shortening of myocardial T2*-weighted MRI to less than 20 ms is associated with a 10% likelihood of decreased left ventricular ejection fraction (LVEF), and the risk increases to 70% when it falls to below 5 ms. ^[29]

The LVEF measured by echocardiography has been found to be insensitive for detecting high myocardial iron as a single measurement, but serial echocardiography has proven to be accurate and reproducible. A reduction in the LVEF of 7% or greater over time is a strong predictor for cardiac morbidity. ^[30]

The liver can be cleared of iron loading much earlier than the heart, so persistent abnormal results from cardiac T2*-weighted MRI should not be ignored. ^[31]

Hepatic complications

Iron deposition in the liver can cause liver enlargement, but liver enzyme levels are not typically elevated. A report on chelation use and iron burden in over 300 North American and British patients with thalassemia who were followed from 2002-2011 showed that advances in organ-specific imaging and the availability of oral deferasirox have improved clinical care and outcome in this patient population. ^[16]

Liver biopsy has historically been used to assess liver iron concentration and is a sensitive method to assess total body iron burden, but it is an invasive procedure and has been mostly replaced by T2* MRI of the liver. Normal iron values in liver biopsy are up to 1.8 mg Fe/g dry weight, with levels of more than 15 mg/g/dry weight associated with progression to liver fibrosis. ^[28]

Gallstones

Associated with chronic hemolysis, multiple pigment gallstones are seen in over half of patients with beta-thalassemia major by age 15 years.

HCV and other infections

Hepatitis C virus (HCV) infection is the paramount risk in patients who have been receiving blood transfusions all of their lives. However, a 2004 report using the TCRN registry indicated that after 1990, when HCV screening of the US blood supply was initiated, the incidence of infected thalassemia patients dropped from 70% to 5%. ^[32]  Unfortunately, a high incidence of HCV continues to occur in developing countries, where securing adequately screened blood is a challenge.

Venous and arterial thrombosis

Venous thrombosis embolism (VTE) was encountered in significant numbers of patients with thalassemia intermedia and may manifest with pulmonary hypertension. Patients with thalassemia are mildly hypercoagulable due to endothelial dysfunction and increased platelet reactivity. Treatment with hydroxyurea may ameliorate this problem. In contrast, splenectomy worsens coagulability, and low-dose aspirin is recommended for patients who have been splenectomized. ^{[33, 34]}

HbE/β-thalassemia has been associated with silent cerebral infarction, with research indicating the prevalence to be 24%. In addition, the vascular disorder moyamoya syndrome has been reported in a patient with this form of thalassemia. ^{[35, 36]}

Endocrine complications

People with thalassemia major frequently exhibit features of diabetes mellitus; 50% or more exhibit clinical or subclinical diabetes. This is usually associated with some degree of iron overload. Other endocrine issues are not uncommon. Osteoporosis is a severe complication of thalassemia and may be related to a Wnt-signaling inhibitor termed sclerostin, which inhibits osteoblast function. ^[37]

Growth retardation

Growth retardation is frequently severe in patients with thalassemia, occurring in about 30% of individuals with beta-thalassemia major, and is exacerbated by hypoxia associated with chronic anemia. As a result, children with non–transfusion-dependent thalassemia may need to be temporarily put on regular PRBC transfusions to restore and/or allow normal growth. Growth hormone (GH) deficiency has been postulated, and some recommend testing, but GH therapy remains controversial; it has been shown by some to be ineffective and by others to be effective. ^[38]

Bony complications

Osteoporosis and osteopenia may occur even in patients who are well transfused and may result in pathologic fractures.

Compression fractures and paravertebral expansion of extramedullary masses, which can behave clinically like tumors, more frequently occur during the second decade of life, when red cell production is confined to the central skeleton. These changes usually disappear when marrow activity is halted by regular transfusions. In a series of adolescents and young adults from Thailand with thalassemia syndrome, 13% were found to have fractures, and 30% of this group had multiple vertebral fractures. ^[22]

Fertility and pregnancy complications

Adult patients with beta-thalassemia major have low fertility, which is thought to be related to endocrine toxicity as a consequence of iron overload. One study reported that in 12 males with thalassemia major with a mean age of 24.8 years and a long history of transfusion and chelation, 50% had low sperm count. ^[39]

Females with thalassemia major are frequently oligomenorrheic or amenorrheic, and gonadal dysfunction that results in arrested or delayed puberty has been reported. Nevertheless, successful pregnancy and delivery of healthy babies is possible, and in-vitro fertilization has shown that the quality of the oocytes is not compromised. ^{[40, 41, 42]}

Renal complications

In a retrospective study in which the charts and imaging studies of 89 patients with beta-thalassemia intermedia were reviewed, renal stones were identified in 11 patients (12%), and 22 patients (25%) were on treatment for hyperuricemia. ^[43]

If both parents have β-thalassemia trait, a detailed discussion with the couple should include all possible outcomes, including the 1 in 4 chance of having a severely affected child with beta-thalassemia major. For α⁰ thalassemia carriers, who are usually of Mediterranean or Southeast Asian origin, the large α-globin gene deletion removes both genes on the same DNA strand, and genetic counseling for the couple is mandatory given the 1 in 4 risk of having a child with lethal hydrops fetalis. In contrast, α⁺ thalassemia carriers (of African origin) have a single α-globin gene deletion and are not at risk for having a newborn with severe alpha thalassemia.  ^[15]

The decision to perform prenatal DNA testing when parents are known to be at risk for having a child with thalassemia is complex and is influenced by several factors, such as religion, culture, education, and the number of children in the family. Prenatal counseling can help the parents make an informed decision concerning such evaluation. ^[2]

New methods for neonatal screening have evolved to replace the complex techniques of DNA sequencing, restriction enzyme PCR (RE-PCR) assay, and amplification refractory mutation system (ARMS) analysis. Such methods include noninvasive NGS of fetal DNA obtained from maternal blood. ^[23]

Successful prevention programs in different parts of the world have resulted in a decline in the number of patients with severe forms of beta thalassemia. Ferrara, Italy; Cyprus; Sardinia; Greece; and the United Kingdom were among the first to report a significant decline in the birthrate of children with thalassemia major. Other regions with more limited resources are struggling to recreate this achievement. Premarital screening programs, genetic counseling, and public education campaigns are all part of the effort.  ^{[19, 18]}

Pain assessment, to screen for back pain, and other bony pain should be performed at each clinic visit. 

Psychosocial review to screen for anxiety and depression and decreased quality of life should be performed more frequently in teenagers and adults.