An overview of current treatment strategies for β-thalassemia

Figures & data

Figure 1. Transfusion dependence distinguishes β-thalassemias and their severity.

Table 1. Clinical requirements for occasional, intermittent or chronic transfusions in patients with β-thalassemia.

Transfusion frequency	Disease	Clinical requirement
Chronic	β-Thalassemia major or severe HbE/β-thalassemia	Patients require regular blood transfusions for survival [12]
	Severe β-thalassemia intermedia	Frequent blood transfusion may become necessary when symptoms are severe [6,12,19,96]
Intermittent	Moderate β-thalassemia intermedia or HbE/β-thalassemia	Patient requires transfusion as a result of specific clinical features and symptoms [6]  Reduction in Hb with profound splenomegaly  Growth failure  Failure of secondary sexual development  Poor quality of life
		Patient requires transfusion for the prevention/management of complications [6]  Thrombotic or cerebrovascular disease  Pulmonary hypertension  Extramedullary hematopoietic pseudotumors  Leg ulcers
Occasional	Mild β-thalassemia intermedia or HbE/β-thalassemia	Patients may require a one-off blood transfusion on the occurrence of a specific event [19,96]  Anticipated acute stress and/or blood loss (e.g., pregnancy, surgery, infection)  Hb decrease

Hb: Hemoglobin.

Table 2. Management options for specific β-thalassemia complications.

Complication	Incidence and diagnosis	Management options
Cardiac complications	Common complication among patients with β-thalassemia major, less prevalent with β-thalassemia intermedia or HbE/β-thalassemia Cardiac iron should be measured by MRI annually, starting after the first decade of life	Cardiac iron increased but cardiac function normal: take measures to improve chelation Cardiac impairment: improve chelation, consider slow blood transfusion with diuretics and cardiac medications (e.g., ACE inhibitors, β-blockers, digitalis) [12]
Hepatic complications	Liver complications, including damage such as fibrosis and cirrhosis, are increasing among β-thalassemia major patients [53,97] HCC frequently complicates hepatic cirrhosis secondary to iron overload. Therefore, both transfusion-dependent and non-transfusion-dependent patients with β-thalassemia are at risk of developing HCC [98] Monitoring the risk of HCC: assessment of α/β protein (with echography) may not be reliable in thalassemia Liver iron assessed annually using MRI	Follow guidelines for effective iron chelation
Infections	Second most frequent cause of mortality in patients with β-thalassemia major, particularly among patients with immune abnormalities, splenectomy, iron overload or severe anemia [12,24,53,61,87]. Major complication in patients with HbE/β-thalassemia [99] Risk of contracting viral agents during transfusion Regular monitoring not required. However, clinicians should be aware of high likelihood of infection and treatment should be prompt	In addition to standard vaccines administered to healthy population, vaccinate high-risk patients – such as those undergoing splenectomy – against organisms including pneumococcus (pre-splenectomy and with boosters every 5 – 10 years, as dictated by antibody titers), hemophilus influenzae type B, meningococcus serogroup C and hepatitis B virus [12] Bacterial and fungal infections treated with appropriate broad spectrum/specific antibiotic; consider treating immediately, prior to confirmed cultures [12,24] Transfusion practices should minimize or eliminate risk of transmission of blood-borne viruses. On infection, antiviral therapy should be administered to achieve sustained virologic response. Studies have shown efficacy of pegylated interferon plus ribavirin in patients with thalassemia. However, standard of care is under constant review with the approval of several new agents, particularly for HCV genotype 1 [100,101] Chelation with deferoxamine suspended on diagnosis of some specific bacterial infections [12,24]
Thrombosis/thromboembolic events	β-Thalassemia intermedia and HbE/β-thalassemia patients at increased risk for thromboembolic events as a result of hypercoagulable state; incidence up to fourfold higher than in patients with transfusion-dependent thalassemia [27,33,102,103] Among β-thalassemia intermedia patients, silent brain lesions are observed in the great majority and overt stokes occur in 5 – 9% with history of thrombosis; incidence correlates with increasing age, splenectomy and transfusion naivety [27,103,104] Patients should be assessed individually and high-risk patients identified based on intrinsic (thalassemia type, number of circulating red blood cells) and extrinsic (splenectomy, transfusion status) factors. Patients can then be referred for further testing [105]	Transfusion reduces rates of thromboembolic events; consider more regular transfusions to increase Hb and avoid/delay splenectomy [6] Consider aspirin therapy for splenectomized patients with elevated platelet counts [27] Hydroxyurea therapy may also provide benefit. However, data to support this approach are limited
Pulmonary hypertension	Most common in β-thalassemia intermedia and HbE/β-thalassemia, although it can occur in β-thalassemia major [106] Annual echocardiographic assessment, particularly in high-risk groups Diagnosis via right heart catheterization and ventilation/perfusion lung scan for patients considered likely to have pulmonary hypertension	Confirmed cases should be referred to a cardiologist Transfusion, hydroxyurea, sildenafil citrate, iron chelation, bosentan and anticoagulant therapy may be of some benefit [6]
Extramedullary hematopoietic pseudotumors	Occurrence ∼20% in β-thalassemia intermedia and HbE/β-thalassemia patients [33], but infrequent with β-thalassemia major [107] Many sites can be affected. However, paraspinal involvement has a particularly negative impact on patient quality of life [108,109] No regular monitoring recommended. MRI of the spine to confirm diagnosis if suspected based on clinical features	Mild-to-moderate neurological deterioration: transfusion, radiotherapy, steroids and/or hydroxyurea Severe neurological deterioration: preoperative transfusion followed by laminectomy, radiotherapy and/or hydroxyurea [110]
Osteoporosis	Affects high proportion of β-thalassemia major patients and also many β-thalassemia patients [111] Diagnosis by bone density scan	Preventative measures include diet and exercise changes, as well as calcium, vitamin D and hormonal supplementation, antiresorption agents (bisphosphonate) or combination therapy (bisphosphonate + HRT) [12,107]
Endocrinopathies	Common in β-thalassemia major, β-thalassemia intermedia and HbE/β-thalassemia patients, as a result of iron overload Assessment of thyroid function using FT4, TSH and TRH [107] For diabetes, HbA1C assessment may be unreliable in patients with hemoglobinopathies and those receiving regular transfusion. Glucose tolerance test or monitoring of fructosamine levels more appropriate [112,113]	Hypogonadism: early HRT with treatment individualized to each patient [107] Hypothyroidism: replacement treatment and chelation depending on severity of condition Diabetes: acarbose and possibly insulin therapy and chelation therapy [107,114,115]
Leg ulcers	More common in β-thalassemia intermedia and HbE/β-thalassemia patients [106] Diagnosed by physical examination	Raise legs and feet above heart level for 1 – 2 h during day and while sleeping; topical antibiotics and occlusive dressing; consider transfusion [6] Where ulcers are persistent, options include transfusion, hydroxyurea with/without erythropoietin, oxygen chamber, zinc supplementation, pentoxifylline and skin grafts

ACE: Angiotensin-converting enzyme; FT4: Free total thyroxine; Hb: Hemoglobin; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HRT: Hormone replacement therapy; TRH: Thyrotropin-releasing hormone; TSH: Thyroid stimulating hormone.

Figure 2. Major complications observed in patients with either transfusion-dependent or non-transfusion-dependent β-thalassemia. Patients with β-thalassemia intermedia or HbE/β-thalassemia exhibit a unique profile of complications compared with those with β-thalassemia major, although several complications including osteoporosis, endocrinopathies and hepatic complications, are observed across all patient types.

Figure 3. Flow chart depicting the mean number of complications that occurred in patients with β-thalassemia intermedia undergoing different management schemes. Numbers reported are mean incidences for the 584 patients included in the retrospective OPTIMAL CARE study, according to the management strategy applied that may have involved hydroxyurea, red blood cell transfusion and iron chelation.

Table 3. Frequency and relative expense of observation strategies for monitoring iron overload and other complications in β-thalassemias.

Observation	Frequency	Expense
Iron intake	Each transfusion
Chelation dose and frequency	Every 3 months
Growth and sexual development	Every 6 months in pediatric patients
Occurrence of endocrinopathies	Every 6 months from age 10 years
Bone mineral density	Yearly
Liver function	Every 3 months
Sequential serum ferritin	Every 3 months
Glucose tolerance test, thyroid, calcium metabolism	Yearly in adult patients
Liver iron	Yearly from age 8 to 10 years
Cardiac function	Yearly from age 8 to 10 years
Cardiac iron (T2*)	Yearly from age 8 to 10 years (some suggestion that this could be from 7 years) [116]

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