Approach
All patients with beta-thalassaemia trait, beta-thalassaemia intermedia, or beta-thalassaemia major require genetic counselling.
Beta-thalassaemia trait
These individuals are generally asymptomatic and do not require transfusions. They should be advised to avoid iron supplementation for their anaemia unless they are actually iron deficient.
Beta-thalassaemia intermedia
Patients with beta-thalassaemia intermedia do not usually require regular transfusions. These patients are regarded as having non-transfusion-dependent thalassaemia (NTDT), and are able to grow and develop at a nearly normal rate in spite of the moderate anaemia. However, during periods of stress, such as perioperatively or following a major illness or infection, the anaemia may become severe and symptoms may develop. Transfusions may be administered at such times, the frequency of such transfusions being very variable from one person to another. Splenomegaly is almost inevitable in beta-thalassaemia intermedia, and splenectomy may be performed.
Transfusion-dependent beta-thalassaemia intermedia
Some patients with beta-thalassaemia intermedia may have profound anaemia caused by marked ineffective erythropoiesis, which may lead to lethargy, effort intolerance, and a general feeling of malaise. In the long term, this will cause impaired growth and development, as well as changes in appearance and habitus. The latter include bony abnormalities of the skull, skeletal changes, and abdominal distension from marked hepatosplenomegaly. These patients may require regular transfusions to manage symptoms and to reduce the risk of complications; therefore, they are regarded as being transfusion-dependent, and should be managed in a similar way to patients with beta-thalassaemia major.
Transfused patients should receive monitoring for iron overload, and appropriate iron chelation. In those who are transfusion-dependent, there is evidence to suggest that normalising total body iron load may have the additional benefit of improving glucose tolerance and reducing other endocrine iron deposition.[27][28] However, large studies are needed to confirm these findings. Stem cell transplantation is the only curative therapy.
Beta-thalassaemia major
Regular red cell transfusions and iron chelation therapy form the mainstay of treatment of beta-thalassaemia major.[29] The goals of treatment are to maintain a haemoglobin level that allows normal growth and development without organ damage from chronic hypoxia, and to suppress ineffective erythropoiesis that may otherwise contribute to skeletal changes with poor cosmetic outcome.
In order to achieve these goals, treatment should aim to keep the haemoglobin level above 100 g/L (10 g/dL) at all times.[29] If left untreated, the severe anaemia that results from ineffective erythropoiesis would eventually lead to heart failure and death in the first or second year of life.
Patients with beta-thalassaemia major usually begin transfusion in infancy, receiving split units of packed red blood cells every 4 weeks, with the goal of maintaining the haemoglobin level above 95-100 g/L (9.5-10.0 g/dL) at all times.[30] By the time they are 18 months to 2 years old, these children are on a regular schedule, being transfused with 1 unit of packed red cells every 3 to 4 weeks. Transfusion with 1 unit of blood continues until the patient reaches a weight of 35 to 40 kg, after which they begin to receive 2 units at each transfusion. Split units are not optimal, because of the exposure to additional donors without the full benefit of the whole unit being transfused.
Adults are typically transfused with 2 units every 2 to 3 weeks. In the absence of a more definitive curative therapy, such as stem cell transplantation, this regimen is continued lifelong. In most centres this is done in an outpatient setting, and leuko-reduced packed red cells are the product of choice.[30]
Transfused patients should receive monitoring for iron overload, and appropriate iron chelation. In transfusion-dependent patients, there is evidence to suggest that normalising total body iron load may have the additional benefit of improving glucose tolerance and reducing other endocrine iron deposition.[27][28] However, large studies are needed to confirm these findings. Stem cell transplantation is the only curative therapy.
Development of iron overload
In beta-thalassaemia intermedia and major, iron accumulation inevitably results from a combination of increased intestinal absorption secondary to ineffective erythropoiesis (more so in intermedia) and iron derived from transfused red cells (more so in major). While transfusional iron overload is more predictable, NTDT patients may also have significant amounts of iron loading and must be monitored carefully.[31]
The primary goal of chelation therapy is to prevent tissue deposition of excess iron, thereby preventing organ damage and resulting morbidity and mortality. Safe levels of tissue iron can be maintained by achieving a balance between the amount of iron entering the body and that being removed.
Several variables are important in determining the morbidity related to the increased body iron burden. These include:
Age at which transfusion therapy began
Duration of transfusion therapy
Initiation and maintenance of effective chelation.
Additional modifying factors include genetic determinants, alcohol use, co-existing viral hepatitis, and drugs and medications that the patient may be taking. The complex interplay between the underlying disorder and these factors play a key role in the pathophysiology of iron toxicity in the individual patient.
Measurement of body iron burden
The goal of therapy for patients with transfusional iron overload is to maintain iron balance at low levels of tissue iron, thereby preventing the development of overload and complications.[32][33] The liver iron concentration (LIC) is used to assess the body iron burden; serial measurement of LIC over time is an accurate and reliable means of monitoring the progression of iron loading and the efficacy of chelation therapy. LIC >7 mg Fe/g dry weight is associated with an increased risk of hepatic fibrosis, diabetes, and other complications of iron overload.[34]
Based on these data, maintaining LIC in the suggested 'ideal range' of 3 to 7 mg Fe/g dry weight should minimise iron deposition in non-storage parenchymal sites and prevent significant toxicity. In patients who are transfusion-dependent, there is evidence to suggest that normalising total body iron load may have the additional benefit of improving glucose tolerance and reducing other endocrine iron deposition.[27][28] However, large studies are needed to confirm these findings.
Consistent rising serum ferritin levels or intermittent transfusions given at a volume likely to require chelation (e.g., 6 to 8 transfusions of 15 mL/kg each) should trigger R2 (1/T2) or R2* (1/T2*) MRI assessment of LIC.[35][36]
Cardiac iron burden
Correlation between hepatic and cardiac iron concentrations is not satisfactory, and independent assessment of myocardial iron is recommended. A surrogate for cardiac iron burden, myocardial T2* (a relaxation parameter arising from local magnetic field inhomogeneities that are increased with iron deposition), has been shown to correlate with function.[37] The threshold for 'severe' cardiac disease has also been reduced to a T2* value of 8 msec, below which there is very high risk for development of cardiac disease.
Avoid interpretation of serum and pancreatic iron levels
Caution is advised in interpreting serum ferritin level, as it is not a reliable indicator of total body iron burden or as a parameter for the monitoring of chelator activity.[38]
Some centres have begun to assess pancreatic iron by similar MRI techniques. However, correlation with other tissue iron levels is not robust, and the standard recommendation remains measurement of hepatic and cardiac iron.[33]
Chelation therapy for iron overload
The body cannot excrete excess amounts of iron that accumulate from the breakdown of transfused red cells or from the increased gastrointestinal iron absorption; therefore, chelating agents must be used to bind this excess iron and facilitate its excretion.
The ideal chelator should form a high-affinity 1:1 uncharged complex with iron, be able to chelate intracellular iron, be orally effective with a long half-life, have a high chelator efficiency and low toxicity profile, and be effective in removing iron from (and preventing deposition in) all organs that may be affected with long-term usage. Such a chelator is not yet available. A meta-analysis of the available data on iron chelation therapy was inconclusive with respect to the chelator of choice.[39]
Initiating chelation therapy
Chelation should be considered in both transfusion-dependent and non-transfusion-dependent beta-thalassaemia patients when LIC is >5 mg Fe/g dry weight. In patients receiving regular blood transfusions, the increase in LIC can be estimated based on the total number of transfusions, or by using the following calculation: total transfusion iron intake (i.e., total volume of pure packed red cells transfused [mL/kg] multiplied by haematocrit [%] of transfused red cell units) divided by 10.6.[40]
Transfusion-dependent patients
An LIC >5 mg Fe/g dry weight is usually reached after 6 to 8 red cell transfusions at 15 mL/kg. For young children (who need iron for growth and development), chelation is not used until 2 years of age, at which time they should have an MRI to obtain a baseline measurement of LIC. Older children should have an MRI to assess LIC after 9 to 12 red cell transfusions, at which point chelation would likely be indicated.
Non-transfusion-dependent patients
The rate of iron loading is variable. Therefore, periodic MRI measurements of LIC should be done when there is a clear trend of increasing iron burden, or the patient has received intermittent red cell transfusions at a volume likely to require chelation (e.g., after 6 to 8 transfusions at 15 mL/kg). Iron overload in non-transfusion-dependent patients is a cumulative process that occurs much later in life compared with transfusion-dependent patients.
Choosing a chelating agent
Three chelators are used.[41]
Desferrioxamine
Short half-life (15 min), not absorbed orally; therefore administered by parenteral infusion, with resulting variability in adherence.
Side effects are relatively mild and it is the recommended first choice agent for chelation therapy.[42][43] It is contraindicated in patients severe renal impairment, renal failure, or anuria. Dose modifications may be necessary.
Monitoring for toxicity includes regular (e.g., every 3 months) ophthalmic evaluation and audiogram.
Deferasirox
Plasma half-life of 12 to 16 hours and once-daily oral administration means the drug is present in the circulation throughout the day, enabling constant effective scavenging of iron.
Two formulations of deferasirox are available: a dispersible tablet and a film-coated tablet.
Prospective data indicate that deferasirox is effective in:
At the lower dose, most patients are not able to achieve negative iron balance, but are able to maintain stable body iron burdens.[46]
There is a risk of hepatic and renal toxicity, particularly at higher doses, and it is contraindicated in patients with severe renal impairment or renal failure.
Often used as the primary form of iron chelation therapy because of its good safety and efficacy profile, convenient route of administration, and potential for better adherence.[47][48]
Deferiprone
Has a short half-life (<2 hours) and must be taken orally two to three times a day. Excretion occurs in the urine.
Less effective than desferrioxamine in reducing LIC, but has been suggested to have greater effectiveness in removing myocardial iron.[49]
Serious idiosyncratic complications have been reported with its use, including neutropenia (up to 5%) and agranulocytosis (up to 0.5%), the development of an erosive arthropathy (5% to >20%), and the development of a neurological syndrome of cerebellar and psychomotor retardation. Weekly monitoring for development of neutropenia and agranulocytosis is indicated.[50]
Deferiprone may be considered:
as monotherapy in patients who do not tolerate either desferrioxamine or deferasirox[51]
in combination with either desferrioxamine or deferasirox by patients with insufficient response to monotherapy (particularly those with life-threatening complications from iron overload).
Adherence to and intensification of chelation therapy
Good adherence to chelation therapy is important as iron overloading can lead to significant cardiovascular and endocrine complications. Non-adherence to chelation therapy may result in significant cardiac and endocrine morbidity and increased risk of death from heart disease in transfusion-dependent patients.[52]
The chelation regimen may need to be intensified if the iron burden is high (e.g., following poor adherence to chelation therapy). This is more likely to occur in transfusion-dependent patients than non-transfusion-dependent patients (in whom it very rarely occurs).
An intensification regimen should be started when:
LIC is 8 to 15 mg Fe/g dry weight, or T2* is <20 msec, with no clinical cardiac disease; or
LIC is >15 mg Fe/g dry weight, or T2* is <10 msec, or with the onset of clinical cardiac disease.
For the intensification regimen only, desferrioxamine should be given subcutaneously in (1) above, or by continuous intravenous infusion in (2) above.
Patients with prolonged high iron burden are at high risk for developing congestive heart failure. Prolonged intensive chelation is required in such instances, with improvement of function as the iron is removed from the myocardium.[53]
Vigilance for symptoms and signs of infection is very important, particularly in patients who have undergone splenectomy. Chelation therapy should be temporarily suspended if there is any suspicion of a bacterial or fungal illness, until this is appropriately managed.
Stem cell transplantation
Allogeneic haematopoietic stem cell transplantation is the only therapy that offers a cure for beta-thalassaemia.[54]
Stem cell transplantation is recommended early, before much iron deposition in organs has occurred. It is essentially an elective procedure and is associated with significant morbidity and mortality. Several factors are considered, including parental and patient motivation, compliance history, and organ function pre-transplantation.
Stem cell transplantation should be considered for all patients with the more severe intermedia phenotype (transfusion dependence, progressive iron loading) who have a matched related donor and good prognostic indicators (Pesaro class 1 and 2).
The Pesaro classification was introduced in 1990 and is based on 3 variables:
Class 1: degree of iron overload
Class 2: presence or absence of hepatomegaly
Class 3: presence or absence of fibrosis on liver biopsy.
HLA-antigen-matched related donors are most often the source of haematopoietic stem cells, although in recent years alternative sources have been used, including mismatched related or matched unrelated donors and matched related or unrelated umbilical cord blood.[55][56] Results have been generally superior when bone marrow from matched siblings was used, and to date this is the recommended source. Recently, non-ablative conditioning regimens have also been used, with inferior results compared with standard ablative regimens.
Overall beta-thalassaemia-free survival is 91% for class 1 and 84% for class 2, with those in class 3 having significantly worse outcomes.[57]
Splenectomy
Optimal clinical management may delay or prevent hypersplenism, increasing the efficiency of transfusion therapy and reducing the need for splenectomy.[58]
Splenectomy is performed if the spleen is massively enlarged with risk of spontaneous or traumatic rupture, or if the transfusion requirement is so high that the resulting iron overload would not be adequately managed by regular chelation, usually consistently over 200 ml/kg/year.[29] Splenectomy may reduce transfusion requirements by 20% to 30%.[30][59]
Splenectomy may be performed laparoscopically if the spleen is not markedly enlarged, but may have to be done via laparotomy when massive enlargement is present. If gallstones are present, cholecystectomy is recommended at the same time. Partial splenectomy and embolisation of the splenic artery are not recommended.
Beta-thalassaemia major
Splenomegaly usually develops in patients with beta-thalassaemia major as a result of multiple transfusions, iron deposition, and some ineffective extramedullary erythropoiesis (especially in inadequately transfused patients). This usually results in hypersplenism, leading to an increase in transfusion requirement secondary to decreased red cell survival, as well as leukopenia and thrombocytopenia. With massive enlargement, symptoms of abdominal distension and flank pain may also develop.
Splenectomy results in a reduction of transfusion requirement, usually by 20% to 30%, and therefore reduces iron loading.
Beta-thalassaemia intermedia
Splenomegaly is also almost inevitable in beta-thalassaemia intermedia as a result of extramedullary erythropoiesis. Hypersplenism may develop, and destruction of red cells may result in profound anaemia requiring transfusions. Despite the lack of good quality evidence, splenectomy is recommended in this scenario as it can reverse pancytopenia and reduce the need for transfusions.[59][60]
Infection risk and prophylaxis
Splenectomised patients may have an increased susceptibility to some bacterial infections, particularly pneumococcal, and may be at risk for development of thromboembolism and pulmonary hypertension, in part as a result of thrombocytosis that usually follows the procedure. Prophylaxis with penicillin and vaccination against pneumococcus is recommended for all splenectomised patients.
Chelation therapy should be temporarily suspended if there is any suspicion of a bacterial or fungal illness, until this is appropriately managed.
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