Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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beta-thalassemia trait

1st line – genetic counseling + iron advice

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beta-thalassemia trait
1st line – 

genetic counseling + iron advice

All patients with beta-thalassemia trait require genetic counseling.

Genetic testing may be necessary if the person is planning a family with a partner who also has the trait, or if there is a high suspicion that the partner is a silent carrier.

Patients who have beta-thalassemia trait are generally asymptomatic and do not require transfusions. They should be advised to avoid iron supplementation for their anemia unless they are actually iron deficient.

beta-thalassemia intermedia: non-transfusion-dependent

1st line – transfusions at times of symptomatic anemia

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beta-thalassemia intermedia: non-transfusion-dependent
1st line – 

transfusions at times of symptomatic anemia

Patients with beta-thalassemia intermedia do not usually require regular transfusions (non-transfusion-dependent thalassemia). They are able to grow and develop at a nearly normal rate despite the moderate anemia.

Occasionally, patients become severely anemic and develop symptoms as a result. This usually occurs at times of major stress to the body, such as perioperatively, or during a serious illness or infection. At such times it may become necessary to transfuse these patients. The spleen is usually enlarged, but splenectomy is only required when it is massively enlarged.[62]

Consider – iron monitoring + chelation

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beta-thalassemia intermedia: non-transfusion-dependent
Consider – 

iron monitoring + chelation

Treatment recommended for SOME patients in selected patient group

Serial measurement of liver iron concentration (LIC) over time is an accurate and reliable means of monitoring the progression of iron loading and the efficacy of chelation therapy. The rate of iron loading varies between patients.

Even in the absence of regular transfusions, patients with non-transfusion-dependent beta-thalassemia intermedia may become significantly iron overloaded from increased gastrointestinal absorption of iron, driven by ineffective erythropoiesis. This is a cumulative process that occurs much later in life compared with transfusion-dependent patients. Intermittent transfusions also add to the iron burden. The complications of iron overload are the same regardless of how it develops.

Chelation therapy with deferoxamine or deferasirox should be considered in non-transfusion-dependent beta-thalassemia patients when LIC is >5 mg Fe/g dry weight. The latter is particularly effective in reducing iron burden in patients with non-transfusion-dependent beta thalassemia intermedia.[47] Chelation should be stopped when LIC is <3 mg Fe/g dry weight (and only restarted when >5 mg Fe/g dry weight).[33]

Two formulations of deferasirox are available: a dispersible tablet and a film-coated tablet.

Deferiprone monotherapy can be considered in patients who cannot tolerate deferoxamine or deferasirox. It may be used in combination with either deferoxamine or deferasirox by patients with insufficient response to monotherapy (particularly those with life-threatening complications from iron overload); however, non-transfusion-dependent patients almost never need combination chelation therapy.

Although rare in non-transfusion-dependent patients, chelation may need to be intensified if the iron burden is high in order to prevent progression of damage to the heart, liver, and other organs. High iron burden generally occurs from poor adherence to the chelation regimen. 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.[55]

An intensification regimen should be started when: (1) the LIC is 8 to 15 mg Fe/g dry weight, or T2* (a relaxation parameter arising from local magnetic field inhomogeneities that are increased with iron deposition) is <20 msec, with no clinical cardiac disease; or (2) the 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, deferoxamine should be given subcutaneously in (1) above, or by continuous intravenous infusion in (2) above.

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.

Once a patient is receiving chelation therapy, MRI is strongly recommended on an annual basis or prior to any changes in chelation regimen.[33]

Primary options

deferasirox: initial regimen: 7-14 mg/kg orally (tablet) once daily, or 10-20 mg/kg orally (tablet for suspension) once daily; intensification regimen: 14-28 mg/kg orally (tablet) once daily, or 20-40 mg/kg orally (tablet for suspension) once daily

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OR

deferoxamine: initial regimen: 35-40 mg/kg/day by subcutaneous infusion given over 8-12 hours on 5-7 days of each week; intensification regimen: 50 mg/kg/day by subcutaneous/intravenous infusion given over 8-12 hours

Secondary options

deferiprone: initial regimen: 75 mg/kg/day orally given in 2-3 divided doses; intensification regimen: 99 mg/kg/day orally given in 2-3 divided doses

Plus – genetic counseling

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ONGOING
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beta-thalassemia intermedia: non-transfusion-dependent
Plus – 

genetic counseling

Treatment recommended for ALL patients in selected patient group

All individuals with beta-thalassemia intermedia should receive genetic counseling.

beta-thalassemia intermedia: transfusion-dependent

1st line – regular transfusion

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beta-thalassemia intermedia: transfusion-dependent
1st line – 

regular transfusion

Some patients with beta-thalassemia intermedia may have profound anemia 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-thalassemia major.

Plus – iron monitoring + chelation

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beta-thalassemia intermedia: transfusion-dependent
Plus – 

iron monitoring + chelation

Treatment recommended for ALL patients in selected patient group

Chelation therapy should be initiated when liver iron concentration (LIC) is >5 mg Fe/g dry weight, and transfusions are being continued.

A 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. The LIC can also be estimated 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.[42]

Good adherence to chelation therapy is important as iron overloading can lead to significant cardiovascular and endocrine complications. Nonadherence to chelation therapy may result in significant cardiac and endocrine morbidity and increased risk of death from heart disease in transfusion-dependent patients.[54]

Deferoxamine is the first-choice chelator for regularly transfused patients.[44][45]

Deferasirox (with a plasma half-life of 12 to 16 hours) is an alternative option to deferoxamine. Its once-daily oral administration means the drug is present in the circulation throughout the day, enabling constant effective scavenging of iron. Many hematologists use this agent as the primary form of iron chelation therapy because of its good safety and efficacy profile, convenient route of administration, and, therefore, potential for better adherence.[49][50]

Two formulations of deferasirox are available: a dispersible tablet and a film-coated tablet.

Deferiprone can be considered in patients who cannot tolerate deferoxamine or deferasirox.

Chelation may need to be intensified if the iron burden is high in order to prevent progression of damage to the heart, liver, and other organs. High iron burden generally occurs from poor adherence to the chelation regimen. 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.[55]

An intensification regimen should be started when: (1) the LIC is 8 to 15 mg Fe/g dry weight, or T2* is <20 msec, with no clinical cardiac disease; or (2) the 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, deferoxamine should be given subcutaneously in (1) above, or by continuous intravenous infusion in (2) above.

In patients with life-threatening complications from iron overload, deferiprone can be used in combination with deferoxamine or deferasirox to intensify chelation.

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.

Primary options

deferoxamine: initial regimen: 35-40 mg/kg/day by subcutaneous infusion given over 8-12 hours on 5-7 days of each week; intensification regimen: 50 mg/kg/day by subcutaneous/intravenous infusion given over 8-12 hours

OR

deferasirox: initial regimen: 7-14 mg/kg orally (tablet) once daily, or 10-20 mg/kg orally (tablet for suspension) once daily; intensification regimen: 14-28 mg/kg orally (tablet) once daily, or 20-40 mg/kg orally (tablet for suspension) once daily

More

Secondary options

deferiprone: initial regimen: 75 mg/kg/day orally given in 2-3 divided doses; intensification regimen: 99 mg/kg/day orally given in 2-3 divided doses

OR

deferiprone: consult specialist for guidance on dose

-- AND --

deferoxamine: consult specialist for guidance on dose

or

deferasirox: consult specialist for guidance on dose

Plus – genetic counseling

Back
ONGOING
|
beta-thalassemia intermedia: transfusion-dependent
Plus – 

genetic counseling

Treatment recommended for ALL patients in selected patient group

All individuals with beta-thalassemia intermedia should receive genetic counseling.

Consider – splenectomy

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ONGOING
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beta-thalassemia intermedia: transfusion-dependent
Consider – 

splenectomy

Treatment recommended for SOME patients in selected patient group

Splenomegaly is also almost inevitable in beta-thalassemia intermedia as a result of extramedullary erythropoiesis. Hypersplenism may develop, and destruction of red cells may result in profound anemia 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.[28][61]

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 embolization of the splenic artery have not been shown to be consistently effective and are not recommended.

Splenectomized 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 splenectomized patients.

Chelation therapy should be temporarily suspended if there is any suspicion of a bacterial or fungal illness, until this is appropriately managed.

Consider – assessment for stem cell transplantation

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ONGOING
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beta-thalassemia intermedia: transfusion-dependent
Consider – 

assessment for stem cell transplantation

Treatment recommended for SOME patients in selected patient group

Allogeneic hematopoietic stem cell transplantation is the only therapy that offers a cure for beta-thalassemia.[56]

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 pretransplantation. 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).

beta-thalassemia major

1st line – regular transfusion

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ONGOING
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beta-thalassemia major
1st line – 

regular transfusion

Regular red cell transfusions and iron chelation therapy form the mainstay of treatment of beta-thalassemia major.

The goals of treatment are to maintain a hemoglobin 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. If left untreated, the severe anemia that results from ineffective erythropoiesis would eventually lead to heart failure and death in the first or second year of life. In the absence of a more definitive curative therapy, such as stem cell transplantation, a transfusion regimen is continued lifelong.

In order to achieve these goals, patients with beta-thalassemia usually begin transfusion in infancy. Treatment should aim to keep the hemoglobin level above 9.5-10.0 g/dL at all times.[32] Transfusion typically starts between the age of 18 months and 2 years with 1 unit of packed red cells every 3 to 4 weeks. When the patient reaches a weight of 35 to 40 kg they begin to receive 2 units at each transfusion. Adults are typically transfused with 2 units every 2 to 3 weeks.

Monitoring for body iron burden, chelation efficacy, and development of iron-overload related complications is required.

Plus – iron monitoring + chelation

Back
ONGOING
|
beta-thalassemia major
Plus – 

iron monitoring + chelation

Treatment recommended for ALL patients in selected patient group

Chelation therapy should be initiated when liver iron concentration (LIC) is >5 mg Fe/g dry weight, and transfusions are being continued.

A 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. The LIC can also be estimated 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.[42]

Patients with beta-thalassemia major must continue chelation as long as they receive transfusions, and sometimes after they have undergone transplantation, in order to keep the body iron burden below the threshold for development of complications.[63]

One meta-analysis of 18 studies of patients with transfusion-dependent beta-thalassemia has highlighted the importance of adherence to chelation therapy.[54] The analysis showed that nonadherence results in significant cardiac and endocrine morbidity and increased risk of death from heart disease.

There is evidence that normalizing total body iron load in transfusion-dependent patients may have the additional benefit of improving glucose tolerance and reducing other endocrine iron deposition.[30][31] However, large studies are needed to confirm these findings.

Deferoxamine is the first-choice chelator for regularly transfused patients.[44][45]

Deferasirox (with a plasma half-life of 12 to 16 hours) is an alternative option to deferoxamine. Its once-daily oral administration means the drug is present in the circulation throughout the day, enabling constant effective scavenging of iron. Many hematologists use this agent as the primary form of iron chelation therapy because of its good safety and efficacy profile, convenient route of administration, and, therefore, potential for better adherence.[49][50]

Two formulations of deferasirox are available: a dispersible tablet and a film-coated tablet.

Deferiprone can be considered in patients who cannot tolerate deferoxamine or deferasirox.

Chelation may need to be intensified if the iron burden is high in order to prevent progression of damage to the heart, liver, and other organs. High iron burden generally occurs from poor adherence to the chelation regimen. 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.[55]

An intensification regimen should be started when: (1) the LIC is 8 to 15 mg Fe/g dry weight, or T2* is <20 msec, with no clinical cardiac disease; or (2) the 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, deferoxamine should be given subcutaneously in (1) above, or by continuous intravenous infusion in (2) above.

In patients with life-threatening complications from iron overload, deferiprone can be used in combination with deferoxamine or deferasirox to intensify chelation.

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.

Primary options

deferoxamine: initial regimen: 35-40 mg/kg/day by subcutaneous infusion given over 8-12 hours on 5-7 days of each week; intensification regimen: 50 mg/kg/day by subcutaneous/intravenous infusion given over 8-12 hours

OR

deferasirox: initial regimen: 7-14 mg/kg orally (tablet) once daily, or 10-20 mg/kg orally (tablet for suspension) once daily; intensification regimen: 14-28 mg/kg orally (tablet) once daily, or 20-40 mg/kg orally (tablet for suspension) once daily

More

Secondary options

deferiprone: initial regimen: 75 mg/kg/day orally given in 2-3 divided doses; intensification regimen: 99 mg/kg/day orally given in 2-3 divided doses

OR

deferiprone: consult specialist for guidance on dose

-- AND --

deferoxamine: consult specialist for guidance on dose

or

deferasirox: consult specialist for guidance on dose

Plus – genetic counseling

Back
ONGOING
|
beta-thalassemia major
Plus – 

genetic counseling

Treatment recommended for ALL patients in selected patient group

All individuals with beta-thalassemia major should receive genetic counseling.

Consider – splenectomy

Back
ONGOING
|
beta-thalassemia major
Consider – 

splenectomy

Treatment recommended for SOME patients in selected patient group

Optimal clinical management may delay or prevent hypersplenism, increasing the efficiency of transfusion therapy and reducing the need for splenectomy.[60]

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.[27] Splenectomy may reduce transfusion requirements by 20% to 30%.[32][61]

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 embolization of the splenic artery are not recommended.

Splenectomized 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 splenectomized patients.

Consider – assessment for stem cell transplantation

Back
ONGOING
|
beta-thalassemia major
Consider – 

assessment for stem cell transplantation

Treatment recommended for SOME patients in selected patient group

Allogeneic hematopoietic stem cell transplantation is the only therapy that offers a cure for beta-thalassemia.[56]

It is essentially an elective procedure and is associated with significant morbidity and mortality. Stem cell transplantation should be considered for patients who have a matched related donor and good prognostic indicators (Pesaro class 1 and 2).

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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