Guidelines For Management of Children with Thalassaemia in Leeds Children’s Hospital

• Mechanism for referral
• When to refer from the community
• Acute Clinical Presentation in the Treated Thalassaemia Patient
• General advice

• Outpatient management
  • New diagnosis
  • Initial Review of Patients Previously Treated Outside the UK
  • Review before initiation of transfusion and decision to start transfusions
  • Protocol for transfusion
  • Monitoring recommendations for patients at risk of iron overload including after transfusion programme started
  • Iron chelation treatment
  • Management of thalassaemia intermedia, including haemoglobin E/β thalassaemia
  • Transition to adult services
  • Clinic organisation

• Appendices
  • Clinical features of thalassaemia
  • Haemoglobinopathy screening
  • Iron Loading
  • Iron Chelation
  • Referral for Consideration of Bone Marrow Transplantation Surgery, including Splenectomy
  • Cardiac Complications
  • Endocrine Complications
  • Liver Complications
  • Bone Complications
  • Dental care
  • Fertility and Management of Pregnancy
  • Prenatal Diagnosis and Preimplantation Genetic Diagnosis
  • References

Mechanism for referral

Urgent concern regarding child or young person <18 years old with possible new diagnosis or complications of thalassaemia including those presenting to the Emergency Department?

Ask for specialist registrar covering paediatric haematology or consultant on call for paediatric haematology/oncology.

Unless there is a specific contraindication, all such patients should be cared for on the paediatric haematology wards.

All new patients who may have sickle cell disease or thalassaemia who are <18 years old who are not presenting unwell and need outpatient referral should be discussed with/referred to the Paediatric Haematology Department, Martin Wing, Leeds General Infirmary, LS1 3EX. This includes infants identified through the neonatal haemoglobinopathy screening programme.

Tel 0113 3928776
Fax 0113 3928488

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When to refer from the community

Previously undiagnosed patient

Emergency referral

Clinically, the presentation of a child with thalassaemia major or intermedia may be insidious, with poor feeding, faltering growth, pallor, and increased susceptibility to infection. If untreated, progressive anaemia and metabolic stress eventually cause heart failure and death. There is enlargement of the liver and spleen. The ineffective expansion of the erythropoietic marrow results in bone thinning and deformity. Untreated, children with β thalassaemia major die from heart failure or infection before the age of five. It is from four to six months of age onwards that infants with thalassaemia major can become symptomatic.

If a patient with such a presentation is identified in the community make contact with the haemoglobinopathy team as described above.

Outpatient referral

Possible new case of thalassaemia presenting through neonatal screening, new presentation at an older age or following movement of a family to the Leeds area. Make contact with the haemoglobinopathy team as described above

Essential longer term management in the community

Guidance for management in the community will be described in clinic letters/discharge summaries but ongoing interventions in partnership with the thalassaemia clinic will include:

• Ensuring adherence to the immunisation programme.
• Provision of support for the family at home and in school to disseminate appropriate advice in the community and school and facilitation of regular review or emergency presentation at Leeds Children’s Hospital or the local paediatric unit.
• Supporting the thalassaemia centre in providing ongoing treatment with adjunctive treatment.  

Treatment with iron chelation or more complex therapy will be managed by the thalassaemia centre.

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Acute Clinical Presentation in the Treated Thalassaemia Patient

Key questions

• What is the transfusion history?
  Is the patient on a regular transfusion programme, intermittently transfused or not transfused? When was the last transfusion? Are the symptoms compatible with a transfusion reaction? What was the Baseline Hb/pre transfusion Hb? Are alloantibodies present?

Consider

Transfusion reactions including: delayed transfusion reaction, hyperhaemolysis syndrome, transfusion transmitted bacterial infection, transfusion-transmitted acute lung injury, fluid overload, anaphylactic reactions.

• Is there an indwelling venous device – e.g. Portacath, Hickman line?
  Check when line last accessed.
  Any anticoagulation – is this therapeutic?
  Consider
  Sepsis – local or systemic
  Venous thromboembolism
  
  
• Any features of sepsis?
  
  Note: Sepsis Six; consider as immunocompromised
  Does the patient have an indwelling line?
  Has the patient undergone splenectomy, and if so, has appropriate post-splenectomy infection prophylaxis been continued?
  Is the patient chelating with deferiprone, and if so, has neutrophil count been checked to exclude agranulocytosis?
  Is the patient chelating with desferrioxamine and if so, are the clinical features compatible with Yersinia or Klebsiella sepsis?
  
  Consider
  Gallstones, CNS sepsis, UTI, endocarditis
  Klebsiella and Yersinia sepsis more common in iron loaded patient, may include meningitis, cerebral abscess, UTI.
  Yersinia enterocolitica may mimic appendicitis.
  Malaria if relevant travel

Despite splenectomy, and perhaps because of successful pneumococcal prophylaxis, the majority of bacteraemia is now with gram negative organisms: Klebsiella, E Coli and sometimes salmonella species. Presentation is with high fever and sometimes associated circulatory collapse, there may be evidence of pneumonia, biliary tract infection, meningitis or cerebral abscess.

If suspicion of infection treatment with broad spectrum antibiotics such as intravenous tobramycin and piptazobactam after blood cultures have been taken. Where individuals have central venous catheters consider vancomycin or teicoplanin.

Yersinia enterocolitica causes infection in this patient group far in excess of others, as it thrives in high iron conditions. It can cause localised infection in the tonsil or bowel, or can cause septicaemia. There is usually high fever and abdominal pain, sometimes vomiting and diarrhoea. It can be mistaken for appendicitis or other acute surgical abdomen. The organism can be cultured from blood or stool specimens. If it is suspected, all chelation treatment should be stopped until the infection is treated, or - if not confirmed - until abdominal symptoms resolve. Treatment for Yersinia is usually with ciprofloxacin, initially intravenously in an acutely ill patient; septrin and co-amoxiclav are also reported to be effective. Antibiotic treatment should be commenced on clinical suspicion of Yersinia infection, in a chelated patient with fever and abdominal pain, pending a diagnosis. If Yersinia enterocolitica infection is suspected, desferrioxamine treatment must be stopped and not restarted until the infection is fully resolved.

Uncommonly, other specific transfusion transmitted infections such as hepatitis B (although not likely in vaccinated individuals), hepatitis C or rarely HIV cause the patient to present acutely and should be borne in mind. The risk of neutropenia or agranulocytosis in patients receiving deferiprone should be borne in mind, so in such patients presenting with fever or other features of infection, an urgent FBC should be requested. Suitable broad spectrum intravenous antibiotics (as per local febrile neutropenia protocol) should be started immediately if the neutrophil count is significantly low.

• Has the patient undergone splenectomy?
  Consider
  Sepsis
  VTE – especially in nontransfusion-dependent thalassaemia
  Pneumococcal, meningococcal and haemophilus infection risk
  
  
• What drugs are used for iron chelation?
  Consider drug side effects
  Deferiprone: neutropenia and agranulocytosis
  Deferasirox: renal and liver toxicity, upper gastrointestinal ulceration and haemorrhage, acquired Fanconi’s syndrome (acute renal tubular damage)
  Desferrioxamine: Sepsis with Yersinia, Klebsiella, mucormycosis.
  
  
• What is the degree of iron overload – is this patient at risk of cardiac iron?
  Is there a history of palpitations?
  Is there increasing iron loading as suggested by ferritins, recent MRI results - cardiac T2*, liver iron
  Cardiac drugs - ACE inhibitor, amiodarone, digoxin
  89% patients in cardiac failure seen when Cardiac T2* < 10ms
  Those with previous cardiac iron may still develop arrhythmias.
  T wave abnormalities are common in thalassaemia patients and are nonspecific.
  Other symptoms and signs should be used to support a diagnosis of ischaemic cardiac complications.
  
  
• What history of liver disease?
  Recent liver iron concentration measurements, viral hepatitis, B or C
  Liver disease may be advanced if the patient also has hepatitis, or a history of poor iron chelation over a prolonged period or alcohol excess.
  
  
• Is the patient diabetic? What is their control like?
  Hypo-/hyperglycaemia?
  Review fructosamine to consider control. If this is not available the HbA1c can be used but this is diluted with blood transfusion and may mask poor control.
  
  
• Is there any other endocrine complication, treated or undiagnosed?
  Hypocalcaemia, hypothyroidism, hypoparathyroidism, adrenal insufficiency, undiagnosed diabetes
  May impair cardiac function/rhythm
  Adrenal function presentation may be subacute, only manifesting at times of acute illness
  
  
• Could thalassaemia explain acute pain?
  Wide range of complications including gallstones, renal stones, fracture, pancreatitis, PE.
  
  Use wider history to focus on underlying cause

Key symptoms

• Acute breathlessness?
  Assess for pneumonia, PE, sepsis, acidosis, severe anaemia
  BP may be low normally in these patients – check previous records
  
  
• Acute abdominal pain?
  Gallstones, biliary tract sepsis
  Renal stones (hypercalciuria)
  Hepatic congestion from cardiac failure?
  Yersinia infection
  Non transfusion dependent thalassaemia post splenectomy – VTE?
  Portal vein thrombosis, mesenteric infarction
  
  NB Review medical pathologies prior to any surgical intervention
  Pancreatitis ± gallstones
  NB: Measure splenomegaly – compare to baseline, consider splenic infarcts
  
  
• Acute back pain?
  On treatment for osteoporosis?  Recent DXA results - risk osteoporotic fracture?
  Confirm any history of trauma
  Assess for spinal cord compression – e.g. weakness, paraesthesia, bladder control.
  At risk of extramedullary haematopoeisis? e.g. non transfusion dependent thalassaemia, under transfused although can occur in any patient
  Urgent MRI spine should be undertaken if suspected
  
  
• Acute neurological presentation?
  Any features of sepsis consider specific infections above.
  Leg weakness, bladder or bowel dysfunction
  Extramedullary haematopoiesis with spinal cord compression
  Imaging, blood and CSF cultures where indicated
  Urgent MRI spine if any possibility
  
  
• Acute anaemia?
  Baseline Hb, transfusion history?
  Any intercurrent illness, fevers, diet issues?
  Parvovirus (and if considered possible, any other family members with thalassaemia should have review/Hb check)
  Folate deficiency

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General advice

For most presentations, desferrioxamine treatment should be continued. The exception is suspected Yersinia enterocolitica infection, where it must be stopped and not restarted until the infection is fully resolved.

When acutely unwell, patients may not tolerate any degree of anaemia and should be transfused to a haemoglobin of >12 g/dl.

Recommended assessment for the acutely presenting patient should include the following (those starred * depending on clinical presentation):

• FBC, group and antibody screen, direct antiglobulin test, U+E, LFT, Calcium and Phosphate, Glucose, thyroid function.
• Blood cultures, urine culture, culture of stool*, CSF*
• ECG CXR*
• Echocardiogram*
  CMV IgG, EBV IgG, VZV IgG, HSV IgG and toxoplasma IgG
• Ultrasound of abdomen

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Outpatient management

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New diagnosis

Learning that their infant has a serious blood condition inevitably comes as a shock to the parents. Parents should be aware of their risk of having an affected child through counselling during pregnancy. This counselling should have included information about inheritance, the option of pre-natal diagnosis and other choices, and the effects of thalassaemia and its treatment on the child and the family. It should be backed up by suitable written information. Additionally, if the risk was not identified during the pregnancy, affected infants may be identified through the newborn screening programme. Whenever the diagnosis is made, the way in which it is conveyed to the parents, and the initial conversations they have with professionals, will colour their expectations and attitudes. The first discussions must therefore be accurate, unhurried, considered and sensitive.

The baby and parents should be seen as soon as possible and preferably within two weeks after birth or diagnosis, for babies identified by the screening programme, an initial home visit is preferred. The neonatal heel prick test is a screening, not diagnostic, test and early confirmation is required.

If the presentation is a clinical one, then assessment may be urgent, within one to two days.

A professional interpreter is essential at this consultation if the family are not primary English speakers.

If only one parent is present, it is advisable that a friend or relative is also present

Strenuous efforts should be made to involve both parents from the start.

The first discussions must be accurate, unhurried, considered and sensitive.

Information regarding the key contacts for advice and queries should be provided.

Appropriate written information should be made available. The family should additionally be given the contact details for the UK Thalassaemia Society and any local branches/support organisations.

A management plan tailored to the individual child must be agreed and implemented. The family will meet their ‘key contact’ within the clinical team, and given contact numbers for subsequent use.

Investigations at first visit

• Full blood count and blood film examination
• Haemoglobin analysis by electrophoresis or high performance liquid chromatography (HPLC)
• Genetic analysis for β thalassaemia mutations, α thalassaemia genotype and Xmn1 C-> T polymorphism. Family studies may be informative.

For diagnosis confirmation ensure two test results are available confirming the diagnosis including one after the age of 6 months. It should be emphasised that the clinical phenotype cannot be predicted accurately in the early stages, and that the child will be monitored carefully for clinical signs indicative of the need to commence transfusion.

Organise the testing of parents and siblings unless already available.

Send information regarding diagnosis and management plan to the general practitioner and shared care paediatrician as appropriate.

A copy should also be sent to the parents / patient as appropriate.

If patients move a referral letter and copy letters will be sent to the new consultant.

Every person with thalassaemia will have the opportunity for their care and condition to be reviewed at least annually with a team of health care professionals who have particular experience in caring for thalassaemia disorders. This can take place during a visit to the Specialist Centre, or at an outreach clinic where members of the Specialist Team visit the local centre at which the person receives their routine care.

The assessment should cover all aspects of care including educational and lifestyle factors that may affect health or influence adherence to treatment. See proforma used for clinic review.

Discussion of treatment options should include any new information which has become available, and an individual treatment plan for the next 12 months will be agreed.

A copy of the annual review consultation including the care plan will be copied to the patient or, for children, their parents as well as health professionals involved in their care.

Data should be entered into the annual review screens of the NHR for consented patients.

People in families affected by thalassaemia should be able to meet and gain support from other affected families at the Centre or in the community.

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Initial Review of Patients Previously Treated Outside the UK

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Review before initiation of transfusion and decision to start transfusions

Follow up clinics leading up to initiation of transfusion programme

During the early clinic visits, treatment options for the child in future should be discussed including the different options for iron chelation and the availability of stem cell transplantation.  Families should be made aware of the need for frequent monitoring of growth, development, and blood test results. Where possible, the family should be given the opportunity to meet with other families who have children with thalassaemia.

After diagnosis, monitor regularly from the age of 4 months at least monthly until the clinical phenotype is established.
History: feeding difficulties, infections, ill health, developmental delay
Examination: assess bone expansion (including head circumference), growth curves and hepatosplenomegaly.

Investigation:

Haemoglobin level should be checked at least monthly

Consent should be sought from all patients for entry of their details on the National Haemoglobinopathy Registry (NIHR), and data entered in a timely fashion to assist audit and assessment of good quality outcome information.

If from neighbouring clinic will need annual review in Leeds.

Stem cell transplantation

Refer for consideration of stem cell transplantation at around age of 12 - 18 months. It is paramount in all discussions of this treatment option to stress the usually excellent results of conventional transfusion and chelation therapy.

If the mother of a child with thalassaemia becomes pregnant, referral to the specialist transplant centre should be made for discussion of possible cord blood stem cell harvesting as a source for donor material for the affected child. If not already tested, the HLA type of the affected child should be established.

Current list of indications for stem cell transplantation can be found at bsbmt.org/indications-table.

Prevention Using Prenatal Diagnosis and Preimplantation Genetic Diagnosis 

All couples at risk of having children with a thalassaemia disorder should be referred to specialist genetic counselling as soon as the risk is recognised. Counselling is provided by a genetic specialist with specific experience in both prenatal diagnosis and preimplantation genetic diagnosis for haemoglobin disorders. DNA analysis is provided for all at risk couples.

All at risk couples should be informed of prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) as options to achieve a healthy family. If the woman has a thalassaemia disorder, her treating haematologist should be involved in the management plan prior to PGD.

Decision re transfusion:

A decision to commence transfusion will be made by the designated consultant for the service. It should be based on the presence of anaemia (usually below 70 g/l) which is accompanied by inappropriate fatigue, poor feeding, developmental delay or regression, faltering growth, or any symptoms or signs of cardiac failure.

Exclude correctable problems such as iron deficiency or intercurrent infection, or compounding factors such as G6PD deficiency.

An ‘acute’ case of anaemia, eg. due to a viral infection, does not necessarily indicate a regular transfusion programme. Where possible, the decision to start regular transfusions should not be delayed until after the 3rd year, as the risk of developing multiple red cell antibodies increases, with subsequent difficulty in finding suitable units for transfusion.

Once it is decided that transfusion is probable start course of hepatitis B vaccinations aiming to complete before first vaccination

Further investigations

Before the first transfusion, the following investigations should be carried out:

Where transfusion is started because of fall in height velocity or bony changes (often intermedia) it should not be assumed that lifelong transfusion will then be necessary. After maximum height is achieved, and bones are fused, in some cases it is possible to 'wean off' and then stop regular transfusions entirely, although the patient still needs to be carefully monitored for other complications.

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Protocol for transfusion

Consent for transfusion should be recorded using the organisations policy for consenting long term multi-transfused patients.

Pre-transfusion haemoglobin level should be between 90 - 105 g/L.

Transfusion interval is usually between 3 and 4 weeks.

Raise Hb to 15g/dl

Formula: Volume of blood (ml) = patient weight (kg) x Hb increment (g/dl) x 3.5*

*This may change - refer to paediatric haematology transfusion policy

Matched red cells for Rh (D, C, c, E, e) and Kell (K) blood group antigens

Large volume units should be chosen, preferably greater than 300 mls (for adults and children when one or more full unit is required), and wherever possible units should be less than 2 weeks old. No more than 2 attempts to site a cannula should be made by any one individual

To reduce donor exposure, transfusions are not normally given to the nearest ml, so for example if the calculated volume is 330 ml and one matched unit is identified containing 305 ml, part of a second unit would not be necessary.

Record dates of transfusion, the patient weight, the volume of blood transfused at each episode and the estimated haematocrit of the transfused blood (available from the blood transfusion laboratory) 

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Monitoring recommendations for patients at risk of iron overload (those on regular top-up transfusions every three months or less, SCD on regular top-up transfusion, manual exchange or on automated apheresis with progressive rise in serum ferritin, non-transfusion-dependent thalassaemia and non-transfused rare inherited anaemia)

@ ≥ 8 years Ferriscan or if not available T2* MRI of liver every year, and additionally if significant changes to therapy occur.

Cardiac T2* MRI every 2 years if T2* >20 ms, every year if T2* 10-20 ms, 6 monthly if T2*<10 ms, 3 monthly if T2*< 10 ms and any evidence of cardiac impairment. MRI monitoring should start from age 8 years but earlier if initiation of chelation therapy has been delayed, or adherence is very poor.

** assume 1 ml of pure red cells contains 1.08 mg of iron. Patients whose transfusion iron loading is more than 0.3 mg/kg/day, require higher doses of chelating agents to achieve negative iron balance.

Non transfusion dependent thalassaemia

NTDT patients should have liver MRI assessment if ferritin is above 800 μg/l at baseline. NTDT patients with previous iron overload or who are receiving iron chelation therapy should have regular liver MRI assessment as the ferritin is unreliable.

Non-transfused rare inherited anaemia

NTRIA patients should have a baseline liver and cardiac MRI assessment if ferritin is >1 000 μg/l. NTRIA patients with defects in the iron metabolism or haem pathway should be considered for MRI assessment if the ferritin is >500 μg/l or sooner if there are features to suggest iron overload on clinical examination.

Poor compliance with chelation therapy should prompt earlier scans if needed.

Rate of iron loading (ROIL) from transfusion

Rate of iron loading

The ROIL in mg/kg/day can be calculated from the number of units given over a measured time period. Patients with average ROIL (0.3–0.5 mg/kg/day) are likely to require average doses, whereas those with ROIL less than 0.2 mg/kg/day or greater than 0.5 mg/kg/day are likely to require dose adjustment accordingly.

Prognostic indicators

Ferritin

Long-term control of ferritin with desferrioxamine therapy has prognostic significance and maintenance of the ferritin below 2500 μg/l is associated with a lower risk of cardiac disease and death. Maintenance of ferritin below 1000 μg/l may be associated with additional advantages in transfusion dependent thalassaemia.  If possible primary aim would be to keep ferritin levels between 500-1000ug/L but from 8yrs more emphasis should be placed on the Ferriscan and T2* MRI results.

Liver iron concentration (LIC)

Long term liver iron concentrations above 7 mg/g dry weight have been associated with increased risk of fibrosis and above 15 mg/g dry weight with increased risk of myocardial iron overload.  Liver biopsies have procedure-associated risks and the distribution of iron in the liver may be inhomogeneous. Liver biopsies are now undertaken only where histology will contribute to management.

Cardiac T2*

Cardiac T2* values less than 20 ms are associated with increased myocardial iron and T2* less than 10 ms is associated with an increased risk of developing cardiac failure.

Iron loading kinetics

For the majority of transfusion dependent thalassaemia patients, iron is stored in the liver first  before extrahepatic iron loading occurs so liver iron concentrationwill reflect total body iron.  When iron is removed via chelation, it is removed from the liver first before the heart, so cardiac T2* values are slow to change relative to LIC.  Patients who have undergone a splenectomy will experience iron shunting to the heart more quickly even with a relatively low liver iron concentration. The spleen acts as a buffer as part of the macrophage system and stores and regulates iron

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Iron chelation treatment

The most important long-term problem associated with regular transfusions in thalassaemia is iron overload. Blood contains iron which cannot be excreted from the body, and a typical thalassaemia patient on a regular transfusion programme will accumulate 0.3-0.5mg/kg of iron per day. Excessive iron is toxic, the most vulnerable organs being the heart, liver and endocrine glands. Once the body has accumulated 12-24 g of iron significant clinical manifestations of iron toxicity can be expected. Without treatment to remove the iron, the majority of patients develop cardiac problems and died of heart failure by the age of 20. Therapy to remove or 'chelate' excess iron is therefore essential and this must be started within a year or so of starting regular transfusions.

The aim of therapy with all chelation regimes is to attain and maintain annual average serum ferritin at 1000 ±500 μg/l , liver iron 3-7 mg/ g dry weight, and cardiac T2* >20 ms. Persistently high ferritin levels (>2500μg/l) are associated with an increased risk of cardiac disease and death

Treatment

Initiation of chelation treatment

Transfusion dependent thalassaemia patients should be commenced on iron chelation therapy after 10 transfusions or when the serum ferritin >1 000 μg/l on two occasions.

Non transfusion dependent thalassaemia patients should be offered iron chelation therapy if ferritin is above 800 μg/l or liver iron is above 5 mg/g/dry weight.

Non-transfused rare inherited anaemia patients should be assessed on a disease and individual basis and chelation therapy or venesection (if Hb is adequate) considered if there is evidence of iron overload (ferritin > 500 μg/l or LIC > 5mg/g/dry weight).

Sickle Cell Disease patients receiving top-up transfusions should be commenced on iron chelation as per transfusion dependent thalassaemia patients. SCD patients on exchange transfusion programmes should be offered iron chelation therapy on an individualised basis according to the type of exchange and the severity of the existing iron overload as measured by liver iron MRI assessment.

Chelation regimens

Under 6 yrs of age

First line : Desferrioxamine

Start at 20 mg/kg/day 3 nights a week for 2 weeks then introduce 5 nights a week. Review dose every 3 months to see if dose escalation/decrease needed. The lowest effective dose should be used. The average daily dose will probably lie between 20 and 40 mg/kg/day. Doses in excess of 40mg/kg/day should only be prescribed following discussion with the consultant Haematologist and only if benefit for the patient outweighs the risk of unwanted effects. Patients with serum ferritin levels of < 2000 mcg/L should require about 25 mg/kg/day, and those with levels between 2000 and 3000 nanogram/mL about 35 mg/kg/day.

Therapeutic index. Mean daily dose (mg/kg)/ferritin (μg/l). Aim to keep <0.025 at all times  to reduce the risk of toxicity especially to eyes and ears.

After one month of treatment prescribe ascorbic acid orally on days of Desferrioxamine chelation. The recommended dose is 200mg for adults and 100 mg for children.

Second line : Add deferiprone 

If maximum dose Desferrioxamine achieved, after 6 months, if inadequate chelation and adequate adherence and tolerant of desferrioxamine add deferiprone. Deferiprone to start at at 25mg/kg/ od, then increasing to bd after 2 weeks and then tds after 2 weeks. Dose increases based on side effects and severity of iron overload to maximum of but should not exceed 100 mg/kg/day.

Third line: Substitute deferiprone with deferasirox-FCT

After maximum dose of deferiprone achieved, after a further 6 months, if inadequate chelation and if adequate adherence and tolerant of desferrioxamine stop deferiprone and substitute with Deferasirox-FCT; start at 7 mg/kg/day for 2 weeks then increase to 14mg/kg if no significant side effects.  Dose escalation of Deferasirox at 3 months based on side effects and tolerability.

6yrs or over or if 2 yrs or over and intolerant to Desferrioxamine

First line : Deferasirox-FCT

Film-coated tablets/granules. Start at 7 mg/kg/day for 2 weeks then increase to 14mg/kg if no significant side effects. Review dose every 3 months to see if dose escalation/decrease needed based on assessment of iron loading. If needed, every 3-6 months increase by 3.5 - 7 mg/kg/day up to 21 mg/kg/day. Usual maximum 21mg/kg/day so consider adherence and if combination therapy needed if ineffective. Maximum quoted dose is 28mg/kg/day.

Second line : Add deferiprone

When maximum dose of deferasirox achieved, after 6 months if inadequate chelation and adequate adherence and tolerant of deferasirox add deferiprone. Deferiprone to start at at 25mg/kg/ od, then increasing to bd after 2 weeks and then tds after 2 weeks . Dose increases based on side effects and severity of iron overload to maximum of but should not exceed 100 mg/kg/day.

Third line : Substitute deferiprone with desferrioxamine

When maximum dose of deferiprone achieved, after 6 months, if inadequate chelation and if adequate adherence and tolerant of Deferasirox, substitute deferiprone with desferrioxamine. Initiate at appropriate dose of Desferrioxamine for age and Deferasirox-FCT at 14 mg/kg/day.

Monitoring for complications of iron chelation

Adjustments to chelation regime – dose decreases with low iron stores

The risk of chelator toxicity is likely to be higher when body iron stores are either low (Ferritin persistently < 1000 μg/dl and/or desferrioxamine mg/kg to serum ferritin ratio > 0.025, or when LIC is < 3 mg/g dw) or when ferritin is decreasing rapidly. The association of chelator toxicity and low iron stores is less clear in the case of deferiprone and deferasirox but the same precautions should nevertheless be taken, particularly in ferritin < 500 μg/L). Deferiprone is probably the least toxic chelator in this scenario.

Chelator dose should be reduced and may need to be maintained in a very low range (e.g. desferrioxamine 10 – 20mg/kg per infusion 5 per week; deferasirox 5 – 10mg/kg/day, deferiprone 50 – 75 mg/kg/day) in these patients. Licensing of deferasirox recommends considering an interruption of chelation when ferritin is <500. This may not be the best strategy in regularly transfused patients as they will continue to load iron at a rate of 0.3 – 0.5 mg/kg/day. An alternative approach is to continue chelation at very low dosage (e.g. deferasirox 5 – 10 mg/kg/day) with monthly monitoring of adverse symptoms, increment in ferritin, creatinine, ALT and urinalysis. Chelator dose should be reduced if there is a rapid decline in ferritin (> 500 over a three month period), and ferritin is persistently < 1000 μg/dl, and when LIC is <3 mg/g dw, cardiac T2* is > 20ms. Desferrioxamine dose per infusion should be reduced rather than the frequency of infusion. Conversion from desferrioxamine to oral chelation should be considered if ferritin is consistently in the range 500 – 750 μg/l or LIC < 3 mg/g dw.

Adjustments to chelation regime with severe myocardial iron loading

(Myocardial T2* < 10 ms) not clinically in Heart Failure

If iron stores are low (Ferritin < 1000 μg/l, LIC < 7 mg/g dw), deferiprone monotherapy should be considered first line therapy. The dose should be escalated to 100 mg/kg/day.

If iron stores are high (Ferritin > 1000 μg/l, LIC > 7 mg/g dw), desferrioxamine / deferiprone combination is recommended.

Deferiprone should be given at 85-100 mg/kg/day and combined with desferrioxamine infusions (40 – 60mg/kg/day), either continuous i.v., continuous s.c., or intermittent s.c. infusions over 12 hours, 5 – 7 times per week depending on iron levels.

If deferiprone therapy is not tolerated, the alternative options are continuous i.v. desferrioxamine (40-60mg/kg/day, 7 days per week) or high dose deferasirox (30-40 mg/kg/day) with careful monitoring for adverse effects.

Chelator doses should be adjusted based on ferritin and LIC for avoiding chelator toxicity.

Adjustments to chelation regime with severe myocardial iron loading

(Myocardial T2* < 10 ms), clinically in Heart Failure

Desferrioxamine at a dose 50-60 mg/kg should be started immediately via a peripheral line and given as a continuous 24 hour i.v. infusion. A long-term intravenous line should be inserted to facilitate long-term therapy. Simultaneous deferiprone (75-100mg/kg/day) should be combined with the desferrioxamine infusions as soon as possible.

Notes on cardiac iron loading

Myocardial iron appears to clear more quickly with continuous i.v. desferrioxamine (Anderson, Westwood et al. 2004) or desferrioxamine / deferiprone combination (Tanner, Galanello et al. 2007) compared to deferasirox regimes. This may result from differing chelator efficacy, but could also relate to the degree of iron loading. It has been shown that cardiac iron decreases only after liver iron is controlled, and it is noteworthy that patients in the deferasirox trials had higher LIC than in the deferiprone trials. Despite these reservations it is advisable for patients with the severest degrees of myocardial iron loading to be chelated with continuous intravenous desferrioxamine or desferrioxamine / deferiprone combination. Deferasirox monotherapy (at a dose around 40mg/kg/day) should only be used in patients unwilling or unable to sustain treatment with continuous desferrioxamine or desferrioxamine / deferiprone combination. In all patients careful review of compliance and trends in ferritin, and echocardiographic parameters should be undertaken regularly to ensure that the patient continues to engage with treatment.

Notes on chelators 

Desferrioxamine

Desferrioxamine doses of 40 mg/kg five days a week have been used, but these are often insufficient to promote a negative iron balance. Thus at an average rate of iron loading in transfusion dependent thalassaemia (0.3–0.5 mg/ kg/day) only 65% of patients will be in negative iron balance, whereas at 50–60 mg/kg five days a week this rises to 86% of patients. Due to potential desferrioxamine toxicities (growth and audiometry) children should not receive a mean daily dose exceeding 40 mg/kg. Adults generally tolerate 50 mg/kg well.
Mean daily doses should be adjusted downwards as ferritin values fall in line with the therapeutic index.

Parents and patients should be taught how to administer subcutaneous desferrioxamine infusions. The training and performance should be documented in the patient's records. Their technique should be assessed regularly. Children should be encouraged to participate in setting up and administering the desferrioxamine infusions at an early age. Initiation of desferrioxamine infusions in very young children (age <5) is best done starting with 2- 3 infusions per week and gradually increasing to 5 infusions over a 3 month period. Means of facilitating the delivery of desferrioxamine such as Thalaset® needles, anaesthetic cream, disposable elastomeric pre-filled infuser pumps (not in very young children as the infused volumes are too large) should be offered to all children and adults. Ascorbic acid should be taken approximately 30 minutes after starting each desferrioxamine infusion. Monitoring for adverse effects should include 3 monthly sitting and standing height, annual audiometry, and radiological investigation of any bony symptoms. Desferrioxamine should be stopped if there are symptoms of gastrointestinal disturbance (abdominal pain, severe diarrhoea) or high fever. Patients should be aware of the risk of overwhelming infection due to Yersinia and Klebsiella, and seek medical attention as soon as possible if they have symptoms or signs of severe infection.

Deferasirox

Dosing is also critical to response with deferasirox: thus while over 80% of transfusion dependent thalassaemia patients with average ROIL respond to daily deferasirox-FCT at 21 mg/kg/day, this falls to just over half of patients at 14 mg/kg). Adjustment in doses should be in line with ferritin trends and LIC values as well as the presence of any derangement in serum creatinine and transaminase levels.

Deferiprone

The relationship of dosing to iron balance with deferiprone is less clear as long-term LIC trends show considerable interstudy variation, reflecting the heterogeneity of dosing schedules, ROIL, baseline LIC values, and follow-up periods. Unlike desferrioxamine, the response to deferiprone depends on baseline LIC; thus at 75 mg/kg/day, a negative iron balance was achieved in less than a third of patients overall but in 50% of patients where baseline LIC exceeded 9 mg/g dry weight. Note risk of agranulocytosis and need for urgent FBC if any infection symptoms.

Ascorbic acid

Use in conjunction with Desferrioxamine. Ascorbic acid orally on days of chelation may increase urinary iron excretion. The recommended dose is 200mg for adults and 100 mg for children. There is a potential risk of increasing toxic iron levels and precipitating cardiac toxicity in patients who are heavily iron loaded and at risk of cardiomyopathy. Ascorbic acid should not be used on non-Desferrioxamine days in all patients and in the early stages of intensive chelation therapy for patients with cardiac failure or with myocardial T2* <10msec. 

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Management of thalassaemia intermedia, including haemoglobin E/β thalassaemia

Patients should receive regular folic acid supplementation.

After transfusion for an episode of acute anaemia, for example after infection, the patient should be observed carefully for several months to determine steady-state symptomatology and haemoglobin level.

The decision for regular transfusions should be made by the lead consultant.  Indications for long-term transfusions include symptomatic anaemia, falling growth velocity, delayed puberty, bone problems (facial deformities, recurrent fractures, premature epiphyseal fusion), pulmonary hypertension, symptomatic extramedullary haematopoietic masses, chronic ankle ulceration.

The rationale for transfusion should be carefully discussed with the patient and/or parents and family, perhaps over the course of several clinic visits. This will entail accepting the reality of a chronic condition in an older child, and preparing for the problems association with regular transfusion.

Where transfusion is started because of fall in height velocity or bony changes (often intermedia) it should not be assumed that lifelong transfusion will then be necessary. After maximum height is achieved, and bones are fused, in some cases it is possible to 'wean off' and then stop regular transfusions entirely, although the patient still needs to be carefully monitored for other complications.

Red cell units transfused must be phenotype compatible, and matched for ABO, Rhesus (C/c,D,E/e) and Kell.

Assessment of iron stores should take into account the severity of the anaemia, number of transfusions received, and clinical evidence of iron-related toxicity (heart, liver and endocrine disease).

As the serum ferritin is unreliable in thalassaemia intermedia, an additional measure of iron stores should be undertaken; this will usually be by a non-invasive MRI technique.

Liver iron concentration is the most important parameter for assessing iron overload in NTDT and should be assessed using Ferriscan or T2* MRI. Assessments should start from age 8 and repeated every 2-5 years.

Ferritin should be measured at least once per year, and correlated with LIC. Increasing ferritin levels (particularly > 800μg/l) should prompt a repeat LIC assessment.

Myocardial T2* should be considered for assessment of myocardial iron loading in older patients and those who require more frequent transfusions (3-6 per year).

Non transfusion dependent thalassaemia patients should be offered iron chelation therapy if ferritin is above 800 μg/l or liver iron is above 5 mg/g/dry weight.

Careful consideration should be given to the risks/benefits of splenectomy in these patients. The decision must be made after consultation with the lead consultant, and requires careful counselling and discussion.

Patients with thalassaemia intermedia should be transfused for several months prior to splenectomy to reduce spleen size, suppress marrow activity, and reduce the numbers of circulating, pro-thrombotic thalassaemic red cells.

Prior to the procedure, an abdominal ultrasound scan should be done to detect gall stones. If present, a cholecystectomy should also be considered. A wedge liver biopsy should be taken at the time of laparotomy, for histological assessment and analysis of liver iron content.

Thalassaemia intermedia patients should have regular echocardiography from age 15 years. Where echocardiography proves inconclusive in regard to pulmonary pressures, further investigation with cardiac MRI and right heart catheter studies should be considered to confirm the diagnosis.

If pulmonary hypertension is found, treatment with regular transfusion should be strongly considered. Regular transfusion is normally recommended for these patients.

Growth and pubertal development should be monitored regularly from the age of 10, and referral to the designated endocrinologist made if abnormalities are documented.

A period of regular transfusion during the years of peak potential growth and puberty should be considered.

Symptoms due to extra-medullary haematopoietic masses should be investigated, usually with MRI imaging, and treated. Radiotherapy can be considered if there is urgent need to reduce the mass; hyper transfusion and hydroxycarbamide act more slowly. Asymptomatic masses may require therapy depending on their position (eg if impinging on the spinal cord), but if not threatening vital structures, may simply be monitored.

Hydroxycarbamide therapy should be instituted only after careful definition of the expected benefits. The decision should be made with the Centre consultant. The patient should be made fully aware of possible adverse effects of the drug, and supplied with written information. It should be started at a dose of 10-15 mg/kg/day, and the full blood count monitored frequently. The maximal dose is not known, but it is unlikely that patients will tolerate doses in excess of 20-25 mg/kg/day.

(See LHP Sickle cell guidelines for more details).

Referral to the lead consultant for stem cell transplantation should be offered to families, for detailed discussion of transplant as an option.

Patients with moderate/severe thalassaemia intermedia should be reviewed at least annually at the specialist Centre.  

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Transition to adult services

Transition is ‘the purposeful planned movement of adolescents and young adults with chronic physical and medical conditions from child-centred to adult-oriented health care systems.’

The importance of transitional care has been highlighted in the Children’s National Service Framework Hospital Standards , Improving the transition of young children with long term conditions to adult health services and the intercollegiate report, Bridging the gaps: health care for adolescents. This includes a requirement for children and adult services to take the needs of this group of patients into consideration when planning and developing services.

Here at Leeds we follow the “Ready, Steady, Go” programme developed by Southampton University Hospital. This is a generic programme, as many of the problems faced by each sub-speciality group during transition are similar. Through this program we ensure the medical, psychosocial and vocational needs of the young person are being addressed by following a structured, but adaptable, transition plan. A key principle throughout the process is ‘empowering’ the young person to take control of their lives and equipping them with the necessary skills to be able to function independently and confidently in adult services.

The transition programme starts with a “Moving to Adults” information leaflet and a questionnaire which, through a series of structured questions, is designed to establish when the patient is likely to be ready to move to adult services and what needs to be done to get “Ready” for the move to adult services. In due course this is followed up by a questionnaire to assess progress and keep them “Steady” and ensure that they have all the skills to “Go” to adult services at a time which has been mutually agreed by the patient, medical professionals and where appropriate parents.

The programme is facilitated through our Annual Review Clinic. The idea of transition and the gradual switch of focus from parent to young person, should be introduced at the first Annual review visit, as part of an overview of what parents can expect from annual review sessions. 

The Moving to Adults Leaflet should be given to the young person when they move from primary to secondary education. Progress should then be assessed at each visit until the patient is ready to move to adult services.

At the point of transition to adult services, the annual review session will be attended by both Adult and paediatric Haematologists together with the Adult specialist nurse for red cell disorders and Charge Nurse for Paediatric Haematology.

Before the first appointment with adult services, the patient will attend a “Welcome to adult services” session. This session will include, a tour of the unit (outpatient clinic, day unit, in patients wards); information about how to book or rearrange an appointment and who to contact in an emergency.

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Clinic organisation

• All regions in England should be covered by a clinical network incorporating local thalassaemia Clinics and one or more Specialised Thalassaemia Centres.
• Procedures within the network should ensure that all patients have access to a specialist Centre, either for their regular care if living nearby or for regular review at least once a year, and for additional specific consultations as needed, if living more distantly.
• A ‘Key Contact’ health professional will be designated for each patient.
• Local Clinics and specialised Centres within the network, should record and exchange information relating to clinical events monitoring investigations, and changes in treatment.
• Patients and carers should have access to peer support groups.

Patient-held records can be an effective way of transmitting information between clinical staff in different clinics, and also provide an opportunity for the patient to gain a better understanding and become more involved in their own care and monitoring.

Expectations of local Clinics

• provide regular transfusions at times convenient to the patient and family, and prescriptions for chelation and any other necessary therapy
• undertake regular blood tests and provision of compatible red cell units
• monitor growth, and general health and wellbeing
• organise some, or all, of the regular assessment tests
• offer support to the patient and family.

Expectations of a thalassaemia Centre (in addition to the above) should:

• offer consultation at specific key 'milestones' (at diagnosis, at initiation of regular transfusion, at initiation of regular chelation therapy, at transfer to adult clinic)
• offer annual review for all the patients in the network, for overview of transfusion
• chelation efficacy and side effects, and review of monitoring investigations
• supervise complex management (eg switching chelation regime, problems with adherence to chelation, decisions about splenectomy , management of endocrine, bone/joint, cardiac, liver complications and fertility treatment, bone marrow transplantation, psychosocial issues)
• guide management of acute clinical events, or take over care of such events by transfer of patient
• supervise moderate to high intensity surgery
• manage pregnancy
• offer education and training for staff at local Clinics and the Centre
• audit performance and outcomes
• be involved in clinical research studies

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