Iron Chelation therapy

In all people, Iron moves from one area to another bound to a protein which makes it safe. In individuals with a moderate to severe form of  thalassaemia, this protein is rapidly fully loaded with iron leaving the harmful excess iron to move around in the blood freely. This free form of iron causes serious damage to how the major organs such as the liver and heart work.

Some free iron can be stored safely and this is mainly in the liver and spleen, but once these are fully loaded, iron then will also start to load into the heart and endocrine organs (the glands that make hormones). The ferritin test generally reflects the storage form of iron. The free form of iron can only be measured in research labs.

There are two goals of iron chelation therapy; the primary goal of chelation therapy is to maintain safe levels of body iron and the secondary goal is to rescue patients who have developed toxic levels of iron resulting in organ damage.
Unfortunately once iron overload has occurred the removal of excess iron is slow and may need several years of excellent compliance to treatment to completely clear the iron.

There are three drugs used for iron overload but in four regimes:

• • • • Desferrioxamine (Desferal)
      • Deferiprone (Ferriprox)
      • Deferiprone and Desferrioxamine in combination
      • Deferasirox (Exjade)

Our oldest members with thalassaemia major in the UK are now in their 60’s and have lived full lives due to taking their iron chelation medication as prescribed. Life expectancy for younger people with thalassaemia is predicted to be even longer if current treatment guidelines are followed rigorously .  We know taking your iron chelation medication as prescribed is difficult and we are developing new resources to help you with this. We want you to live long and full lives so taking your iron chelation medication as preserved is essential!

 

Desferrioxamine:

This was first used in the 1960’s but has been mainstream treatment for iron overload since the late 1970’s.
It is a good liver and heart iron chelator, however due to issues with compliance and concerns around toxicity it is used less often.

Desferrioxamine has to be given either subcutaneously or intravenously via an indwelling device such as a Hickman Line or Port-o-cath. In general the recommendation is to take Desferrioxamine on 5 nights a week as a 12-hour infusion. Patients with more severe iron loading either in the heart or liver often receive Desferrioxamine as 24-hour infusions. Desferrioxamine can push the ferritin down quite rapidly and it is important to monitor the liver iron regularly to make sure that toxicity related complications do not develop and that the Desferal dose is not reduced too quickly if the liver iron is still high. Desferrioxamine is excellent for stabilising and reducing free iron and therefore good in acute heart failure or if there are abnormal heart rhythms. (Long term data for over 50 years).

 

Important things for you to know:

Desferrioxamine is only effectively working for as long as the pump is attached. It is therefore important to ensure that the pump does finish before it is removed in the morning and not to leave any infusion in the balloon or syringe otherwise the full dose is not administered.

It is important to not do 2 pumps in a day if you have 12-hour pumps!

Many patients do this in order to avoid 2 needles BUT by doing this you get effectively double the dose in a 24-hour period!

If there are reactions at the sites of the infusion let your doctor know, we can have a small dose of hydrocortisone added into the infusion to reduce the reactions or increase the volume of water so it is less irritating.

 

Deferiprone:

This has been in clinical use since the 1990’s. Several studies have shown it to be very effective for clearing heart iron especially in conjunction with Desferrioxamine infusions. It is taken three times a day in either a tablet or syrup form. Deferiprone does reduce ferritin in the majority of patients but there may still be raised liver iron levels. In this case patients are often given combination therapy to control the liver iron. This usually means Desferrioxamine on 2 to 3 nights a week.

 

Important things for you to know:

Side effects can limit a person’s ability to take Deferiprone in particular the gastrointestinal (nausea and vomiting) effects and joint pains. In some cases a condition called agranulocytosis can occur, so you need to monitor your white blood cells regularly to avoid developing this!

Most of the nausea and vomiting side effects do settle down so persevere with it and discuss with your doctor if there is anything that can be done to help manage them.Always take the tablets three times a day as the short half-life means the medicine is removed from your blood soon after taking it. If you miss doses or only do it twice a day you have less hours of chelation and the Deferiprone is less effective.
Always try to get your full blood count checked as advised (weekly). If you develop a fever and sore throat stop the Deferiprone and have a blood test to make sure your blood count is OK.

If you are planning to start a family you need to stop Deferiprone 3 months prior to a planned pregnancy. If you accidentally become pregnant on Deferiprone stop this straight away.

 

Deferasirox:

This has been available for clinical use since 2006 and has been shown to be effective for both liver and heart iron in stable patients. It is available in a dissolvable or tablet form and is usually taken once daily.

Deferasirox can be given at an iron-reducing dose where the dose is slightly higher than iron loading from the blood transfusions in order to bring down the body iron, or it can be given at a maintenance dose where the aim is to maintain a stable body iron. There is now good data from clinical trials showing improvement in heart iron so it can now be used in stable patients with iron loading in the heart. Careful monitoring is required of kidney function and nausea, vomiting, diarrhoea and taste can affect compliance.

 

Important things for you to know:

Most of the nausea and vomiting and diarrhoea side effects do settle down so persevere with it. You can take Deferasirox with food and it often helps if you leave the tablets for half an hour (in lukewarm water) to allow them to disperse properly in water before drinking. This makes the drink less chalky and gritty.

Kidney and urine tests should be monitored monthly and if the ferritin falls very quickly the kidney tests are more likely to go up. In this situation reducing the dose or having a short break is advised and this does correct the tests back to normal.
Exjade can also cause gastrointestinal issues as well as other side effects, you must let your haematology team know.

If you are planning to start a family you need to stop Deferasirox 3 months prior to a planned pregnancy. If you accidentally become pregnant on Deferasirox stop this straight away.

All three chelation agents and the four regimes of using them have distinct advantages and disadvantages. Treatment is adjusted according to you as an individual and to meet your health and lifestyle needs.

There are general broad recommendations based on clinical evidence to guide Doctors as to which regime may be best for you and your health needs at the time.

Current treatment recommendations based broadly on the UKTS Standards for Care of Patients with Thalassaemia 2008 are followed in the UK.

Using chelation therapy as prescribed and with appropriate monitoring to help adjust treatment in a timely fashion is critical to ensuring that you live a long a healthy life. It is really important the critical tests such as MRI monitoring for hepatic and liver iron and blood tests such as glucose tolerance tests are done on a regular basis as many complications especially cardiac failure and diabetes can be avoided if there is timely changes in treatment. Remember it is your health and your life that is put at risk by missing these important tests and more importantly by missing treatment!

 

Chelation guidelines according to the UKTS national Standards:

Chelation Young Child: Age 2-5 yrs.

Should start on Desferrioxamine infusions once ferritin is >1000ug/l
Offer Deferasirox if unable to tolerate infusions

 

Age 6 years or older:

Offer Deferasirox or Deferiprone
Use Desferrioxamine if side effects such as renal impairment, deranged liver function tests or unable to tolerate Deferasirox
Well-chelated adult or adolescent patients with no cardiac and low hepatic iron loading:
If happy with existing treatment to continue.
If patient wants to stop using Desferrioxamine then offer Deferasirox or Deferiprone
If not tolerating oral switch over then go back to Desferrioxamine.
Patient with High liver iron but no cardiac iron:

 

Existing treatment Desferrioxamine:

Optimise doses and tackle compliance issues, consider adding in Deferiprone as combination therapy if not previous used this in combination.
Consider switching to Deferasirox at an iron reducing dose

 

Existing treatment Deferiprone:

Optimise doses to 75-100mg/kg/day
Add in Desferrioxamine infusions as combination therapy on 1 to 5 days a week if patient is willing to use these according to severity of iron load. As liver iron burden falls gradually reduce the frequency of the Desferal infusions but aim to keep at least 1 to 2 infusions per week as iron burden will go up on monotherapy.
Switching to Deferasirox if patient is not willing to use Desferrioxamine infusions.

 

Existing treatment Deferasirox:

Optimise dose going up to 40mg/kg/day if needed, tackle compliance if dose is optimal.
If despite optimal doses Liver iron not improving consider changing to Desferrioxamine infusions or combination therapy with Deferiprone and Desferrioxamine.
Patient with Myocardial iron loading but not heart failure:

 

Existing treatment Desferrioxamine:

Optimise doses and tackle compliance issues, consider adding in Deferiprone as combination therapy if not previous used this.
Consider using Deferasirox at a 40mg/kg/day dose

 

Existing treatment Deferiprone:

Optimise doses to 75-100mg/kg/day and tackle compliance issues.
Add in Desferrioxamine infusions on 5 days a week if patient is willing to use these according to severity of liver iron load. As liver iron burden falls gradually reduce the frequency of the Desferal infusions but aim to keep at least 1 to 2.
Switching to Deferasirox if patient is not willing to use Desferrioxamine infusions.

 

Existing treatment Deferasirox:

Optimise dose going up to 40mg/kg/day if needed, tackle compliance if dose is optimal.
If despite optimal doses cardiac iron not improving and liver iron is low, or patient developing renal toxicity then switch to Deferiprone monotherapy with careful monitoring.

 

Patient with myocardial iron and heart failure:

Start on IV Desferrioxamine 24 hours a day 7 days a week along with all appropriate cardiac care. Keep on this regime until ejection fraction improves and patient stable.
Consider adding in Deferiprone, as combination therapy if patient is stable.

Dr Farrukh Shah
Consultant haematologist
Red Cell Disorders Unit Whittington and UCLH hospitals
London