Guideline:Iron chelation treatment

'''1. Protocols for conventional iron chelation treatment - these recommendations address ‘advanced’ centres whose aim is research as well as routine care. They canot be regarded as final but are posted on the portal as an evolving set of guidelines to be altered as members add comments and as new research contributes additional evidence. They also include points which serve as research ideas which the collaborators may take up for future projects. No guidelines can be regarded as science’s final word!'''

a) Standard iron chelation

State of the art: new oral iron chelators are now available: these are Deferiprone and Deferasirox. These chelators may deeply influence the standard iron chelation. For deferiprone, approved since 1999 a sufficiently clear efficacy (dose dependence, cardioprotection, lack of response in a proportion of patients) and toxicity (G.I. intolerance, arthropathy, agranulocytosis) profile has been established. Deferasirox has been largely evaluated in the context of clinical trials for the approval for clinical use, but an extended clinical experience is not yet available. Clinical trials with Deferasirox have shown that this compound is safe in children. It seems clear that the different chelators may access iron pools in different organs. Monitoring of iron stores is essential in order to make correct clinical decisions regarding chelation therapy. New methods (SQUID or MRI) for the assessment of iron overload directly and accurately in organs (liver and heart) have been introduced in the clinical setting. However, these methods are not yet widely available and are expensive. While overall mean serum ferritin in patients as a group correlates with morbidity and mortality, in the single patient serum ferritin may not be accurate in evaluating the severity of iron overload and in predicting the risk of iron-related complications.

When to start chelation:

Usually, in clinical practice, chelation starts with desferrioxamine (DFO) which is prescribed at 20 mg/Kg/d after patients have received 12 – 15 transfusions and / or when the level of ferritin is around 1000 ng/ml. This is recommended in most clinical guidelines and textbooks (see: Guidelines  for the clinical management  of Thalassaemia, published by TIF, 2000 and 2007), and later tailored on the basis of serum ferritin determined every 3 months. The reason for this approach is empirical and based on the toxicity of DFO in the absence of iron overload. For this reason chelation is not initiated until there is evidence of iron accumulation.

The main source of iron in thalassaemia is transfused blood so that the iron intake from this source must be taken into account before chelation therapy starts. In this respect it is important to consider the indications for regular blood transfusions: these include the inability of the patient to maintain a haemoglobin (Hb) level above 7g/dl, impairment of growth, bone deformities and progressively enlarged spleen. Regular transfusions should be maintained in order to keep pre-transfusion Hb concentration between 9-9.5 g/dl. With these indications in mind the iron load can be estimated by using the following calculation:

Transfused iron (mg) = packed red cell volume(ml) x Hct(%) x 1.08mg iron/ml

The transfused iron is usually estimated when the serum ferritn has increased to about 1000μg/l. Other suggested parameters to be considered before starting chelation are the following:


 * The iron load status of each patient before the first transfusion indicated by: serum iron, serum transferring, TIBC, serum transferring saturation, serum ferritin (and possibly isoferritin?), CRP (? to exclude  any inflammatory condition influencing the ferritin level), and non-transferrin bound iron (NTBI). NTBI (or labile plasma  iron – LPI) is useful in research but has not yet been assessed as a guide to routine clinical management and is not yet widely available as a test.


 * 24 hour urinary iron excretion of iron before the first transfusion. After the 5th transfusion a Desferal test should be performed to assess the efficacy of the treatment  and to decide on the need for dose modification: before starting the DFO infusion the bladder is emptied and then DFO 20-25 mg/kg is infused subcutaneously for 12 hours – urine is then collected with accuracy for 24 hours for iron estimation. (this test may be difficult to perform in infants without catheterisation)


 * The dietary habits of the patient should be recorded. Even though there is increased iron absorption from the gut in thalassaemia diet is a minor source of iron compared to the transfused iron. However factors such as meat consumption of meat, tea, and foods rich in vitamin C should be known (from adolescence the intake of alcohol and smoking should also be recorded).


 * Magnetic resonance imaging of the liver – MRI(R2) is also a possible guide to starting chelation: i.e. when liver iron is >3.2mg/g.

Formal prospective  studies to evaluate when  to start iron chelation are lacking. However, insights gained by following the guidelines described above with long term follow up may provide evidence based suggestions about when chelation therapy should be initiated.

Another decision which requires further studies is when to start iron chelation in thalassaemia intermedia  patients who  are not transfused  or receive irregular transfusions. One suggestion is to monitor Serum ferritin and commence therapy when the level reaches 1000μg/l. However in view of the slow rate loading this level may remain steady for long periods. Other parameters such as LIC should also be taken under consideration.

It is also possible that these criteria for initiating chelation are not applicable to other chelating agents.

Which chelation regime to adopt for routine cases? There are now three iron chelating agents available to the clinician, which can be used as monotherapy or in combination:
 * 1) Desferrioxamine (DFO) – this has been used as a monotherapy for many decades. The starting dose in children is 20mg/kg/day by slow subcutaneous infusion over 8-12 hours. This is escalated to 40mg until growth ceases and can be increased to 50-60mg/kg in adults.
 * 2) Deferasirox – this oral drug has been approved for use in children above the age of 2 years with no adverse effects on growth (Piga 2005, Galanello 2006). Starting  dose is 20mg/kg. The same starting criteria have been adopted arbitrarily as those that had applied for DFO. Dose can be increased to 30mg/kg/day according to iron overload.
 * 3) Deferiprone – there are no data on the use of this drug in children under the age of 6 years, and limited data for its use between 6-10 years according the manufacturer’s SPC. A liquid formulation of the drug is now ready which will have an impact on the use of this drug in children. The standard dose is 75mg/kg/day and can be increased to 100mg/kg /day.
 * 4) The use of two drugs alternatively. This means giving each chelator on different or alternate days, such as giving one for 4 days/week and the other for 3days (or 5 days and 2 days). Another possibility is to alternate the drugs on a monthly basis using each for a whole month. The two agents that have been used in this way are Deferiprone and DFO. There have been no reports on alternating with Deferasirox. Such rotation of chelators does not achieve 24 hour coverage so that protection from labile iron cannot be ‘fully’ achieved. This method cannot be regarded as intensive chelation but may increase patient compliance and so improve chelation results. At this time there is insufficient information on the results of these regimes so that careful monitoring of results on an investigational basis is recommended.

It is suggested that treatment should start as a monotherapy using one of the available agents. Which one should be used to start with depends to a certain extent on availability but it must be taken into account that Deferiprone cannot be used before the age of six years, since there are limited data on its use between the ages of 6 -10 years and none before the age of 6 years (see the drug’s SPC). This means that the classical approach of starting with Desferrioxamine will be used by the majority but increasingly Deferasirox will or may replace this for reasons of convenience for children.

Method to be used for efficacy monitoring :


 * Serum Ferritin: this should be measured every 3 months. Some partners suggest that the effect of inflammation can be reduced if there is avoidance of analysis at times of acute infection and at least 2 weeks from an episode. Monitoring CRP along with ferritin may also be useful in interpreting results.


 * Liver iron concentration: the two methods available to most centres are liver biopsy and MRI, while SQUID is available only to a minority and will not be discussed here.

a) liver biopsy, preferably needle biopsy, is an invasive procedure and accuracy depends on the size of the sample obtained and the uneven distribution of iron deposited in the liver. It should probably be considered only for patients whose ferritin levels deviate from expected trends (TIF 2008 Guidelines)

b) MRI is widely available and various techniques have been validated (eg. Christforidis et al 2006, St Pierre et al 2005). The initial test can be caried out before starting chelation or in adolescence when the first assessment; frequency of further assessments. MRI R2 may be examined once or twice per year.


 * Heart iron: Echocardiography to evaluate ventricular function and T2* MRI. It is suggested to start monitoring the cardiac load after the first 40 blood transfusions and then every 6 months.


 * The Desferal test of iron excretion is used for patients taking this chelating agent but a similar test may be used for those taking Deferiprone monotherapy.

Proposal:

1. Non-Transferrin Bound Iron (NTBI) or Labile Plasma Iron (LPI) have not been evaluated as clinical monitoring tools. Serial measurements are needed before a new regime is started and several measurements in the next few hours after the patient takes the chelator. This may be used in selected patients in laboratories where the method is established. A point of discussion is therefore whether a group of Ithanet partners or users may decide to collaborate on a project to investigate the possibility of routine use of such measurements.

2. Isoferritins, measured in serum and in 24-hour urine samples. This information may be useful in a minority of patients where serum ferritin levels are low yet the heart or liver are found to loaded by MRI techniques. No studies have been carried out in this respect and so this suggestion is purely for research purposes.

Comments:

Aim 3. Chelator’s toxicity monitoring: Prof R. Galanello proposed to follow the SPC (summary of product characteristics) recommendations. These of course would differ according to each chelating agent and its main toxic effects. For Deferiprone for example, the most serious toxic effect is agranulocytosis so that weekly monitoring of neutrophil counts is essential to early identify patient s who are affected. This is not necessary for those taking DFO which requires different monitoring such as growth velocity and sensory monitoring while Deferasorox requires monthly measurements of serum creatinine.

Proposals for advanced toxicity monitoring over and above SPC recommendations the following were proposed by p19:


 * Growth velocity
 * Ophthalmic and auditory acuity
 * Ejection fraction and systolic artery pressure
 * Changes in Ca/P metabolism, the possible effect on the 24 hour excretion of Calcium and the effect on BMD as measured by DEXA.
 * Effect on serum Mg and Zn
 * D-dimers and procoagulants.
 * Serum Transferrin saturation
 * Total anti-oxidant capacity and markers of oxidative stress in the serum and urine.
 * Endothelin and markers of endothelium activation and dysfunction.
 * Markers of immunological  abnormalities e.g. RF, C3, C4, CIC, antinuclear antibodies, anticardiolipin antibodies etc
 * Microalbuminuria
 * Markers of fibrosis
 * CRP

Comments

Aim 4. Monitoring compliance: Do you regularly monitor compliance in all your patients or in selected patients?

How do you monitor compliance with:

DFO -
 * a) Counting returned empty vials
 * b) Keeping a diary or schedule indicating the days of chelation

Deferiprone -
 * a) Counting returned empty blisters
 * b) A schedule indicating missed doses or days

Exjade – as above.

Intensive iron chelation

State of the art: intensive iron chelation can be defined as an increase in the exposure or amount of the chelator, a change in the route of administration (i.e. intravenous DFO) or combination of two chelators. Intensive chelation is generally prescribed when iron overload is severe and / or in presence of serious iron related complications, such as cardiac disease. However, a clear definition of the appropriate indications and type of chelation is not available. Many studies have been published on the intravenous use of DFO and on combination of DFO and DFP, but almost all are retrospective observational studies, since it is difficult to design prospective randomized trials. Based on personal experience and on the published data aims of this protocols are

1. To define clinical conditions and / or laboratory parameters for prescribing intensive chelation


 * Proposal for clinical conditions:

b) the presence of cardiac involvement: as indicated by the presence of arrhythmia, overt heart failure and MRI T2* indication of heavy iron load. c) Heavy liver siderosis and marked  hepatomegaly,  including compensated cirrhosis

d) Chronic thromboembolic disease


 * Proposal for laboratory parameters:


 * a) Serum ferritin above >3000μg/l


 * b) LIC by biopsy >15mg/g dry weight


 * c) NTBI (or LPI) persistently high at more than two time points in a day


 * d) MRI T2* <15msec


 * e) LVEF (ECHO) <55%
 * Comments

2. indicate the most used type of intensive chelation in your personal experience:


 * Type of intensive chelation used:

P19: In our centre intensive chelation meant continuous Desferrioxamine by IV infusion over 24 hours, at a dose up to 100mg/day. This has been largely replaced by ‘combination therapy’ using Desferrioxamine 4-7 days per week and Deferiprone daily, at 75-100mg/day.

P23: Use ‘combination therapy’ of DFO at least three times per week + Deferiprone daily. The number of DFO days is increased according to severity of the risk or the urgency to reduce the iron load.

P14: ‘Combination therapy’ using DFO 2 days per week with daily Deferiprone. This is according to a controlled study now under publication.

P25: Continuous IV Desferrioxamine  over 24 hours at a dose of 60mg/kg/day. Combination therapy is also used with DFO 4-7 days per week and daily Deferiprone at 75mg/kg/day.

Comments: The regimes vary from centre to centre but all have the basis with combination therapy gaining ground over continuous IV DFO. It may be recommended that IV therapy may be used for short periods in hospital while combination treatment, tailored to individual needs can be used for prolonged periods.

3. To indicate the duration of the intensive treatment:


 * Duration of intensive chelation: Partners use intensive treatment for several weeks or months after hospitalisation since maintenance is important. Criteria for discontinuing intensive chelation include the fall in serum ferritin to around 1000μg/l and there is clear evidence of clinical improvement.

Comments: These criteria are arbitrary and most patients now are maintained on some form of combination while DFO days or dose is reduced according to clinical judgement and if serum ferritin levels fall to levels (e.g. below 500μg/l when there concern for the appearance of DFO toxicity)

c) Definition of normal ferritin levels

State of the art: while iron chelation is necessary to reduce iron associated morbidity and mortality, excessive chelation may have consequences since iron is an essential element involved in many critical metabolic processes. It is well known the effect of the excessive DFO administration on the growth. Despite the limited reliability, particularly as a single determination, serum ferritin is the most widely used method for monitoring the efficacy of iron chelation.

Moreover, in a proportion of patients there is no correlation between ferritin levels and organ iron overload, particularly in the heart. Therefore we need to rethink what are the “normal” or optimal ferritin levels.

Aim 1. To indicate what is the target ferritin level to avoid complications from iron overload and side effects from hyperchelation:


 * Ferritin level: it is not known at what level toxic effects of chelators  may appear-  it may be different for each drug used and different for each age group, since in children influence on growth by DFO will be a consideration but not in adults. Also serum ferritin does not only reflect iron stores and its relationship to iron stores is linear up to a certain level of iron overload. Other factors such as vitamin deficiencies can also influence ferritin levels. A careful study is required to answer this question with a starting ferritin of below  1000μg/l,  and then comparing  various parameters, such as those listed under toxicity monitoring, as the ferritin level falls. Such a project may require very long follow up since side effects, such as bone toxicity or sensory loss, may take a along time to appear. The alternative is to accept an arbitrary level of 500-1000μg/l and monitor morbidity over a long period and compare with patients who have higher levels ferritin.


 * Comments:

Aim 2. Do you consider serum ferritin the only measurement to monitor iron chelation and iron overload or do you suggest other methods?


 * Proposal: the methods listed in efficacy monitoring above should be used.
 * Comments