1. Iron Overload in Chronic Anaemias
Dick Wells MD, DPhil, FRCPC
Director, Crashley Myelodysplastic Syndrome Research Laboratory

2. Preview Why we need iron The iron economy
Why too much iron is a bad thing
Pumping (out) iron
Current recommendations for treatment of iron overload in MDS

3. Why we need iron Enzymes Oxygen transport
Haemoglobin (red blood cells)
Myoglobin (muscle cells)
About 70% of the body’s iron is in these proteins

4. The iron economy

5. The iron economy is well-balanced.
70%
30%

6. We cope well with iron shortage…
Iron deficiency is the most common deficiency state in the world
Blood loss
dietary
About 1000 mg of iron is stored as ferritin (1/3 of total body iron)
Intestinal absorption of iron increases in response to deficiency

7. …but poorly with iron excess.
Iron is excreted by shedding of intestinal cells
There is no physiologic mechanism to excrete excessive iron

8. Blood transfusion overwhelms the iron balance
Normal daily iron flux:
1-2 mg
Each unit of PRBC: mg

9. Summary: Iron is in a fine balance
In normal circumstances, not much iron enters or leaves the body
The body cannot increase its excretion of iron.
Blood transfusions contain much iron, so patients who need frequent transfusions will build up excess iron.

10. Why too much iron is a bad thing

11. Reticuloendothelial System
Free Iron
Reticuloendothelial System
Dying RBC
Liver
Endocrine organs
CIRRHOSIS
Heart
DIABETES
ARRHYTHMIA HEART FAILURE

12. Lessons from thalassaemia

13. When does iron become a problem?
Normally 2.5 – 3 grams of iron in the body.
Tissue damage when total body iron is 7 – 15 grams
After units of red blood cells

14. How do we know if there’s too much iron?
Serum ferritin concentration
Used in clinical practice globally
Liver biopsy
Reference methodology (‘gold standard’)
Magnetic resonance imaging (MRI)
Investigational, potential for broad access
Magnetic susceptometry (SQUID)
Investigational, very limited access
Speaker Notes
Now let’s turn our attention to the topic of Iron Monitoring, which becomes important once a patient begins therapeutic transfusions of red blood cells. Unfortunately there is no ideal test to accurately determine iron overload. Some methods are simple and easy to perform, but not very accurate or sensitive. Others may provide an accurate assessment of tissue iron stores, but are more difficult to perform.
These are the methods currently used to monitor for iron overload

15. Serum Ferritin Concentration
Easy
Inexpensive
Can be tricky – not purely iron
Inflammation (acute phase reactant)
Liver function abnormalities
Not perfect marker in iron overload
What it lacks in accuracy it makes up for in part with world-wide availability
Speaker Notes
The predictive value of serum ferritin with regard to major complications is not a simple 1 to 1 relationship for all iron overload conditions. It depends on the mechanism by which iron overload occurs and the type and severity of the underlying anemia. For example, the relationship for thalassemia major, in which iron overload is from transfusions, is different from thalassemia intermedia, in which overabsorption of iron plays a major role. In Thalassemia major there is a direct relationship, increasing levels of liver iron concentration (an index of risk) is reflected by increasing levels of serum ferritin. However, for thalassemia intermedia, there is a much weaker relationship.(1)
In summary, although serum ferritin continues to be a cornerstone in monitoring patients with iron overload, many patients will require additional, more specific assessments.
Reference
1. Galanello R, Giagu N, Barella S et al. Lack of Correlation between Serum Ferritin and Liver Iron Concentration in Beta-Zero Thalassemia Intermedia. Abstract #3620. Blood, 2004;104

16. Liver Biopsy LIC accurately reflects total body iron stores
Hepatic iron concentration, mg/g dry weight
Total body iron stores, mg/kg 5 10 15 20 25
300
250
200
150
100 50
r = 0.98
25 patients with iron overload and cirrhosis
 1 mg dry weight liver sample
Speaker Notes
Liver Iron Content (LIC), also referred to as hepatic iron concentration, was measured in one study in 48 patients with thalassemia major and iron overload (1). Patients had undergone successful bone marrow transplant to correct their thalassemia and received phlebotomy to correct existing iron overload. LIC was determined by biopsy and total body iron stores were calculated based on the total amount of blood that needed to be removed to establish a non-overloaded state (quantitative phlebotomy).
As you can see, iron content of liver biopsy samples rose commensurately with total body iron stores in these patients with cirrhosis; serum ferritin levels in the same patients did not show a strong correlation with total body iron stores (1).
Reference
1. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000;343:
LIC accurately reflects total body iron stores
LIC = Liver iron concentration.
Reprinted with permission from Angelucci E, et al. N Engl J Med. 2000;343:

17. Magnetic Susceptometry (SQUID)
Superconducting QUantum Interference Device
High-power magnetic field
Iron interferes with the field
Changes in the field are detected
Noninvasive, sensitive, and accurate
Limited availability
Superconductor requires high maintenance
Only 4 machines worldwide
Speaker Notes
SQUID stands for Superconducting Quantum Interference Device.
Even small amounts of iron can be detected by SQUID since they interfere with the magnetic field SQUID creates. It is an excellent diagnostic method because it is noninvasive, sensitive, and accurate. However, there is limited availability of this equipment due to high cost. In addition, the superconductor requires extensive maintenance and regular replacement of the coolant (liquid helium).
Photograph courtesy of A. Piga

18. Magnetic Resonance Imaging
Speaker Notes
Another method for measuring iron content is through magnetic resonance imaging or MRI. Because of the magnetic properties of iron, MRI is highly sensitive and specific for showing the concentration and distribution of iron throughout the body, or, as mentioned before, in the liver as an indication of total body iron, or iron content of other organ systems. This allows diagnosis of iron overload. (1)
Here is an image of the liver in a patient with significant iron overload (2). This is a processed image consisting of two images, a T2 weighted anatomical picture with an R2 map of the liver superimposed. Unlike liver biopsy, MRI can assess iron overload throughout the liver and does not require a tissue sample. MRI is the only option for monitoring cardiac iron overload, for example, over an extended period of time, because repeated liver biopsies are risky and are performed only when absolutely necessary.
Reference
1. Siegleman ES, Mitchell DG, Semelka RC. Abdominal iron deposition: metabolism, MR findings, and clinical importance. Radiology 1996;199:13-22.
2. Clark PR, et al. Magn Reson Med. 2003;49:
Bright = high iron concentration; dark areas = low iron concentration

19. Summary: Too much iron is bad
Iron overload caused by transfusions causes malfunction of the liver, heart, and endocrine organs.
Problems may begin after 30 units of RBC (or even earlier)
We use serum ferritin level to estimate iron levels
MRI might be better

20. Iron chelation
Out

21. What is Chelation Therapy?
Toxic
Non-Toxic
Metal
Metal
Chelator
Chelator +
Outside the Body
Speaker Notes
Chelation therapy involves the use of a drug that is capable of binding with a metal in the body to form what is called a chelate. By doing so, the metal loses its toxic effect, or physiological activity, and is then more readily removed from the body. Chelation therapy is generally reserved for the forms of iron overload in which phlebotomy cannot mobilize iron stores adequately or cannot be tolerated because of concurrent anemia.
“Chelate”

22. How to chelate? Currently licensed in Canada: Alternatives
Deferoxamine
Alternatives
Deferiprone (L1)
Available on compassionate release
Deferasirox (ICL670, Exjade)
Undergoing accelerated review by
Health Canada

23. Deferoxamine: Mode of Action
Speaker Notes
In the circulation and tissues, deferoxamine binds iron and the iron-bound form can be excreted efficiently in the urine and bile [1]. This is accomplished via the following steps [2]:
Iron released by the reticuloendothelial system following catabolism of dying RBCs is chelated by deferoxamine and immediately excreted in the urine
Unbound deferoxamine also penetrates tissues
– Iron bound in the liver is excreted in the bile
– Iron bound and removed from other locations such as the heart is excreted in the urine
References
1. Thalassemia management. Parts I and II. Semin Hematol. 1995; 32, 1996:33
2. Hershko, C, Konijn, AM, Nick, HP, et al. ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture. Blood. 2001; 97:1115

24. Challenges of Deferoxamine
Subcutaneous/Intravenous route of administration
Expensive
Cumbersome
Uncomfortable
Rapid metabolism (30 minute half-life) necessitates prolonged infusion (12-15 hours)
Complications due to iron overload still occur due to poor compliance with therapy
Speaker Notes
As we saw on the last slide, for patients with serum ferritin values higher than 2500 µg/L, despite therapy, the prognosis is relatively poor. Deferoxamine is not orally bioavailable and is rapidly excreted. It must therefore be given subcutaneously or intravenously over an extended period of time, a major obstacle to achieving positive results, which we will discuss in further detail. The complex nature of deferoxamine therapy leads to poor compliance, resulting in complications from iron overload, despite the availability of this effective therapy.

25. Deferoxamine infusion

26. Common Side Effects of Deferoxamine
Local reactions
Erythema (localized redness)
Induration (localized swelling)
Pruritus (itchiness)
Ophthalmologic
Reduced visual acuity
Impaired color vision
Night blindness
Increased by presence of diabetes
Hearing loss
Zinc deficiency
Speaker Notes
Local reactions are by far the most common adverse events of deferoxamine administration and include erythema, induration, pruritis, and pain at the site of infusion. These problems may be limited in some patients by decreasing the concentration of deferoxamine, although this just lengthens the time required for dosage infusion. Ophthalmologic toxicity includes reduced visual acuity, impaired color vision and night blindness. [1] Diabetes may also increase the risk of ocular toxicities. [2] High-frequency hearing loss is another possible adverse effect that is more common in those who receive high doses of deferoxamine in relationship to their iron stores. [1] Dose adjustment may help to limit toxicity to the eye and ear [3]: The ratio of deferoxamine dose per kilogram of body weight to the serum ferritin level should be maintained at less than
In addition, deferoxamine may increase zinc excretion and lead to subclinical or clinically-apparent zinc deficiency. This may be particularly relevant for patients who have sickle cell disease, who may be zinc deficient even without chelation and in whom zinc deficiency has been associated with poor growth [4]. Periodic monitoring of zinc levels in patients who have SCD and receive deferoxamine is advisable.
References
1. Olivieri NF, Buncic JR, Chew E et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med 1986;314:
2. Arden GB, Wonke B, Kennedy C et al. Ocular changes in patients undergoing long term desferrioxamine treatment. Br J Ophthal 1984;68:
3. Porter JB, Jaswon MS, Huehns ER et al. Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage. Br J Haematol 1989;73:
4. Leonard MB, Zemel BS, Kawchak DA et al. Plasma zinc status, growth, and maturation in children with sickle cell disease. J Pediatr 1998;132:

27. Survival of patients with thalassaemia
Are we certain it helps?
Survival of patients with thalassaemia

28. Summary: Iron chelation and deferoxamine
Chelation works by attaching a drug to iron, which allows the body to excrete it.
Deferoxamine is awful stuff…
Inconvenient and uncomfortable to take
Many nasty side effects
…but it works
Enormous extension of lifespan in thalassaemia.

29. ICL670: Deferasirox, Exjade
Oral, dispersible tablet
Taken once daily
Highly specific for iron
Chelated iron excreted mainly in faeces
Less than 10% excreted in the urine
Speaker Notes
Let’s take a closer look at ICL670. This is an oral tablet that disperses readily in liquid, making it easier to administer to children and anyone who might have a problem swallowing tablets or capsules. The resulting solution is odorless and tasteless. Because of its pharmacology, it is well absorbed from the GI tract and has a long serum half-life of 12 to 16 hours, ICL670 only needs to be given once daily.
Another important feature is that it is highly specific for iron, minimizing the potential for loss of zinc and other nutritional trace metals as a side effect of therapy. Finally, once ICL670 has chelated a quantity of iron, the chelate is excreted largely in the feces – less than 10 percent is excreted in the urine.

30. ICL670 works. g/L Deferoxamine < 25 25-35 35-50 ≥ 50
Speaker Notes
A similar phenomenon was observed in the reduction of serum ferritin values, suggesting that the lowest dose of ICL670 that is potentially therapeutically effective in regularly transfused patients is 20 mg/kg per day.
Deferoxamine < ≥ 50
ICL
All doses in mg/kg/day

31. ICL670 is Generally Tolerable
The most common adverse events were mild and transient:
Nausea (10%)
Vomiting (9%)
Abdominal pain (14%)
Diarrhea (12%)
Skin rash (8%)
Rarely required discontinuation of study drug
Mild increases in serum creatinine
No agranulocytosis observed
Speaker Notes
ICL670 is generally well tolerated. The most common adverse events in trials were transient nausea (10%), vomiting (9%), abdominal pain (14%), diarrhea (12%) and skin rash (8%) that rarely required discontinuation of the drug.
There were mild increases in creatinine in some patients, but these exceeded the upper limits of normal in only 3% of thalassemia patients and 16% of patients with rare anemias. It should be noted that these increases were largely subclinical and would not have been noted by a clinician outside the framework of a clinical trial.
Finally, no agranulocytosis has been observed in over 800 patients exposed to ICL670 to date.

32. When can we have Exjade? Already FDA-approved in the USA
Health Canada approval expected September 2006
Provincial formularies will need to decide whether to include Exjade.

33. What do the experts say?

34. Recommended Treatment for Iron Overload in MDS
Why: to prevent end-organ complications of iron overload and extend lifespan
Whom: transfusion-dependent patients with expected survival > 1 year
When: after 25 units RBC transfused, ferritin >1000.
How: Desferal by subcutaneous infusion (for now); keep ferritin<1000

35. Summary
Iron overload is an inevitable consequence of chronic RBC transfusion
Iron toxicity affects the function of the liver, heart, and endocrine organs
Chelation therapy should be offered to iron overloaded patients with life expectancy >1 year
Desferal is the only drug currently available; Exjade will be available soon.

36. Thank you!