iron overload in chronic anaemias dick wells md, dphil, frcpc director, crashley myelodysplastic...
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Iron Overload in Chronic Anaemias
Dick Wells MD, DPhil, FRCPCDirector, Crashley Myelodysplastic Syndrome Research Laboratory
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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
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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
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The iron economy
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The iron economy is well-balanced.
70%
30%
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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
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…but poorly with iron excess.
• Iron is excreted by shedding of intestinal cells
• There is no physiologic mechanism to excrete excessive iron
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Blood transfusion overwhelms the iron balance
• Normal daily iron flux:
1-2 mg
• Each unit of PRBC:
200-250 mg200-250 mg
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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.
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Why too much iron is a bad thing
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Dying RBC
Reticuloendothelial System
Free Iron
Liver
Heart
Endocrine organsCIRRHOSIS
ARRHYTHMIA HEART FAILURE
DIABETES
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Lessons from thalassaemia
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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 30-50 units of red blood cells
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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
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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
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Liver Biopsy
LIC = Liver iron concentration.Reprinted with permission from Angelucci E, et al. N Engl J Med. 2000;343:327-331.
25 patients with iron overload andcirrhosis
1 mg dry weight liver sample
Hepatic iron concentration, mg/g dry weight
To
tal
bo
dy
iro
n s
tore
s, m
g/k
g
0 5 10 15 20 25
300
250
200
150
100
50
0
r = 0.98
• LIC accurately reflects total body iron stores
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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
Photograph courtesy of A. Piga
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Magnetic Resonance Imaging
Bright = high iron concentration; dark areas = low iron concentration
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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
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Iron chelation
Out
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MetalChelatorChelator + ChelatorChelator
Toxic Non-Toxic
“Chelate”
Outsidethe
BodyMetal
What is Chelation Therapy?
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How to chelate?
• Currently licensed in Canada:– Deferoxamine
• Alternatives– Deferiprone (L1)
• Available on compassionate release
– Deferasirox (ICL670, Exjade)• Undergoing accelerated review by Health Canada
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Deferoxamine: Mode of Action
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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
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Deferoxamine infusion
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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
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Are we certain it helps?Survival of patients with thalassaemia
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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.
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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
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ICL670 works.
Deferoxamine < 25 25-35 35-50 ≥ 50ICL670 5 10 20 30
All doses in mg/kg/day
-3000
-2000
-1000
0
1000
2000
3000
4000
Desferal 0107
ICL670 0107
ICL670 0108
g/L
Deferoxamine 0107
ICL670 0107
ICL670 0108
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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
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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.
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What do the experts say?
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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
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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.
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Thank you!