Iron Overload in Chronic Anaemias Dick Wells MD, DPhil, FRCPC Director, Crashley Myelodysplastic...
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Transcript of Iron Overload in Chronic Anaemias Dick Wells MD, DPhil, FRCPC Director, Crashley Myelodysplastic...
Iron Overload in Chronic Anaemias
Dick Wells MD, DPhil, FRCPCDirector, Crashley Myelodysplastic Syndrome Research LaboratoryOdette Cancer Centre
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• 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
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
The iron economy
Adapted with permission from Andrews NC. N Engl J Med. 1999;341:1986–1995
Body Iron Distribution and Storage
We cope well with iron shortage…
• Iron deficiency is the most common deficiency state in the world– Blood loss– diet
• About 1000 mg of iron is stored as ferritin (1/3 of total body iron)
• Intestinal absorption of iron increases in response to deficiency
…but poorly with iron excess.
• Iron is excreted by shedding of intestinal cells
• There is no physiologic mechanism to excrete excessive iron
Blood transfusion overwhelms the iron balance
• Normal daily iron flux:
1-2 mg
• Each unit of PRBC:
200-250 mg200-250 mg
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.
Why too much iron is a bad thing
Dying RBC
Reticuloendothelial System
Free Iron
Liver
Heart
Endocrine organsCIRRHOSIS
ARRHYTHMIA HEART FAILURE
DIABETES
Lessons from thalassaemia
Hepatic fibrosis Cirrhosis
Arrhythmia
Hypogonadism
Diabetes
Hypothyroidism
Hypoparathyroidism
Cardiomyopathy
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
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
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
Liver Biopsy
• The “Gold Standard”• Invasive• Potentially risky
Not often used in MDS
Direct measurement of iron content
Magnetic Resonance Imaging
Bright = high iron concentration; dark areas = low iron concentration
Iron overload impairs survival in MDS
<10001000-1500
>25001500-2000
>10001000-1500
>25001500-2000
Pro
po
rtio
n s
urv
ivin
g
40 4080 80120 120
Survival time (months)
Malcovati, Haematologica, 2006
RA, RARS, 5q- RCMD, RCMD-RS
?
Ferritin Ferritin
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
What can we do about it?
Iron chelation
Out
MetalChelatorChelator + ChelatorChelator
Toxic Non-Toxic
“Chelate”
Outsidethe
BodyMetal
What is Chelation Therapy?
How to chelate?
• Currently licensed in Canada:– Deferoxamine (Desferal)– Deferasirox (ICL670, Exjade)
• Alternative– Deferiprone (L1)
• Available on compassionate release
Deferoxamine: Mode of Action
Deferoxamine works!
Survival of patients with thalassaemia
No data like these are available for iron chelation in MDS
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
Deferoxamine infusion
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
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.
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
Exjade 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 0108g/L
Deferoxamine 0107
ICL670 0107
ICL670 0108
Exjade 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 drug Reports of :
Kidney failure Worsening of blood counts
Exjade is Available (…sort of)• Health Canada approval received Oct 2006
– chronic iron overload in patients with transfusion-dependent anemias aged 6 years old and older.
– chronic iron overload in patients with transfusion-dependent anemias aged 2 to 5 years old who cannot be adequately treated with deferoxamine
• Provincial formularies still need to decide whether to include Deferasirox.
What do the experts say?
Canadian Guidelines 2007
• Why: to prevent end-organ complications of iron overload and extend lifespan
• Whom: transfusion-dependent patients with expected survival > 1 year or BMT candidates
• When: ferritin >1000, TfSat > 0.5• How: DSX 20 mg/kg/d or DFO 50 mg/kg/d
5/7; target ferritin<1000
Iron Overload in Myelodysplastic Syndromes: A Consensus Guideline. Submitted 2007
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 and Exjade are both effective.
Thank you!