Iron Overload
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Transcript Iron Overload
Iron Overload in
Chronic Anaemias
Dick Wells MD, DPhil, FRCPC
Director, Crashley Myelodysplastic Syndrome Research Laboratory
Odette 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
Body Iron Distribution and Storage
Adapted with permission from Andrews NC. N Engl J Med. 1999;341:1986–1995
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 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
Free
Iron
Reticuloendothelial
System
Dying
RBC
Liver
CIRRHOSIS
Heart
ARRHYTHMIA
HEART FAILURE
Endocrine
organs
DIABETES
Lessons from thalassaemia
Cardiomyopathy
Hypoparathyroidism
Hypothyroidism
Diabetes
Hypogonadism
Arrhythmia
Hepatic fibrosis
Cirrhosis
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
RA, RARS, 5q<1000
1000-1500
1500-2000
>2500
Ferritin
Proportion surviving
RCMD, RCMD-RS
>1000
1000-1500
1500-2000
>2500
Ferritin
?
40
80
120
40
80
Survival time (months)
Malcovati, Haematologica, 2006
120
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
What is Chelation Therapy?
Toxic
Chelator
+
Metal
Non-Toxic
Chelator Metal
“Chelate”
Outside
the
Body
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.
4000
3000
2000
g/L
1000
Desferal
0107 0107
Deferoxamine
ICL670
ICL6700107 0107
0
ICL670
ICL6700108
-1000
-2000
-3000
Deferoxamine
ICL670
< 25
5
25-35
35-50
10
20
All doses in mg/kg/day
≥ 50
30
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 transfusiondependent anemias aged 6 years old and older.
– chronic iron overload in patients with transfusiondependent 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!