Download Iron Overload

Iron Overload in
Chronic Anaemias
Dick Wells MD, DPhil, FRCPC
Director, Crashley Myelodysplastic Syndrome Research Laboratory
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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
The iron economy is wellbalanced.
70%
30%
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
…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
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
• Magnetic susceptometry (SQUID)
– Investigational, very limited 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
Total body iron stores, mg/kg
Liver Biopsy
300
r = 0.98
250
200
25 patients with
iron overload and
cirrhosis
150
100
 1 mg dry weight
liver sample
50
0
0
5
10
15
20
25
Hepatic iron concentration, mg/g dry weight
• LIC accurately reflects total body iron stores
LIC = Liver iron concentration.
Reprinted with permission from Angelucci E, et al. N Engl J Med. 2000;343:327-331.
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
Magnetic Resonance Imaging
Bright = high iron concentration; dark areas = low iron concentration
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
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
• Alternatives
– Deferiprone (L1)
• Available on compassionate release
– Deferasirox (ICL670, Exjade)
• Undergoing accelerated review by
Health Canada
Deferoxamine: Mode of Action
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
Are we certain it helps?
Survival of patients with thalassaemia
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
ICL670 works.
4000
3000
g/L
2000
1000
Deferoxamine
Desferal 01070107
ICL670
ICL670 01070107
ICL670
ICL670 01080108
0
-1000
-2000
-3000
Deferoxamine
ICL670
< 25
5
25-35
35-50
10
20
All doses in mg/kg/day
≥ 50
30
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
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.
What do the experts say?
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
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.
Thank you!