Transcript Iron Deficiency & Clinical Sequelae, Diagnosis

Indications for Successful
Iron Overload
Treatment and Monitoring:
Thalassaemia
M. Domenica Cappellini, MD
Professor of Internal Medicine
University of Milan
Maggiore Hospital
Milan, Italy
1
Thalassaemia major:
transfusion without
chelation
250
50
Hereditary
haemochromatosis
(homozygous)
Hereditary
haemochromatosis
(heterozygous)
200
40
30
150
Threshold for cardiac
disease and early death
100
20
Increased risk of complications
50
10
Optimal level in chelated patients
0
0
Normal
10
20
30
40
0
Hepatic Iron (mg/g of Liver, Dry Weight)
Hepatic Iron (µmol/g Wet Weight)
Iron Loading Rates in Thalassaemia Major and
Hereditary Haemochromatosis
50
Age (years)
Olivieri N, et al. Blood. 1997;89:739.
2
Transfusion Therapy Results
in Iron Overload


1 blood unit contains 200 mg iron1
A 60-kg thalassaemia patient receiving 45 units of blood
annually has transfusional iron intake of 9 g iron/year
– 0.4 mg iron/kg body weight/day

In addition, up to 4 mg/day may be absorbed from the
gut1
– up to 1.5 g iron/year

Overload can occur after 10–20 transfusions1
Transfusional iron intake = volume of packed RBCs (mL) x 1.082
Volume of packed RBCs (mL) = volume of blood (mL) x haematocrit (%)2
Example:
285 mL blood transfused x 65% haematocrit =
185 mL RBCs x 1.08 mg iron/mL RBCs = 200 mg iron
1. Porter JB. Br J Haematol. 2001;115:239. 2. Cappellini MD, et al. Blood. 2006;107:3455.
3
Iron Intake Rates in Thalassaemia
Major1,2
Iron Intake (mg/kg/day)
0.2
0.3
0.4
0.6
0.5
Deferasirox
(n = 296)
Desferrioxamine
(n = 290)
Range between 25th and 75th percentile of daily iron intake
Mean daily iron intake
Iron loading
Transfusion
Subjects
Mean Rate
Annual
<0.3 mg/kg/day
24%
0.25 mg/kg/day
129 mL/kg
0.3–0.5 mg/kg/day
59%
0.39 mg/kg/day
203 mL/kg
>0.5Data
mg/kg/day
17%
0.55 mg/kg/day
286 mL/kg
Novartis.
on file.
1. Cohen A, et al. Blood. 2005;106:Abstr 822. 2. Cappellini MD, et al. Blood. 2006;107:3455.
4
Threshold Levels of Liver Iron


Liver iron concentration (LIC) predicts total body storage
iron in thalassaemia major1
Liver pathology
– Abnormal alanine aminotransferase (ALT) level if LIC >7 mg/g dry
weight2
– Liver fibrosis progression if LIC >16 mg/g dry weight3

Cardiac pathology at high levels
– LIC >15 mg/g dry weight associated with cardiac death
 All of 9/53 thalassaemia major patients who died4
 Improvement of subclinical cardiac dysfunction with venesection
post–bone-marrow transplant5
1. Angelucci E, et al. N Engl J Med. 2000;343:327. 2. Jensen PD, et al. Blood. 2003;101:91.
3. Angelucci E, et al. Blood. 2002;100:17. 4. Brittenham GM, et al. N Engl J Med. 1994;331:567.
5. Mariotti E, et al. Br J Haematol. 1998;103:916.
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

Change in serum ferritin
over time reflects change in LIC
Proportion of ferritin
measurements >2500 ng/mL
affects cardiac disease-free
survival1 (see graph)
Maintenance of serum ferritin
<2500 ng/mL
– Significantly correlates with
cardiac disease-free survival2–
5
<33% ferritin measures
>2500 ng/mL
1.00
1.00
0.75
0.50
Survival probability

Proportion Without Cardiac Disease
Benefits of Ferritin Control
33%–67% ferritin
measures
Ferritin
>2500 ng/mL
>2500
ng/mL
on >1/3 of occasions
0.75
0.50
0.25
>67% ferritin
measures
Maintenance of Lower Ferritin Levels
>2500 ng/mL
0.25
a Positive Indicator for Survival
0
. UCLH (unpublished data)
at
0.00
0
0
2
5
10
15
4
6 Years
8 of
10Follow-Up
12 14 16
Chelation Therapy (years)
1. Olivieri NF, et al. N Engl J Med. 1994;331:574. 2. Gabutti V, Piga A. Acta Haematol. 1996;95:26.
3. Telfer PT, et al. Br J Haematol. 2000;110:971. 4. Davis BA, et al. Blood. 2004;104:263.
5. Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.
6
T2* MRI—Emerging New Standard
for Cardiac Iron
90
80
LVEF (%)
70
60
50
Cardiac T2* value of
37 in a normal heart
40
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
Heart T2* (ms)
Relationship between myocardial T2* values and left ventricular ejection
fraction (LVEF). Below a myocardial T2* of 20 ms, there was a progressive
and significant decline in LVEF (R = 0.61, P < .0001).
Photos courtesy of Dr. M. D. Cappellini.
Anderson LJ, et al. Eur Heart J. 2001;22:2171.
Cardiac T2* value of
4 in a significantly
iron overloaded
heart
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Recommendations for Managing Iron
Overload in Thalassaemia




Thalassaemia major vs intermedia
Who is a candidate for iron chelation?
How should iron chelation treatment be
initiated?
What parameters should be monitored in
patients receiving iron chelation?
8
Current Status of Guidelines for Managing
Iron Overload




Various recommendations, standards, and guidelines are
currently in existence
Most based on experience in managing transfusiondependent thalassaemia
No single comprehensive guideline exists for managing
iron overload in thalassaemia, sickle cell disease, or
myelodysplastic syndromes
A growing number of health authorities are using
guidelines and evidence-based data to determine
reimbursement of drug costs
– Thus, there is a need to produce guidelines, which include oral
chelation therapy
9
New Thalassaemia Guidelines

Thalassaemia International Federation.
Guidelines for the Clinical Management of
Thalassaemia, 2nd edition. 2007.

Angelucci E, et al. Italian Society of
Hematology Practice Guidelines for the
Management of Iron Overload in Thalassemia
Major and Related Disorders.
Haematologica. 2008, In press.
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Iron Overload in Thalassaemia

Thalassaemia major
– Iron overload primarily a
function of chronic
transfusion1
– Iron loading in a
regularly transfused
patient with
thalassaemia major is
approximately 7–9
g/year

Thalassaemia intermedia
– Iron overload primarily a
function of increased GI iron
absorption1
 Sporadic transfusion
– Although rate of iron
accumulation is slow,
complications do occur late
in life
– Iron loading may be on the
order of 2–5 g/year
1. Thalassaemia International Federation. Guidelines for the Clinical Management
of Thalassaemia, 2nd ed. 2007.
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Goals of Chelation Therapy
in Thalassaemia

Prevent accumulation of harmful levels of body iron
– Start treatment before iron accumulation is excessive
– Maintain iron balance
 Match iron excretion with transfusional loading

Prevent tissue damage from labile iron pools
– Provide 24-hour chelation to
 Minimize non–transferrin-bound iron uptake into tissues
 Minimize exposure to labile iron in tissues and plasma


Minimize toxicity from excessive chelation
Rescue
– Necessary if iron has already accumulated in tissues
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The Challenge of Iron Chelation
A Question of Balance

Uncoordinated iron

Uncoordinated chelator

Free-radical generation

Inhibition of metalloenzymes

Organ damage

Neurotoxicity

Growth failure

Growth failure

Organ failure

Bone marrow toxicity

Cardiac death
Too much iron
Graphic courtesy of Dr. J. Porter.
Too much chelator
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Candidates for Iron Chelation

Thalassaemia major1

– >10 transfusions
– Serum ferritin levels
>1000 ng/mL
– LIC >normal range of method
used
LIC = liver iron concentration; UIE = urinary iron excretion.
* M. Domenica Cappellini, MD (oral communications, 2008)
1. Angelucci E, et al. Haematologica. 2008; In press.
Thalassaemia
intermedia*
– Assess iron overload in
patients receiving 0–≤4 units
=year through testing of
serum ferritin, transferrin
saturation, and LIC (or UIE if
LIC is not available)
– Patients with transferrin
saturation constantly >60%
and LIC >4 mg/g dry weight
(or UIE >3 mg/24 h, if LIC not
available), should start iron
chelation therapy
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Treatment Options for
Iron Chelation
Agent
Indication
TM
TI

Desferrioxamine1
Treatment of acute iron poisoning and
chronic iron overload due to transfusional
anaemias

Deferasirox2
Treatment of chronic iron overload due to
frequent transfusion in patients with
thalassaemia major, or due to infrequent
transfusion when desferrioxamine therapy is
inadequate or contraindicated

Treatment of iron overload in patients with
thalassaemia major when desferrioxamine
therapy is inadequate or contraindicated

Deferiprone3
TM = Thalassaemia major; TI = Thalassaemia intermedia
1.
2.
3.
Desferal (desferrioxamine). International Package Leaflet. Basel, Switzerland; Novartis, 1998.
Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006.
Ferriprox (deferiprone). Summary of Product Characteristics. EMEA, 2007.
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Administration of Chelating Agents
Agent
Administration
Desferrioxamine1,2
8–12 hours subcutaneous infusion 5–7 days per week;
dose, infusion duration, and number of administrations
to be decided according to patient age and severity of
iron overload
Deferasirox3
Once-daily oral dosing; initial daily dose of 20 mg/kg
(10–30 mg/kg)
Deferiprone4
Thrice-daily oral dosing; total daily dose of 75 mg/kg
1. Desferal (desferrioxamine). International Package Leaflet. Basel, Switzerland; Novartis, 1998.
2. Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia,
2nd ed; 2007. 3. Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006. 4. Ferriprox
(deferiprone). Summary of Product Characteristics. EMEA, 2007.
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Increasing Efficacy of Chelation Therapy Has
Significantly Improved Patient Survival
1.00
Survival Probability
0.75
Birth cohort
1985–1997
1980–1984
1975–1979
1970–1974
1965–1969
0.50
1960–1964
0.25
(P < .00005)
0
0
5
10
15
Age (years)
Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.
20
25
30
17
Monitoring Iron Load in Patients on Iron
Chelation Therapy

Thalassaemia major1
– Periodic monitoring of serum
ferritin level
 Assess LIC if increasing or
decreasing (<1000 ng/mL)
serum ferritin trend to avoid
under- or overtreatment
– In patients with LIC prior to
start, LIC (liver biopsy,
SQUID, or MRI) should be
repeated every year

Thalassaemia intermedia*
– Periodic monitoring of serum
ferritin, transferrin saturation
and LIC (or UIE, if LIC not
available)
– Decrease iron load to safe limit,
ie, LIC <4 mg/g dry weight (or
UIE <3 mg/24 h, if LIC not
available)
LIC = liver iron concentration; SQUID = superconducting quantum interference;
MRI = magnetic resonance imaging; UIE = urinary iron excretion.
* M. Domenica Cappellini, MD (oral communications, 2008)
1. Angelucci E, et al. Haematologica. 2008; In press.
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Candidates for Aggressive
Iron Chelation



Serum ferritin values persistently >2500 ng/mL
Liver iron >15 mg/g dry weight
Significant cardiac disease
– Cardiac dysrhythmias
– Evidence of failing ventricular function
– Evidence of severe cardiac iron loading

Other indications
– Female patient considering pregnancy
– Patients planning bone marrow transplant
– Patient with active hepatitis C
Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia,
2nd ed. 2007.
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Switching Chelating Agents

Patients receiving desferrioxamine standard-dose therapy who
develop severe iron overload (LIC >15 mg/g dry weight or serum
ferritin >3000 ng/mL)
– First, advise to strictly adhere to the chelation protocol
– In absence of a reversal of iron overload, shift to an intensive or
combined chelation therapy (grade B)


Available evidence favours use of deferiprone as chelator to be
associated with desferrioxamine (grade B)
Switch to alternative iron chelator is mandatory in cases of
nonadherence to desferrioxamine, or the occurrence of severe
adverse effects that preclude its continuation (grade D)
Angelucci E, et al. Haematologica. 2008, In press.
20
Conclusions






Many tools are available for assessing iron overload
Combining these tools allows more accurate
assessment of iron load
Serial ferritin evaluation (every 3–4 months) is the
most practical tool for following iron load and iron
chelation efficacy
Measure LIC (biopsy/MRI/SQUID) at least once
Assess cardiac iron load by MRI at least once
Closer monitoring is indicated in certain cases
–
–
–
Changes in transfusional iron load
Changes in chelation therapy
New signs of iron load toxicity
21