1
Indications for Successful Iron Overload
Treatment and Monitoring: Thalassaemia
M. Domenica Cappellini, MD
Professor of Internal MedicineUniversity of MilanMaggiore Hospital
Milan, Italy
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50
30
0
40
10
20
Increased risk of complications
Normal
0 20 5010 30 40
Age (years)
Thalassaemia major: transfusion without chelation
Hereditary haemochromatosis (homozygous)Hereditary haemochromatosis(heterozygous)
Optimal level in chelated patients
Hep
atic
Iro
n (
mg
/g o
f L
iver
, D
ry W
eig
ht)
Threshold for cardiacdisease and early death
Olivieri N, et al. Blood. 1997;89:739.
Hep
atic
Iro
n (
µm
ol/
g W
et W
eig
ht)
50
100
150
200
250
0
Iron Loading Rates in Thalassaemia Major and Hereditary Haemochromatosis
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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
Transfusion Therapy Results in Iron Overload
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.
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Iron Intake Rates in Thalassaemia Major1,2
Iron loading Subjects Mean Rate Annual Transfusion
<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
>0.5 mg/kg/day 17% 0.55 mg/kg/day 286 mL/kg
0.2 0.3 0.4 0.5 0.6
Deferasirox (n = 296)
Desferrioxamine (n = 290)
Iron Intake (mg/kg/day)
Range between 25th and 75th percentile of daily iron intake
Mean daily iron intake
Novartis. Data on file.1. Cohen A, et al. Blood. 2005;106:Abstr 822. 2. Cappellini MD, et al. Blood. 2006;107:3455.
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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.
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
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Benefits of Ferritin Control
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
Su
rviv
al p
rob
abil
ity
0 5 10 15
0
0.25
0.50
0.75
1.00
Ferritin >2500 ng/mL on >1/3 of occasions
Years of Follow-Up
.
Maintenance of Lower Ferritin LevelsMaintenance of Lower Ferritin Levels
a Positive Indicator for Survival a Positive Indicator for Survival
at UCLH (unpublished data)at UCLH (unpublished data)
Chelation Therapy (years)
0.00
0.50
0.25
0.75
1.00
0 2 4 6 8 10 1412 16
Pro
po
rtio
n W
ith
ou
t C
ard
iac
Dis
ease
<33% ferritin measures>2500 ng/mL
33%–67% ferritin measures >2500 ng/mL
>67% ferritin measures
>2500 ng/mL
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.
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T2* MRI—Emerging New Standard for Cardiac Iron
Photos courtesy of Dr. M. D. Cappellini.Anderson LJ, et al. Eur Heart J. 2001;22:2171.
LVEF (%)
0
50
70
40
30
20
10
60
80
90
0 20 40 60 9080 10010 30 50 70
Heart T2* (ms)
Cardiac T2* value of 37 in a normal heart
Cardiac T2* value of 4 in a significantly iron overloadedheart
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).
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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?
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Current Status of Guidelines for Managing Iron Overload
Various recommendations, standards, and guidelines are currently in existence
Most based on experience in managing transfusion-dependent 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
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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 ChelationA Question of Balance
Too much iron Too much chelator
Uncoordinated iron Free-radical generation Organ damage Growth failure Organ failure Cardiac death
Uncoordinated chelator Inhibition of metalloenzymes Neurotoxicity Growth failure Bone marrow toxicity
Graphic courtesy of Dr. J. Porter.
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Candidates for Iron Chelation
Thalassaemia major1
– >10 transfusions
– Serum ferritin levels
>1000 ng/mL
– LIC >normal range of method used
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
1. Angelucci E, et al. Haematologica. 2008; In press.
LIC = liver iron concentration; UIE = urinary iron excretion.* M. Domenica Cappellini, MD (oral communications, 2008)
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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
Deferiprone3 Treatment of iron overload in patients with thalassaemia major when desferrioxamine therapy is inadequate or contraindicated
1. Desferal (desferrioxamine). International Package Leaflet. Basel, Switzerland; Novartis, 1998.
2. Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006.
3. Ferriprox (deferiprone). Summary of Product Characteristics. EMEA, 2007.
Treatment Options for Iron Chelation
TM = Thalassaemia major; TI = Thalassaemia intermedia
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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.
Administration of Chelating Agents
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Su
rviv
al P
rob
abil
ity
Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.
(P < .00005)
0
1.00
0.75
0.50
0.25
0 5 10 15 20 25 30
Age (years)
Birth cohort
1960–1964
1965–19691970–1974
1975–1979
1980–1984
1985–1997
Increasing Efficacy of Chelation Therapy Has Significantly Improved Patient Survival
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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.
19Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia, 2nd ed. 2007.
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
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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.
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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