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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

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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

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Threshold for cardiacdisease and early death

Olivieri N, et al. Blood. 1997;89:739.

Hep

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ol/

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et W

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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

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0 5 10 15

0

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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

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Pro

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<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 (%)

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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

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Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.

(P < .00005)

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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