1. M. Domenica Cappellini, MD
Indications for Successful Iron Overload Treatment and Monitoring: Thalassaemia
M. Domenica Cappellini, MD
Professor of Internal Medicine University of Milan Maggiore Hospital Milan, Italy

2. Hepatic Iron (mg/g of Liver, Dry Weight)
Iron Loading Rates in Thalassaemia Major and Hereditary Haemochromatosis
Thalassaemia major: transfusion without chelation 50 50
100
150
200
250
Hereditary haemochromatosis (homozygous) 40
Hereditary haemochromatosis
(heterozygous) 30
Hepatic Iron (µmol/g Wet Weight)
Hepatic Iron (mg/g of Liver, Dry Weight)
Threshold for cardiac disease and early death 20
Increased risk of complications 10
Optimal level in chelated patients
Normal 10 20 30 40 50
Age (years)
This research was originally published in Blood. Olivieri N, et al. Blood. 1997;89:739. (c) the American Society of Hematology.

3. 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
Iron overload, a cumulative toxicity, is an inevitable, potentially life-threatening consequence of multiple blood transfusions
Red blood cell transfusion is the mainstay of therapy for thalassemia. Transfusions are initiated when hemoglobin falls below 7 g/dL, or at higher levels to help resolve specific problems such as growth impairment, bone changes or progressive splenomegaly
Transfusions are administered in sufficient quantity and frequency to achieve a hemoglobin level of at least 9.3 g/dL; this level partly suppresses the erythropoietic drive that is producing ineffective red blood cells (RBCs). A regimen that maintains the mean hemoglobin level above 10.5 to 11 g/dL reduces marrow expansion, arrests bone changes and minimizes splenomegaly. This leads to a reduction in plasma fluid volume, allowing an increase in relative concentration of hemoglobin. In children, growth may improve and more normal physical activity can be expected1,2
Table. Equivalent iron intake and transfusional requirements
References
Thalassemia management. Parts I and II. Semin Hematol 1995;32:1996:33(1)
Olivieri NF & Brittenham GM. Blood 1997;89:739–761
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: Cappellini MD, et al. Blood. 2006;107:3455.
Daily
Monthly
Yearly
Transfusional requirements
Iron intake, mg/kg/day
Pure red cells given, mL RBC/kg/month
Pure red cells given, mL RBC/kg/year
Iron intake, g/kg/year
Low
<0.3
<8
<100
<3.3
Intermediate
0.3–0.5
8–14
100–150
3.3–5.5
High
>0.5
>14
>150
>5.5

4. Iron Intake Rates in Thalassaemia Major1,2
Iron Intake (mg/kg/day)
0.2
0.3
0.4
0.5
0.6
Deferasirox (n = 296)
Desferrioxamine (n = 290)
Range between 25th and 75th percentile of daily iron intake
 TRT ICL670 DFO
AVGIN2_C All categories All categories N
MEAN
STD P P Q
MEDIAN Q P P
Mean daily iron intake
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 mL/kg
>0.5 mg/kg/day 17% 0.55 mg/kg/day 286 mL/kg
Novartis. Data on file.
1. Cohen A, et al. Blood. 2005;106:Abstr Cappellini MD, et al. Blood. 2006;107:3455.

5. 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: Jensen PD, et al. Blood. 2003;101: Angelucci E, et al. Blood. 2002;100: Brittenham GM, et al. N Engl J Med. 1994;331: Mariotti E, et al. Br J Haematol. 1998;103:916.

6. Benefits of Ferritin Control
<33% ferritin measures >2500 ng/mL
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
0.00
0.50
0.25
0.75
1.00
1.00
33%–67% ferritin
measures >2500 ng/mL
0.75
Ferritin >2500 ng/mL
on >1/3 of occasions
Proportion Without Cardiac Disease
Survival probability
0.50
0.25
>67% ferritin measures >2500 ng/mL
Maintenance of Lower Ferritin Levels a Positive Indicator for Survival
at UCLH (unpublished data) . 5 10 15 2 4
Years of Follow-Up 6 8 10 12 14 16
Chelation Therapy (years)
Reprinted from Olivieri NF, et al. N Engl J Med. 1994;331, with permission from the Massachusetts Medical Society. 1. Gabutti V, Piga A. Acta Haematol. 1996;95: Telfer PT, et al. Br J Haematol. 2000;110: Davis BA, et al. Blood. 2004;104: Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.

7. T2* MRI—Emerging New Standard for Cardiac Iron90 80 70 60 50
LVEF (%)
Cardiac T2* value of 37 in a normal heart 40 30 20 10 10 20 30 40 50 60 70 80 90
100
Heart T2* (ms)
Cardiac T2* value of 4 in a significantly iron overloaded
heart
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).
Reprinted from Anderson LJ, et al. Eur Heart J. 2001;22:2171, with permission from Elsevier. Anderson LJ, et al. Eur Heart J. 2001;22:2171.

8. 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?

9. 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

10. New Thalassaemia Guidelines
Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia, 2nd edition
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.

11. 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

12. 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

13. The Challenge of Iron Chelation A Question of Balance
Uncoordinated iron
Free-radical generation
Organ damage
Growth failure
Organ failure
Cardiac death
Uncoordinated chelator
Inhibition of metalloenzymes
Neurotoxicity
Growth failure
Bone marrow toxicity
Too much iron
Too much chelator
Graphic courtesy of Dr. J. Porter. 1

14. 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
LIC = liver iron concentration; UIE = urinary iron excretion.
* M. Domenica Cappellini, MD (oral communications, 2008)
1. Angelucci E, et al. Haematologica. 2008; In press.

15. 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
Deferiprone3
Treatment of iron overload in patients with thalassaemia major when desferrioxamine therapy is inadequate or contraindicated
TM = Thalassaemia major; TI = Thalassaemia intermedia
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.

16. Administration of Chelating Agents
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, Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia, 2nd ed; Exjade (deferasirox). Summary of Product Characteristics. EMEA, Ferriprox (deferiprone). Summary of Product Characteristics. EMEA, 2007.

17. Increasing Efficacy of Chelation Therapy Has Significantly Improved Patient Survival
Survival Probability
(P < )
1.00
0.75
0.50
0.25 5 10 15 20 25 30
Age (years)
Birth cohort
1960–1964
1965–1969
1970–1974
1975–1979
1980–1984
1985–1997
Reprinted from Borgna-Pignatti C, et al. Haematologica, 2004;89:1187, with permission from the Ferrata-Storti Foundation.

18. 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.

19. 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

20. 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.

21. 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