1. iron overload in haemoglobinopathies
Dr Farrukh Shah
Consultant haematologist
Joint Red cell disorders unit
Whittington hospital and UCLH

2. Why?

3. Iron turnover in transfusional overload
Erythron
20-30mg/day
20-30mg/day
(0,4 mg/kg/day)
NTBI
Hepatocytes
& other
parenchyma
Macrophages
Transferrin
Gut

4. Sources of iron overload in haemoglobinopathy patients
Dietary iron overload
Thalassaemia intermedia patients
Thalassaemia trait patients given oral iron to correct anaemia
Intermittent transfusion
Sickle cell anaemia
Thalassaemia intermedia
Regular transfusion therapy

5. - Transfusional Iron Overload
Normal total body iron (TBI) 3-5g
Transfusional iron overload without chelation
1 unit of Packed Red Blood Cells (PRBC)= 200 mg Fe
A patient receiving 2-4 units/month receives 4 to 10 grams of iron per year
SPEAKER NOTES
Frequent blood transfusions have been shown to prolong survival and improve quality of life in patients with underlying blood disorders (such as myelodysplastic syndromes, thalassaemia and sickle cell disease).3
References
2. Porter JP. Br J Haematol. 2001;115:
3. Kushner, JP, Porter JP, Olivieri NF. Secondary Iron Overload. Hematology Jan 1:
Porter JP. Br J Haematol. 2001;115:

6. Consequences of iron overload

7. Organ Systems Affected by Iron Overload
Pituitary gland
Heart
Liver
Pancreas
Gonadal
Iron overload results in non–transferrin-bound iron in the plasma
Increased iron uptake into selective organs
Generation of free hydroxyl radicals
Tissue damage

8. Fatal Complications of iron overload
Cardiac
Dysrhythmias
Heart failure
Infections
Liver
iron overload, cirrhosis
viral hepatitis
failure
Asymptomatic fall in EF recommends treatment is intensive 24hr iv dfo.
Infections: hep B, hep C, Yersinnia septicaemia and klebsilla due to central venous devices such as portocaths, or encapsulated bacteria such as pneumococcus in post splenectomy patients

9. non fatal complications of iron overload
Growth failure
Sexual development & fertility
Diabetes
Hypothyroidism
Hypoparathydroidism
Osteoporosis
Figure from uclh clinic couple of yrs ago, vary between clinincs and also patient cohorts/ changing

10. Complication-free survival of Italian β-thalassaemia major patients
1.00
Birth cohort
1960–1964
1965–1969
1970–1974
1975–1979
1980–1984
1985–1997
0.75
Survival probability
0.50
0.25
p < 5 10 15 20 25 30
Age (years)
HR = hazard ratio.
Borgna-Pignatti C, et al. Haematologica. 2004;89: 10

11. Monitoring iron overload

12. Why monitor For adequacy of treatment For complications of chelation
Transfusion
Chelation
For complications of chelation
I will talk mainly about the first two points as the complications of chelation will be discussed later

13. Monitoring iron overload
Tissue iron estimation
Ferritin
Liver iron
Cardiac iron
Effects of iron overload on function
Heart
Endocrine
Pituitary damage
Diabetes
Hypothyroidism
Hypoparathyroidism

14. Serum ferritin reflects
Iron stores
Recent chelation and type of chelation
Inflammation
Tissue damage
Ascorbate status
One of the reasons it is so unreliable is that it is affected by a number of factors that can either artificially low it or raise it.
For example recent chelation can push down the ferritin and one of my patients recently with a liver iron of 20mg/g/dw on ferriscan and a ferritin of 2000 did his chelation every day for a month and the ferritin came back as 980 ug/g/dw and he thought he has removed all the extra iron, But cleary this is an effect of the desferrioxamine artificially pushing down the ferritin.
We know that inflammation raises the ferritin as does tissue trauma, and we also know that in vitamin C deficient patients the ferritin is artificially lower and once the vitamin C is corrected the ferritin in fact rises. 14 22

15. Serum ferritin underestimates iron burden in β-thalassaemia intermedia5 10 15 20 25 30 35 40 45 50
LIC (mg/g dry wt)
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
9,000
10,000
β-Thalassaemia intermedia
β-Thalassaemia major 5 10 15 20 25 30 35
LIC (mg/g dry wt)
Serum ferritin (μg/L)
2,000
4,000
6,000
8,000
10,000
12,000
14,000
β-Thalassaemia intermedia
β-Thalassaemia major
Serum ferritin (μg/L)
Origa R, et al. Haematologica. 2007;92:583-8.
Taher A, et al. Haematologica. 2008;93:

16. Relationship between cardiac T2* and cardiac failure
0.1
0.2
0.3
0.4
0.5
0.6 30 60 90
120
150
180
210
240
270
300
330
360
Proportion of patients developing cardiac failure
Follow-up time (days)
< 6 ms
6–8 ms
8–10 ms
> 10 ms
Kirk P, et al. Circulation. 2009;120:

17. Chelator effect on ferritin
DFO
DFX
DFP
Median LIC
(mg/kg dw) 5
(1.2 -
30.6)
4.8
(0.8
36.5 )
(0.5
34.9)
Median SF (µ
g/L)
1927
(1378
5182)
1713
(312
6085)
1142 (
133
2897
Median SFaverage
2147
(950
6063)
2006
(773
7290)
1240
(230
2734)
Median
SF/LIC gL 1 /µ gg
523
(120
1562) 4 03 2
1188)
181
(56
910)
Predicted LIC
(95% confidence interval) at :
SF 1000 µg/L
SF 2000 µg/L
SF 4000 µg/L
1.9 (0
4.9)
4.4
(2.8
5.9)
9.3
(5.1
13.5)
2.8
(1.9
3.7)
(4.2
5.8)
9.5
(7.3
11.6)
5.1
(3.2
6.9)
9.4
(6.8
12.0) 18
(11.1
24.9)
Ang, Ai leen et al ASH 2010

18. Why is measurement of liver iron concentration (LIC) important?
A patient’s LIC value is the best measure of total body iron stores
A patient’s LIC value enables better informed decisions on when to
Initiate chelation therapy
Increase chelation dose
Decrease chelation dose
Change mode of chelator delivery (e.g. iv mode)

19. Liver iron concentration predicts total body iron stores
Sample < 1 mg dry wt (n = 23)
Sample > 1 mg dry wt (n = 25)
300
250
200
150
100 50 5 10 15 20 25
300
250
200
150
100 50
r = 0.83
r = 0.98
Body iron stores (mg/kg)
Body iron stores (mg/kg) 5 10 15 20 25
Hepatic iron concentration (mg/g dry wt)
Hepatic iron concentration (mg/g dry wt)
Body iron (mg/kg) = 10.6 x hepatic iron concentration (mg/g dry wt)
Angelucci E, et al. N Engl J Med. 2000;343:
1. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000;343:

20. Example: FerriScan® measurements to monitor iron chelation therapy
Before chelation therapy intervention
Mean LIC = 16.0
After 12 months of chelation therapy intervention
Mean LIC = 1.6

21. Cardiac monitoring in Iron Overload
Functional
LVEF
Echo, MUGA, MRI
Rhythmicity
Resting/Exercise ECG
24h ECG
Iron loading:
Low cardiac t2* associated with low LVEF

22. Discordance of liver and heart iron
Severe cardiac iron
Minimal liver iron.
Discordance of liver and heart iron
Severe liver iron
Minimal cardiac iron. 3

23. Causes of death in β-thalassaemia major in the UK10 20 30 40 50 60 70 80 90
100
Hepatitis C complications
Other/unknown
Malignancy
Infection
BMT complication
Anaemia
Iron overload
Patients (%)
1950–1959
1960–1969
1970–1979
1980–1989
1990–1999
2000–2003
This cohort
Mortality rates per cohort
BMT = bone marrow transplantation; CMR = cardiac magnetic resonance imaging
Adapted from UK Thalassaemia Registry data from Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42. Thomas AS, et al. Blood. 2010;116:[abstract 1011]. 23

24. Absence of cardiac siderosis despite elevated LIC and serum ferritin in Lebanese patients with SCD50 45 40 35 30 25 20 15 10 5
1,000
2,000
3,000
4,000
Serum ferritin (µg/L)
High serum ferritin
Normal T2*
Cardiac T2* (msec)
Normal T2*
p = NS
p = NS
Sample size: 23 patients (17 SS, 6 ST)
Inati A, et al. Eur J Haematol. 2009;83: 24

25. Management of iron overload

26. Chelators in clinical use
Desferrioxamine
20- 40mg/kg/day 8-10h 5-6 x/week
start at 3y or ferritin ≥ 1000µg/L
Deferiprone
(L1) 75 mg/kg/day in 3 divided doses
Exjade (ICL670)
20-30mg/kg/day once daily
FSB0701 in phase 2
Lisecnced in EU, but not in north america

28. Effect of DFO IV infusion on removal and return of NTBI ( Porter et al, Blood 1996 )-1 1 2 3 4 5 6 7
DFO (µM)
NTBI or DFO (µM)
NTBPI (µM) 54 48 42 36 30 24 18 12 6
- 6 -
Time (h)

29. Compliance with deferoxamine and its impact on survival
100
80–100%
60–80% 75
40–60%
300–365
225–300
150–225
75–150
0–75
Infusions/year
Cumulative % survival 50
20–40% 25
0–20% 10 20 30 40
Time (years)
Gabutti V, Piga A. Acta Hematol .1996;95:26-36.

30. Complications of Desferrioxamine
Immediate
Local skin reactions
Allergy
Infection: yersinia, other G-
Dose related:
Hearing problems
Eye complications
Growth retardation
Skeletal changes
rare

31. Deferiprone (Ferriprox®, L1)
Indication (Europe)
‘Treatment of iron overload in patients with thalassaemia major when DFO therapy is contraindicated or inadequate’1
Oral three times a day (short plasma half life)
Decreases serum ferritin when baseline levels high
Variable effects on liver iron
Use of deferiprone is limited to second-line therapy in patients with thalassaemia major when DFO therapy is contraindicated or inadequate. This is due to the occurrence of serious side effects such as neutropaenia and agranulocytosis
Ferriprox [package insert]. Apotex Europe Ltd, 2004
2. Pennell et al, Blood 2006 Vol 107;

32. Pharmacokinetics of deferiprone (Kontoghiorghes et al, 1990)
140
120
100 80 60 40 20
Deferiprone
Glucuronide
Concentration (µM)
t1/ hours
Time (minutes)

33. Side effects Neutropenia: 3.9% Agranulocytosis: 0.5-0.9%
Gastrointestinal: 3-33%
liver: 1-3%
Joint pains: 4-15%
Neurological complications in high doses
High drop out rate:
Ceci study 124/532
Cohen study 103/187

34. Cardioprotective effect
61patients DFO 43mg/kg/day for 5.7 days vrs DFP 92mg/kg/day
T2* and EF improved more in the DFP group
Pennell et al; Blood, 1 May 2006, Vol. 107, No. 9, pp

35. deferasirox Nick H, Current Medicinal Chemistry. 2003; 10: 1065-1076OH HO O
Tridentate iron chelator (high specificity)
High therapeutic safety in animal data
Lipophilic but protein bound
Renal target in animal toxicology
Long plasma half life in humans
Excreted in faeces only
Given as once daily drink
(dispersible tablet)

36. Safety profile over time in patients with β-thalassaemia major10 8 6 4 2 9 7 5 3 1
Year 1 (n = 296)
Year 2 (n = 282)
Year 3 (n = 234)
Year 4 (n = 213)
Year 5 (n = 196)
Patients (%)
Increased blood creatinine
Abdominal pain*
Nausea
Vomiting
Rash
Diarrhoea
Adverse event
* Reports of abdominal pain and abdominal pain are combined and presented as abdominal pain.
Cappellini MD, et al. Blood. 2011;118:

37. Cardiac iron reduction with deferasirox: continued improvement in cardiac T2*5 10 20 30 15 25
> 5–< 10 ms
10–< 20 ms
All patients
15.0
17.7‡
20.3‡
22.3‡
17.1‡
15.6‡
13.9‡
12.0
Geometric mean T2* ± 95% CI (ms)
10.5‡
7.7
8.6†
9.4‡
†p = versus baseline; ‡p < versus baseline
Dashed line indicates normal cardiac T2* of ≥ 20 ms
Baseline 12 24 36
Time (months)
Patients, n
< 10 ms 24
10–< 20 ms 47 44
All patients 71 68
CI = confidence interval; LOCF = last observation carried forward.
Pennell D, et al. Haematologica Jan 22. [Epub ahead of print].

38. Impact of monitoring on outcomes

39. A decade of cardiac monitoring at the UCLH/Whittington Hospital
Cohort of 132 patients received first CMR 1999–2000
109 of these available for long-term CMR follow- up
follow-up median 9.2 years (range 7.0–10.6)
minimum CMR follow-up of 7 years
median age at first CMR 27.9 years (range 7.7–49.5)
58 females, 51 males
UCLH = University College London Hospital.
Thomas AS, et al. Blood. 2010;116:[abstract 1011]. 39

40. The proportion of patients with cardiac iron overload decreased 3-fold in a decade
Cohort of 132 patients from UCLH/Whittington hospital
Baseline
Median 9 years follow-up
Proportion of patients (%) 70 50 30 10 60 40 20
T2* ≤ 20 ms
T2* < 10 ms 23 17 7
p < 0.001
Thomas AS, et al. Blood. 2010;116:[abstract 1011]. 40

41. Causes of death in β-thalassaemia major in the UK10 20 30 40 50 60 70 80 90
100
Hepatitis C complications
Other/unknown
Malignancy
Infection
BMT complication
Anaemia
Iron overload
Patients (%)
1950–1959
1960–1969
1970–1979
1980–1989
1990–1999
2000–2003
This cohort
Mortality rates per cohort
BMT = bone marrow transplantation; CMR = cardiac magnetic resonance imaging
Adapted from UK Thalassaemia Registry data from Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42. Thomas AS, et al. Blood. 2010;116:[abstract 1011]. 41

42. Ferriscan liver iron monitoring Whittington audit
Ferriscan part of routine monitoring from December 2007
94 TM patients with at least 2 scans between January 2008-December 2011

43. Long term

45. Patient 1 30 year old TM Arrives in UK as a highly skilled migrant
Heavy iron overload in arrival in 2008
Marked skin deposition
Ferriscan liver iron >43mg/g/dw
No myocardial iron loading
Spontaneous puberty
Initial treatment is deferiprone, agrees to start deferasirox

46. Patient 1
Spontaneous conception on exjade! Around 9 months post arrival in UK!
Immediately stops deferasirox
Healthy baby delivered in 2009
restarts deferasirox at 40mg/kg/day
Almost fully compliant initially

48. In 2011 compliance becomes a challenge
Ferriscan bought forwards