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

Why?

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

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

- 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;115:239-252. 3. Kushner, JP, Porter JP, Olivieri NF. Secondary Iron Overload. Hematology. 2001 Jan 1: 47-61. Porter JP. Br J Haematol. 2001;115:239-252.

Consequences of iron overload

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

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

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

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 < 0.00005 5 10 15 20 25 30 Age (years) HR = hazard ratio. Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-93. 10

Monitoring iron overload

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

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

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

Serum ferritin underestimates iron burden in β-thalassaemia intermedia 5 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;93:1584-5.

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;120:1961-8.

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

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)

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;343:327-31. 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;343:327-331.

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

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

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

Causes of death in β-thalassaemia major in the UK 10 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

Absence of cardiac siderosis despite elevated LIC and serum ferritin in Lebanese patients with SCD 50 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;83:565-71. 24

Management of iron overload

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

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)

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.

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

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; 3738-3744

Pharmacokinetics of deferiprone (Kontoghiorghes et al, 1990) 140 120 100 80 60 40 20 Deferiprone Glucuronide Concentration (µM) t1/2 1.52 hours 0 100 200 300 400 Time (minutes)

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

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. 3738-3744.

deferasirox Nick H, Current Medicinal Chemistry. 2003; 10: 1065-1076 OH 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)

Safety profile over time in patients with β-thalassaemia major 10 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;118:884-93.

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 = 0.0012 versus baseline; ‡p < 0.001 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. 2012 Jan 22. [Epub ahead of print].

Impact of monitoring on outcomes

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

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

Causes of death in β-thalassaemia major in the UK 10 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

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

Long term

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

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

In 2011 compliance becomes a challenge Ferriscan bought forwards