Iron Chelation Basics John B. Porter, MA, MD, FRCP Professor Department of Haematology University College London London, United Kingdom

Goals of Chelation Treatment Iron balance with “safe” tissue iron levels 0.4–0.5 mg/kg day excretion1 Slow process2 Finite chelatable iron pools2 Prevention of heart and endocrine damage Detoxification of iron Extracellular (NTBI) Intracellular (LIP) Iron-chelate complex NTBI = non–trasnsferrin-bound iron; LIP = labile iron pools. 1. Porter J. Hematol/Oncol Clinics. 2005;19:7. 2. Porter JB. Am J Hematol. 2007;82:1136.

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 1

Properties of an Ideal Chelator To control body iron High chelating efficiency High and specific affinity for Fe3+ To minimize iron toxicity 24-hour coverage Slow metabolism and elimination rate Good tissue penetration with stable iron complex Acceptable toxicity-efficacy profile Clear drug-dose relationship to efficacy and toxicity No iron redistribution Simplicity and ease of monitoring Patient acceptance/compliance Oral bioavailability Suitable for monotherapy

How Chelators Bind Iron Deferasirox (DFS) Desferrioxamine (DFO) Deferiprone (DFP) Hexadentate Bidentate Tridentate O O O Fe O O Fe Fe O Adapted from Porter JB, et al. Baillieres Clin Haematol. 1989;2:257.

Chelatable Iron Pools For iron balance For iron detoxification Plasma iron turnover pools Intrahepatic pools For iron detoxification Plasma iron toxic pools (NTBI) Intraparenchymal iron toxic pools eg, heart, liver, endocrine, joints NTBI = non–transferrin-bound iron.

Chelatable Pools and Excretion Pathways with DFO Plasma Bile Storage Fe Macrophage Fe Labile Fe Fe Fe Fe Fe Fe Fe Fe Fe Hepatocyte Fe Fe Fe Fe Fe Kidney Faeces Fe Urine DFO = desferrioxamine. With permission from Cohen AR, Porter JB. In: Steinberg MH, et al, editors. Disorders of hemoglobin: genetics, pathophysiology, and clinical management. Cambridge: Cambridge University Press; 2001.

Decreasing Cellular Toxicity with Chelators Ferritin Non- transferrin iron Lysosomal degradation LVDCC Labile iron pool Transferrin iron Iron proteins Free-radical generation Organelle damage LVDCC = L-type voltage-dependent calcium channel. With permission from Porter JB. Am J Hematol. 2007;82:1136.

Chelatable Iron Pools Prevention of Accumulation More Efficient than Removal of Stored Iron Uncontrolled iron loading of organs, such as: Transferrin saturation occurs due to frequent blood transfusions Subsequent formation of NTBI in plasma Normal: No NTBI produced Iron overload 100% Fe Fe Fe Fe Fe Fe 30% Fe Chelation of storage iron is slow and inefficient Chelators may prevent iron uptake into these tissues Courtesy of Dr. J. Porter.

Chelation Therapy Removes Liver Iron Faster than Heart Iron* Myocardial T2* (ms) Liver T2* (ms) Liver Iron (mg/g dw) LVEF (%) Normal range >20 >19 <1.6 61–81 Baseline 5.1 ± 1.9 1.8 ± 1.0 9.6 ± 4.3 52 ± 7.1 3 months 6.9 ± 2.1 3.4 ± 1.8 6.0 ± 5.6 61 ± 8.1 6 months 7.5 ± 2.5 6.9 ± 5.3 2.9 ± 1.9 62 ± 7.9 12 months 8.1 ± 2.8 10.3 ± 9.2 2.1 ± 1.5 63 ± 6.4 P-value .003 .01 .001 .03 * Desferrioxamine Data dw = dry weight; LVEF = left ventricular ejection fraction. With permission from Anderson LJ, et al. Br J Haematol. 2004;127:348. Anderson LJ, Westwood MA, Holden S, et al. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. Br J Heamatol. 2004;127:348-355.

Desferrioxamine Therapy for Iron Overload Available for > 3 decades with improving survival Hexadentate molecule not absorbed from gut Short half-life (20 min), so must be given by continuous infusion 8 –12 h/d, 5 – 7 d/w (40–50 mg/kg SC) Commenced after 15–20 transfusions or when ferritin >1000 µg/L Audiometric, retinopathic, and growth effects at high doses and low iron loading Compliance often is poor, leading to variable outcome Porter JB, Huehns CR. Baillieres Clin Haematol. 1989;2:459. Courtesy of Dr. J. Porter

DFO–Control of Plasma NTBI Levels DFO (µM) NTBI (µM) Intravenous continuous infusion -1 1 2 3 4 5 6 7 NTBI or DFO (µM) -6 6 12 18 24 30 36 42 48 54 Time (hours) DFO = desferrioxamine, NTBI = non–transferrin-bound iron. Reprinted from Porter JB, et al. Blood. 1996;88:705, with permission from the American Society of Hematology.

Efficacy of DFO - early history Sephton Smith 1962 IM bolus— Urine Fe excretion inc. with dose, no oral effect 1964 Fe excretion inc. with Tf sat, age, transfusions Barry 1974 Daily IM bolus reduces mortality, stabilises hepatic iron & fibrosis Propper, Hussain 1976 Iron balance with 24-h SC infusions using portable devices Pippard 1978 Iron balance achievable with 12-h SC infusions Pippard 1982 Faecal excretion important (≥50%) Freeman 1983 SC therapy improves asymptomatic cardiac disease Marcus 1984 Intensive IV therapy reverses symptomatic cardiac failure Wolfe 1985 Long-term SC therapy reduces incidence of cardiac disease Zurlo 1989 Survival improved in TM cohorts if SC therapy started early Bronspiegel- Weintrob 1990 SC therapy started before age 10 y reduces hypogonadism Olivieri 1994 Long-term control of ferritin reduces heart disease Brittenham 1994 Compliance long-term protects against diabetes mellitus, cardiac disease and mortality Davis BA, Porter JB. Adv Exp Med Biol. 2002;509: 91.

DFO–Improved Survival in TM 1.00 0.75 Birth cohort 1985–1997 Survival Probability 1980–1984 0.50 1975–1979 1970–1974 1965–1969 1960–1964 0.25 P < .00005 5 10 15 20 25 30 Age (years) DFO = desferrioxamine; TM = thalassaemia major. Reprinted from Borgna-Pignatti C, et al. Haematologica. 2004;891:187, with permission from the Ferrata Storti Foundation, Pavia, Italy.

DFO–Decline in Complications Patients with thalassaemia major born after 1960 (n = 977) Birth 1970-1974* Birth 1980-1984† Death at age 20 years 5% 1% Hypogonadism 64.5% 14.3% Diabetes 15.5% 0.8% Hypothyroidism 16.7% 4.9% *DFO IM, 1975; †DFO SC, 1980. In 1995, 121 patients switched to deferiprone (censored at this time). DFO = desferrioxamine. With permission from Porter JB. Am J Hematol. 2007;82:1136.

Iron Balance Over 1 Year with DFO SC x 5/Week . Initial DFO dose (mg/kg/d) <25 25 to <35 35 to <50 ≥50 100% Increase 0% Decrease 100% <0.3 0.3–0.5 >0.5 Iron Intake (mg/kg/d) With permission from Cohen AR, et al. Blood. 2008;111:583.

Unwanted Effects of Desferrioxamine Retinopathy Ototoxicity CNS, coma Growth retardation Bony changes Yersinia infection Sensitivity Misc (pulmonary fibrosis) Contributing factor Dose Dose, ferritin, therapeutic index Iron status, other drugs Dose, age <3 y, ferritin <1000 ug≠L Age, dose, ferritin Natural siderophore Intermittent use Very high dose (short term) Desferal [package insert]. East Hanover, NJ: Novartis Pharmaceuticals, 2006. Porter JB, Huehns ER. Bailliere’s Clin Haematol.1989;2:459.

How to Minimize Desferrioxamine’s Unwanted Effects? Avoid >40 mg/kg mean daily dose when growing1 Avoid >50 mg/kg mean daily dose in routine use Avoid starting too early Dose adjustment as ferritin falls Adjust mean daily dose downwards Try NOT to reduce frequency of treatment Keep therapeutic index <.025 (dose mg/kg / ferritin µg/L) Monitor regularly for toxic effects 1. Desferal [Package insert]. East Hanover, NJ: Novartis Pharmaceuticals, 2006.

Desferrioxamine Summary of Advantages and Disadvantages Recognized first-line treatment in iron overload Long-term experience and data—reduced morbidity and mortality Effective in maintaining near-normal iron stores Specific affinity for iron with high chelating efficiency Achieves negative iron balance Reversal of cardiac disease with intensive therapy Disadvantages Requires maximum exposure for optimal outcome Not absorbed from GI tract Rapidly eliminated—30-minute half-life requires prolonged infusions Requires parenteral infusion Challenges—compliance Dose-dependent adverse events limit achievable goals Ear, eye, bone toxicity

Deferiprone History Pharmacology Efficacy Side effects Patented 1982; licensed in EU 1999 Pharmacology Bidentate, short plasma half-life — given TID Rapidly glucuronidated, low efficiency (7%) Urine excretion Efficacy Indicated for treatment of iron overload in patients with thalassaemia major when desferrioxamine therapy is contraindicated or inadequate1 May be less effective than desferrioxamine in reducing LIC Possible cardioprotective effect 2 Side effects Neutropaenia/agranulocytosis (weekly neutrophil count recommended1) Nausea, vomiting, abdominal pain Arthralgia and arthritis (variable 6%–39%) CH 3 OH N O EU = European Union; LIC = liver iron concentration. 1. Ferriprox® [Summary of Product Characteristics]. Apotex Europe Ltd. 1999. 2. Anderson LJ, et al. Lancet. 2002;360:516. 20

Percentage Deferiprone Patients with Liver Iron >7 or >15 mg/g DW After 1-4 Years of Treatment FU LIC LIC Publication n Years % >7 % >15 Olivieri, 19951 21 3 52 10 Olivieri, 19982 19 4.6 65 39 Tondury, 19983 7 8 53 18 Del Vecchio, 20004 13 1 64 11 Mazza,19985 20 1–3 85 65 Hoffbrand,19986 51(17) 2–4 88 53 DW = dry weight; FU = follow-up; LIC = liver iron concentration. 1. Olivieri N, et al. N Engl J Med. 1995;332:918. 2. Olivieri N, et al. N Engl J Med. 1998;339:417. 3. Töndury P, et al. Br J Haematology. 1998;101:413. 4. Del Vecchio GC, et al. Acta Haematologica. 2000;104:99. 5. Mazza P, et al. Haematologica. 1998;83:496. 6. Hoffbrand AV, et al. Blood. 1998;91:295.

Cardioprotective Effect of Deferiprone Monotherapy? Data n Author DFP more effective than DFO in preventing cardiac disease (retrospective) 54 Piga, 2003 1 DFP more effective than DFO in reducing cardiac T2* (retrospective control) 15 Anderson, 2002 2 Similar decrease in cardiac MRI by both drugs 71 Maggio, 2002 3 4 died of cardiac causes 51 Hoffbrand, 1998 4 9 died of heart failure 532 Ceci, 2002 5 Piga A, et al. Haematologica. 2003;88:489. Anderson LJ, et al. Lancet. 2002;360:516. Maggio A, et al. Blood Cell Mol Dis. 2002;28:196. Hoffbrand AV, et al. Blood. 1998;91:295. Ceci A, et al. Br J Haematol. 2002;118:330.

Prospective Comparison of DFO vs DFP Effect on Myocardial T2* DFP 92 mg/kg orally DFO 43 mg/kg x 5.7 SC 18 17 DFP (delta 3.5 ms; n = 29) 16 Myocardial T2* (geometric mean ± SEM) DFO (delta 1.7 ms; n = 32) 15 14 13 12 Baseline 6 Months 12 Months DFO = desferrioxamine; DFP = deferiprone; SEM = standard error of the mean. Reprinted from Pennell DJ, et al. Blood. 2006;107:3738, with permission from the American Society of Hematology

How to Minimize Deferiprone’s Unwanted Effects Frequent monitoring of white count (1–2 weeks) Avoid exposure if stem cell disorder or neutropaenia Monitor liver function, liver iron, and histology Monitor serum zinc Avoid exceeding recommended dose? Is agranulocytosis dose related? Avoid exposure at young age? Role of dose adjustment? Use of other chelators concomitantly?

Deferiprone Summary of Advantages and Disadvantages Orally active Enhanced removal of cardiac iron Increased effectiveness when combined with desferrioxamine Disadvantages Short plasma half-life and rapid inactivation by metabolism Administered 3 times daily—may negatively impact patient compliance and outcome May not achieve negative iron balance at 75 mg/kg/day Risk of agranulocytosis and need for weekly blood counts Limited data Data in thalassaemia patients but limited use for other indications Relationship of dose to tolerability and efficacy Effects of combined therapy on tolerability Second-line therapy in thalassaemia major

Potential Value of 24-Hour Chelation Minimizes exposure to labile iron In tissues In plasma Continuous capture of iron released from Red cell catabolism in macrophages Ferritin catabolism (mainly in liver) Minimizes new cellular uptake of NTBI

Effects of Monotherapy and Combined Therapy on LPI DFO 40 mg/kg/d given at night Effectively removes LPI at night No protection during the day DFP 75 mg/kg/d given during the day Intermittent decrease in LPI during the day Rebound effect at night DFO 40mg/kg/d given at night + DFP 75 mg/kg/d given during the day Provides 24 hour protection against LPI Cabantchik ZI, et al. Best Pract Res Clin Hematol. 2005;18:277.

Combinations of DFO and DFP Center Year N Design Months DFP dose (mg/kg/d) Days DFO Ferritin (μg/L) LIC (Total Excretion) London1 1998 5 Obs 6–15 88–110 2–6 1/5 ≥ 2500 final Not done Turkey2 1999 7 Obs 6 75 (4/7) 2 30% decrease 4/7 ≥ 2500 final LIC 19% decrease 6/7 ≥ 15 mg/g Malaysia3 2000 9 Obs 12 75–85 2 7/9 ≥ 2500 No significant fall 7/9 ≥ 15 mg/g Lebanon4 2003 14 11 Rand 12 - 75 5 2 Fall in both 6/11 ≥ 2500 final Not done India5 2004 30 Rand 12 - 75 5 2 - Max decrease NS from DFO Less decrease Not done Obs = observational; Rand = randomised. 1. Wonke B, et al. Br J Haematol. 1998;103:361. 2. Aydinok Y, et al. Acta Haematol. 1999;102:17. 3. Balveer K, et al. Med J Malaysia. 2000;55:493. 4. Mourad FH, et al. Br J Haematol. 2003;121:187. 5. Gomber S, et al. Indian Pediatrics. 2004;41:21.

Combinations of DFO and DFP Center Year N Design Months Regimen DFP Dose (mg/kg) DFO Dose mg/kg Duration Ferritin LIC Other Sardinia1 2005 79 Obs ± Simul 31 mean 25 TID x 7 40 (x2-6)/7d, 8-24 h Ferritin fall from high* LIC not done 4% agranulocytosis 8% neutropaenia Improved LVEF Echo* Greece2 2006 50 Obs Simul 12 25 mg TID x 4/7 25mg BID x 3/7 30-55, 3/7 d 8 h Ferritin fall* 4 agranuloytosis/100 pt y T2 heart improved LV shortening fraction incr 3 Centres3 2006 30 Rand Seq - 25mg TID x 7 33 x 5/7 d, 8 h 33 x 2/7 d, 8 h Ferritin ± decr same LIC ± decr same 7% AEs 24% AEs 2 neutropaenia Greece4 2006 42 Obs 3-4 y 25-30mg TID 20-40 x 2-6 d 8-12 h Liver MRI improve* AEs not reported Improved GTT* Improved insulin secr* *Significant Obs = observational; Simul = simultaneous; Seq = sequential. 1. Origar, et al. Haematologica. 2005;90:1309. 2. Kattamis A, et al. Blood Cells Mol Dis. 2006;36:21. 3. Galanello R, et al. Haematologica. 2006;91:1241. 4. Farmaki K, et al. Br J Haematol. 2006;134:438.

Prospective Randomized Comparison of DFO Monotherapy vs Combination Therapy with DFP Design 65 adult patients with TM Mild to moderate T2* shortening (8–20 ms) Normal heart function (LVEF >56%) Pretreatment with SC DFO 30–40 mg/kg/night x5 Randomised to SC DFO monotherapy 43 mg/kg x5/week Placebo or deferiprone 75 mg/kg/day Outcome Improvement better in combined arm for T2* (see graph) Ferritin (-233 vs -976 µg/L) LV function (0.6% vs 2.6%) 8 Combined Desferrioxamine 7 Between groups: P = .02 6 5 Change in Heart T2* (ms) 4 3 2 1 6 12 Months DFO = desferrioxamine; DFP = deferiprone; TM = thalassaemia major; LVEF = left ventricular ejection fraction. With permission from Tanner M, et al. Circulation. 2007;115:1876.

Deferasirox (ICL670) OH O N N N OH HO Tridentate iron chelator (high specificity)1 High therapeutic safety in animal data Lipophilic but protein bound1 Renal target in animal toxicology Long plasma half-life in humans1 Primarily excreted in faeces1 Given as once-daily drink1 Prospective 1-y phase II/III studies in wide range of anaemias, including (TM2,4,5, SCD3, MDS4, DBA4) Randomised 1-y comparison with DFO in adult TM2 (n = 586), children with TM2,3, and adults and children with SCD3 (n = 195) Licensed in US, EU for treatment of iron overload, including children OH O N N N OH HO 1. EXJADE [Package Insert]. East Hanover, NJ:Novartis Pharmaceuticals 2007 2. Cappellini MD, Blood. 2006;107:3455. 3. Vichinsky E, Br J Haematol. 2007;136:501. 4. Porter J. Eur J Haematol. 2008; 80: 168. 5. Piga A. Haematologica. 2006; 91:873.

24-Hour Chelation Coverage After Repeated Daily Dosing Steady-state levels with daily deferasirox 100 80 Plasma Concentration Iron-Free Deferasirox (µmol/L) 60 40 20 Degree of constant chelation coverage with 20 mg/kg dose 4 8 12 16 20 24 Time Postdose with Deferasirox 20 mg/kg/day (hours) Mean values of measurements taken on weeks 2, 4, 8, and 12 are presented Deferasirox Day Dose (mg/kg/day) (n. of subjects) Cmax (µmol/L) mean ± SD AUC0-24h (hµmol/L) mean ± SD Half-life (h) 1 20 (n=5) 68 ± 23 664 ± 265 7.2 ± 1.8 15 107 ± 22 1279 ± 208 8.6 ± 2.9 180 20 (n=4) 99 ± 32 1262 ± 358 9.8 ± 1.4 360 20 (n=8) 95 ± 34 1001 ± 627 9.3 ± 2.3 With permission from Piga A, et al. Haematologica. 2006;91:873.

LPI After Single and Multiple Deferasirox Dosing in β-thalassaemia 2.0 Predose (n = 13) 2 hours postdose (n = 13) 1.8 20 mg/kg/day 1.6 1.4 1.2 Mean LPI (µmol/L) 1.0 0.8 0.6 0.4 P < .0001* P = .0119* P = .1948* 0.2 P = .0187 Washout P = .0007 Baseline Week 4 Week 16 Once-daily administration of deferasirox provides 24-hour chelation coverage and cumulative reduction in peak LPI with multiple dosing *Vs predose Adapted from Daar S, et al. Haematologica. 2006;91:13, with permission from the Ferrata Storti Foundation, Pavia, Italy.

Efficiency of Chelation Therapy Definition Proportion of administered drug that is eliminated in iron-bound forms How calculated Formal iron balance studies Iron excretion or change in body iron (LIC) relative to dose and transfusion rate Desferrioxamine: 13% (10%–17%) efficient when given at 25–50 mg/kg over 8–10 hours, 5 times per week1 Deferiprone: 4% of administered dose eliminated in urine bound to iron at 25 mg/kg/day, 3 times daily2 Deferasirox: 27% of drug eliminated in iron-bound form when given at 10–30 mg/kg/day, once daily1 1. Porter J, et al. Blood. 2005;106:abstr 2690. 2. Hoffbrand V, et al. Blood. 2003;102:17.

Change in LIC (mg Fe/g dw) Change in Ferritin (µg/mL) Deferasirox Dosing Effects Dose-dependent change in ferritin predicts change in LIC, with zero change at dose of 10 mg/kg/day Deferasirox, mg/kg/day 5 10 20 30 20 15 10 n = 325; R = 0.63 5 Change in LIC (mg Fe/g dw) -5 -10 -15 -20 -25 -30 -7500 -6250 -5000 -3750 -2500 -1250 1250 2500 3750 5000 Change in Ferritin (µg/mL) Novartis data on file.

Iron Excretion and Dose Comparison over 1 Year with DFO Thalassaemia major, n=541 . 8 D F O . 7 . 6 Mean Total Body Iron Excretion ± SD (mg Fe/kg/d) . 5 A v e r a g e t r a n s f u s i o n a l i r o n . 4 i n t a k e i n t h a l a s s e m i a . 3 A v e r a g e t r a n s f u s i o n a l i r o n i n t a k e i n M D S 1 2 A v e r a g e t r a n s f u s i o n a l i r o n . 2 i n t a k e i n S C D 1 1 . 1 A c t u a l d o s e s , m g / k g / d 5 1 1 5 2 2 5 3 D e f e r a s i r o x , F o 5 d w D O n / k 3 4 1 2 6 With permission from Cohen AR, et al. Blood. 2008;111;583.

Iron Intake, Dose, and Outcome with Deferasirox Proportion of patients with increase or decrease of LIC Deferasirox dose (mg/kg/d) 5 10 20 30 100% 3 14 16 28 <0.3 (<2 units/mo) 1 10 19 17 >0.5 (>4 units/mo) Increase n = 11 44 42 63 0% Decrease 0.3–0.5 (2–4 units/mo) 100% Iron Intake (mg/kg/d) Reprinted from Cohen AR, et al. Blood. 2008;111;583, with permission from the American Society of Hematology.

Change in Cardiac T2* in Studies 0107 and 0108 in UCLH Patients at Doses 10, 20, 30 mg/kg/day (n = 22) 60 P = .0026 50 16 thalassaemias 6 other anaemias 40 Cardiac T2* ms 30 26.4 ±2.8 (gm = 23.1) 20 20.0 ±2.0 gm = 18.0 10 Pre Post 1 y 1 9 thalassaemia major patients randomized to DFO arm; T2* pre = 18.1, post = 21.1 (not shown) With permission from Porter JB, et al. Blood. 2005;106: abstr 3600.

Tolerability and Unwanted Effects of Deferasirox in Adults and Children During Prospective Studies Generally well tolerated over a range of transfusion-dependent anaemias1,2,3,4 Most common treatment-related adverse events were mild to moderate, transient gastrointestinal disturbances and skin rash1,2,3 No drug-induced agranulocytosis, neutropaenia, or arthralgia Mild, nonprogressive, dose-dependent elevations in serum creatinine (>33% above baseline in 36% of patients, in 10% managed by dose adjustment)1,2,3 No increase of incidence or progression in extension studies 2 cases of suspected drug-related hepatitis1 Cataract/lens opacities: 2 patients discontinued — 2 with DFO also1 30 mg/kg/day generally well tolerated in children as young as 2 years4 Sexual and physical development proceeded within normal parameters4 1. Cappellini MD, Blood. 2006;107:3455. (Study 107, randomised vs DFO in TM, n= 586). 2. Vichinsky E, Br J Haematol. 2007;136:501. (Study, 108…randomised vs DFO in sickle, n= 195) 3. Porter J. Eur J Haematol, 2008;80:168. (Study 109… n TM n= 85, MDS n=47, DBA n=30, other=22) 4. Piga A. Haematologica, 2006;91:873. (Study 106…randomised vs DFO in TM paediatric, n=71)

Deferasirox Summary of Advantages and Disadvantages Orally active with long plasma half-life Generally well tolerated over a range of transfusion-dependent anaemias Once-daily administration Ease of administration, 24-h chelation, increased chelation efficiency Clear dose response effect on iron balance Demonstrated equivalency to desferrioxamine at higher doses Prospective studies in MDS, thalassaemia, SCD, other anaemias Ferritin trend follows trend in LIC and hence iron balance Licensed as first-line treatment in iron overload Disadvantages Long-term data less than 5 years follow-up Need to monitor renal function Limited data on cardiac effects Not all patients achieve negative iron balance at highest recommended dose

Conclusions Most of body iron is not directly available for chelation Chelatable iron pools result from continuous turnover of Catabolised red cells (in macrophages) Catabolised storage iron (ferritin and haemosiderin, mainly in hepatocytes) Toxic (labile) iron pools are small, transient, and constantly turned over Iron chelation protects by Decreasing absolute levels of storage iron (slow) Detoxifying labile iron in cells or plasma (fast) Preventing continuous distribution of iron to key tissues via plasma NTBI Chelation must detoxify iron without producing chelator toxicity 4 decades of clinical experience show chelation is an effective modality Extensive clinical experience with 3 chelators now available