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2. 2 Desferrioxamine for Treatment and Monitoring: Iron overload in Thalassaemia BY: Dr. Mahdi Shahriari

3. 3 50 30 0 40 10 20 Increased risk of complications Normal 020501030 40 Age (years) Thalassaemia major: transfusion without chelation Hereditary haemochromatosis (homozygous) Hereditary haemochromatosis (heterozygous) Optimal level in chelated patients Hepatic Iron (mg/g of Liver, Dry Weight) Threshold for cardiac disease and early death Olivieri N, et al. Blood. 1997;89:739. Hepatic Iron (µmol/g Wet Weight) 50 100 150 200 250 0 Iron Loading Rates in Thalassaemia Major and Hereditary Haemochromatosis

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5. 5 1 blood unit contains 200 mg iron 1 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 gut 1 –up to 1.5 g iron/year Overload can occur after 10–20 transfusions 1 Transfusion Therapy Results in Iron Overload Transfusional iron intake = volume of packed RBCs (mL) x 1.08 2 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.

6. 6 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 major 1 Liver pathology –Abnormal alanine aminotransferase (ALT) level if LIC >7 mg/g dry weight 2 –Liver fibrosis progression if LIC >16 mg/g dry weight 3 Cardiac pathology at high levels –LIC >15 mg/g dry weight associated with cardiac death  All of 9/53 thalassaemia major patients who died 4  Improvement of subclinical cardiac dysfunction with venesection post–bone-marrow transplant 5

7. 7 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 survival 1 (see graph) Maintenance of serum ferritin <2500 ng/mL –Significantly correlates with cardiac disease-free survival 2– 5 Survival probability 051015 0 0.25 0.50 0.75 1.00 Ferritin >2500 ng/mL on >1/3 of occasions Years of Follow-Up. Maintenance of Lower Ferritin Levels a Positive Indicator for Survival at UCLH (unpublished data) Chelation Therapy (years) 0.00 0.50 0.25 0.75 1.00 0246810141216 Proportion Without Cardiac Disease 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.

8. 8 Measuring and Interpreting Serum Ferritin 1-3 AdvantagesDisadvantages Easy to evaluate Inexpensive Serial measures to monitor chelation therapy Positively correlates with morbidity and mortality Allows longitudinal follow-up of patients Indirectly measures iron burden Fluctuates in response to inflammation, abnormal liver function, ascorbate deficiencies Individual measures may not accurately reflect iron levels and response to chelation therapy Serial measurement of serum ferritin is a simple, reliable, indirect measure of total body iron 1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008. 3. Brittenham GM, et al. Blood. 2003;101:15-19.

9. 9 Serum Ferritin Underestimates Iron Burden in Thalassaemia Intermedia Patients 1000 2000 3000 4000 5000 6000 7000 8000 9000 10,000 05101520253035404550 Liver Iron Concentration (LIC) (mg Fe/g dry weight) Serum Ferritin Level (ng/mL) Thalassaemia intermedia (TI) Thalassaemia major (TM) Linear (TI) Linear (TM) With permission from Taher A, et al. Haematologica. 2008;93:1584-1586. 0 Serum ferritin correlates with LIC in patients with TM and TI. However, for the same LIC, patients with TI had lower ferritin levels than corresponding patients with TM.

10. 10 Measuring LIC by Liver Biopsy 1,2 AdvantagesDisadvantages Directly measures LIC (quantitative, specific, sensitive) Validated reference standard Measures nonheme storage iron Evaluates liver histology/pathology Positively correlates with morbidity and mortality Invasive, painful, and potentially serious complications (eg, bleeding) Sampling error risk, especially in patients with cirrhosis Inadequate standardization between laboratories Difficult to follow up 1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.

11. 11 Correlation Between R2 MRI and Liver Biopsy With permission from St. Pierre TG, et al. Blood. 2005;105:855-861. 30 20 40 50 0.51.01.52.0 Biopsy Iron Concentration (mg/g -1 dry weight) 0 100 200 50 150 250 300 010203040 50 R2 MRI is a validated and standardized technique approved by the Australia Therapeutic Goods Administration, FDA, and European Medicines Agency Hereditary haemochromatosis Hepatitis β-thalassaemia β-thalassaemia/ haemoglobin E Mean Transverse Relaxation Rate (s -1 )

12. 12 Measuring LIC with MRI 1,2 AdvantagesDisadvantages Estimates iron content throughout the liver Increasingly available worldwide Status of liver and heart can be assessed in parallel Validated relationship with LIC Allows longitudinal patient follow- up Indirectly measures LIC Requires MRI imager with dedicated imaging method Children younger than age 7 years require a general anaesthetic 1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.

13. 13 T2* MRI—Emerging New Standard for Cardiac Iron Assessment in TM Patients Left Ventricular Ejection Fraction (LVEF) (%) 0 50 70 40 30 20 10 60 80 90 0204060908010010305070 Heart T2* (ms) Cardiac T2* value of 37 in a normal heart Cardiac T2* value of 4 in a significantly iron overloaded heart With permission from Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179. Photos courtesy of Maria D. Cappellini, MD. Myocardial T2* values <20 ms are associated with progressive and significant decline in LVEF

14. 14 Measuring Cardiac Iron with MRI 1,2 AdvantagesDisadvantages Rapidly assesses iron content in the septum of heart Relative iron burden can be estimated reproducibly Functional parameters can be examined concurrently Iron status of liver and heart can be assessed in parallel Allows longitudinal follow-up Indirectly measures cardiac iron Requires MRI imager with dedicated imaging method MRI is a nonvalidated method to rapidly and effectively assess cardiac iron 1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.

15. 15 Measuring Cardiac Iron with MRI 1,2 AdvantagesDisadvantages Rapidly assesses iron content in the septum of heart Relative iron burden can be estimated reproducibly Functional parameters can be examined concurrently Iron status of liver and heart can be assessed in parallel Allows longitudinal follow-up Indirectly measures cardiac iron Requires MRI imager with dedicated imaging method MRI is a nonvalidated method to rapidly and effectively assess cardiac iron 1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.

16. 16 Thresholds for Parameters Used to Evaluate Iron Overload Parameter Normal Range Iron Overload State MildModerateSevere LIC (mg Fe/g dw) 1 <1.23–7>7>15 Serum ferritin (ng/mL) 2,3 <300, male <200, female >1000 to <2500>2500 Cardiac T2* (ms) 4 >2014–208–14<8 1. Wood JC, et al. Blood. 2005;106:1460-1465. 2. Taher A, et al. Semin Hematol. 2007;44 (suppl 3):S2-S6. 3. Brissot P, et al. Blood Rev. 2008;22:195-210. 4. Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179.

17. 17 Iron Overload in Thalassaemia Thalassaemia major –Iron overload primarily a function of chronic transfusion 1 –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 absorption 1  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.

18. 18 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

19. 19 The Challenge of Iron Chelation A Question of Balance Too much ironToo 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.

20. 20 AgentIndicationTMTI Desferrioxamine 1 Treatment of acute iron poisoning and chronic iron overload due to transfusional anaemias  Deferasirox 2 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  Deferiprone 3 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

21. 21 AgentAdministration Desferrioxamine 1,2 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 Deferasirox 3 Once-daily oral dosing; initial daily dose of 20 mg/kg (10–30 mg/kg) Deferiprone 4 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

22. 22 Survival Probability Borgna-Pignatti C, et al. Haematologica. 2004;89:1187. (P <.00005) 0 1.00 0.75 0.50 0.25 051015202530 Age (years) Birth cohort 1960–1964 1965–1969 1970–1974 1975–1979 1980–1984 1985–1997 Increasing Efficacy of Chelation Therapy Has Significantly Improved Patient Survival

23. 23 Monitoring Iron Load in Patients on Iron Chelation Therapy Thalassaemia major 1 –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.

24. 24 Thalassaemia 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

25. 25 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.

26. 26 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

27. 27 Combination of desferrioxamine, defrasirox Both deferasirox and DFO improved cardiac T2* over 2 years in this patient population with severe iron overload. Improvement in cardiac T2* was comparable between patients treated with deferasirox and DFO. in the DFO treatment arm for the extension were low and the study was not powered to detect differences between groups over a 2-year treatment duration. The magnitude of cardiac T2* improvement with deferasirox was consistent with that observed in previous long-term studies of up to 3-year duration. Improvement with defrasirox or DFO treatment was observed in patients with both low and high baseline LIC (< and ≥15 mg Fe/g dw) and with moderate and severe baseline cardiac iron (T2* 10–20 and <6–10 ms).

28. 28 Combination of defroxamine, defrasirox Increased cardiac iron removal over the longer study duration may relate to the continued decrease in LIC from very high baseline levels. – In patients with very high LIC, liver iron burden may have an impact on the rate of cardiac iron removal during defrasirox treatment. Thus, greater improvements in cardiac T2* over the long term may occur because LIC continues to decrease over time, or due to later initiation of cardiac iron removal among patients with high baseline LIC. Mean LVEF was stable and remained within normal limits in defrasirox and DFO patients. The long-term safety profiles of defrasirox and DFO were consistent with those observed in previous reports. We conclude that both defrasirox and DFO at the treatment doses used in this study are effective for improvement of cardiac iron over 2 years in patients with a wide range of baseline LIC and cardiac T2* values.

29. 29 Defroxamine, Desferrioxamine Names IUPAC name N'-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4- oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide Other names N'-[5-(Acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl) propanoylamino]pentyl]-N-hydroxy-butane diamide

30. 30 Preperations Defroxamine is a bacterial siderophore produced by the Actinobacteria Streptomyces pilosus. It has medical applications as a chelating agent used to remove excess iron from the body. The mesylate salt of DFO is commercially available as 500 mg vial & 2 gm for IV and SQ administration.

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33. 33 Mechanism Deferoxamine acts by binding free iron in the bloodstream and enhancing its elimination in the urine. By removing excess iron, the agent reduces the damage done to various organs and tissues, such as the liver, heart and endocrine glands.

34. 34 IV or SQ با توجه به نیمه عمر ده دقیقه ای دفروکسامین هر چه مدت زمان تزریق بیشتر باشد تاثیر بیشتر است بنابراین در شروع تزریق 6-9 ساعته زیرجلدی توصیه میشود ولی در کسانی که هنوز سن کمتر از دوو نیم سال دارند و فریتین بیشتر از 1000؛ تزریق وریدی آهسته طی 4 ساعت یعنی از زمان نمونه گیری تا شروع تزریق خون توصیه میشود تا 200 میلی گرم آهن وارد شده توسص این کیسه خون دفع شود.

35. 35 توجه ! توجه! Deferoxamine Mesylate for Injection, should not be administered concurrently with the blood transfusion as this can lead to errors in interpreting side effects such as rash, anaphylaxis and hypotension.

36. 36 IV or SQ همچنین در کسانی که تزریق زیرجلدی شبانه قادر به کاهش بار آهن نشده و بیمار نمیتواند از دفریپرون (به دلیل عوارض گوارشی یا مفصلی یا هماتولوژیک آن) استفاده کند یا تزریق مداوم زیرجلدی (با یک بار تعویض اسکالپ در شبانه روز) را تحمل نمیکند؛ و فریتین بیشتر از 2500 باشد تزریق وریدی 24 ساعته (3-5 روز در ماه) مفید است.در این صورت دوز دفروکسامین 60-50 میلی گرم در شبانه روز محاسبه میشود.

37. 37 IV INJECTION The reconstituted solution is added to physiologic saline, (e.g., 0.9% sodium chloride, 0.45% sodium chloride), glucose in water, or Ringer’s lactate solution. The intravenous infusion rate should not exceed 15 mg/kg/hr

38. 38 Stability after Reconstitution The product should be used immediately after reconstitution (commencement of treatment within 3 hours) for microbiological safety. When reconstitution is carried out under validated aseptic conditions (in a sterile laminar flow hood using aseptic technique), the product may be stored at room temperature for a maximum period of 24 hours before use.

39. 39 Stability after Reconstitution Do not refrigerate reconstituted solution. Reconstituting Deferoxamine Mesylate for Injection, in solvents or under conditions other than indicated may result in precipitation. Turbid solutions should not be used.

40. 40 Drug Interactions Vitamin C: Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. As an adjuvant to iron chelation therapy, vitamin C in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with Desferal.

41. 41 Vitamin C increases availability of iron for chelation. In general, 50 mg daily suffices for children under 10 years old and 100 mg daily for older children. Larger doses of vitamin C fail to produce any additional increase in excretion of iron complex. Vitamin C supplements should not be given to patients with cardiac failure.

42. 42 Adverse Reactions At the Injection Site: localized irritation, pain, burning, swelling, induration, infiltration, pruritus, erythema, wheal formation, eschar, crust, vesicles, local edema. Injection site reactions may be associated with systemic allergic reactions (see Body as a Whole, below).

43. 43 Adverse Reactions Hypersensitivity Reactions and Systemic Allergic Reactions: generalized rash, urticaria, anaphylactic reaction with or without shock, angioedema. Body as a Whole: Local injection site reactions may be accompanied by systemic reactions like arthralgia, fever, headache, myalgia, nausea, vomiting, abdominal pain, or asthma.

44. 44 Adverse Reactions Infections with Yersinia and Mucormycosis have been reported in association with Deferoxamine mesylate use. Cardiovascular: tachycardia, hypotension, shock. Digestive: abdominal discomfort, diarrhea, nausea, vomiting.

45. 45 Adverse Reactions Hematologic: blood dyscrasia (thrombocytopenia, leukopenia). Hepatic: Increased transaminases, hepatic dysfunction.

46. 46 Adverse Reactions Musculoskeletal: Muscle spasms. Growth retardation and bone changes (e.g., metaphyseal dysplasia) are common in chelated patients given doses above 60 mg/kg, especially those who begin iron chelation in the first three years of life. If doses are kept to 40 mg/kg or below, the risk may be reduced (see WARNINGS, PRECAUTIONS/Pediatric Use).

47. 47 Adverse Reactions Nervous System: neurological disturbances including dizziness, peripheral sensory, motor, or mixed neuropathy, paresthesias, seizures; exacerbation or precipitation of aluminum- related dialysis encephalopathy

48. 48 Adverse Reactions Special Senses: High-frequency sensorineural hearing loss and/or tinnitus are uncommon if dosage guidelines are not exceeded and if dose is reduced when ferritin levels decline. Visual disturbances are rare if dosage guidelines are not exceeded. These may include decreased acuity, blurred vision, loss of vision, dyschromatopsia, night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration), optic neuritis, and cataracts.

49. 49 Adverse Reactions Respiratory: acute respiratory distress syndrome (with dyspnea, cyanosis, and/or interstitial infiltrates) (see WARNINGS). Skin: very rare generalized rash. Urogenital: dysuria, acute renal failure, increased serum creatinine and renal tubular disorders

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52. 52 Patient Presentation 12-year-old boy of Mediterranean origin Previously diagnosed with –β-thalassaemia major at age 6 months –Hepatitis C virus infection at age 4 years Splenectomized at the age of 6 years Received ~45 packed red blood cell transfusions in his childhood Never received iron chelation therapy Presenting for assessment of iron overload

53. 53 Relevant Laboratory Value Serum ferritin level = 7200 ng/mL How reliable is serum ferritin for the assessment of iron overload in this case?

54. 54 Case Continues—Liver Biopsy A liver biopsy was recommended –To determine the liver iron concentration –To evaluate histopathologic changes secondary to hepatitis C infection Patient’s mother refused due to concerns about the associated risks of invasive intervention

55. 55 Measuring LIC by Liver Biopsy 1,2 AdvantagesDisadvantages Directly measures LIC (quantitative, specific, sensitive) Validated reference standard Measures nonheme storage iron Evaluates liver histology/pathology Positively correlates with morbidity and mortality Invasive, painful, and potentially serious complications (eg, bleeding) Sampling error risk, especially in patients with cirrhosis Inadequate standardization between laboratories Difficult to follow up 1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.

56. 56 Case Continues—Assessing Liver Iron Patient underwent R2 MRI of the liver = 16 mg/g dry weight How well does liver R2 MRI correlate with liver biopsy?

57. 57 Correlation Between R2 MRI and Liver Biopsy With permission from St. Pierre TG, et al. Blood. 2005;105:855-861. 30 20 40 50 0.51.01.52.0 Biopsy Iron Concentration (mg/g -1 dry weight) 0 100 200 50 150 250 300 010203040 50 R2 MRI is a validated and standardized technique approved by the Australia Therapeutic Goods Administration, FDA, and European Medicines Agency Hereditary haemochromatosis Hepatitis β-thalassaemia β-thalassaemia/ haemoglobin E Mean Transverse Relaxation Rate (s -1 )

58. 58 Measuring LIC with MRI 1,2 AdvantagesDisadvantages Estimates iron content throughout the liver Increasingly available worldwide Status of liver and heart can be assessed in parallel Validated relationship with LIC Allows longitudinal patient follow- up Indirectly measures LIC Requires MRI imager with dedicated imaging method Children younger than age 7 years require a general anaesthetic 1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.

59. 59 Case Continues—Assessing Cardiac Iron The patient underwent myocardial T2* MRI = 16 ms Can cardiac dysfunction be predicted on the basis of this value alone?

60. 60 T2* MRI—Emerging New Standard for Cardiac Iron Assessment in TM Patients Left Ventricular Ejection Fraction (LVEF) (%) 0 50 70 40 30 20 10 60 80 90 0204060908010010305070 Heart T2* (ms) Cardiac T2* value of 37 in a normal heart Cardiac T2* value of 4 in a significantly iron overloaded heart With permission from Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179. Photos courtesy of Maria D. Cappellini, MD. Myocardial T2* values <20 ms are associated with progressive and significant decline in LVEF

61. 61 T2* and Left Ventricular Ejection Fraction (LVEF) A shortening of myocardial T2* to <20 ms (ie, increased myocardial iron) is associated with an increased chance of decreased LVEF T2* Value (ms) Chance of Decreased LVEF >20Low chance 10–2010% 8–1018% 638% 470% TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.

62. 62 Measuring Cardiac Iron with MRI 1,2 AdvantagesDisadvantages Rapidly assesses iron content in the septum of heart Relative iron burden can be estimated reproducibly Functional parameters can be examined concurrently Iron status of liver and heart can be assessed in parallel Allows longitudinal follow-up Indirectly measures cardiac iron Requires MRI imager with dedicated imaging method MRI is a nonvalidated method to rapidly and effectively assess cardiac iron 1. Taher A, et al. Semin Hematol. 2007;44(suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008.

63. 63 Thresholds for Parameters Used to Evaluate Iron Overload Parameter Normal Range Iron Overload State MildModerateSevere LIC (mg Fe/g dw) 1 <1.23–7>7>15 Serum ferritin (ng/mL) 2,3 <300, male <200, female >1000 to <2500>2500 Cardiac T2* (ms) 4 >2014–208–14<8 1. Wood JC, et al. Blood. 2005;106:1460-1465. 2. Taher A, et al. Semin Hematol. 2007;44 (suppl 3):S2-S6. 3. Brissot P, et al. Blood Rev. 2008;22:195-210. 4. Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179.

64. 64 Conclusions Assessment of iron overload is essential in the clinical management of patients with thalassaemia because it guides chelation therapy Historically, serum ferritin and liver biopsy have been the diagnostic methods of choice –However, limitations to the reliability of the first and invasiveness of the latter call for novel noninvasive approaches Liver R2 MRI and cardiac MRI T2* are becoming highly sought methods for the diagnosis of iron overload and monitoring of chelation therapy