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Iron Overload and Its Management in Non–Transfusion -Dependent Thalassaemia (NTDT)

Iron Overload and Its Management in Non–Transfusion -Dependent Thalassaemia (NTDT). Ali Taher , MD, FRCP Professor Department of Internal Medicine American University of Beirut Medical Center Beirut, Lebanon . Definition.

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Iron Overload and Its Management in Non–Transfusion -Dependent Thalassaemia (NTDT)

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  1. Iron Overload and Its Management in Non–Transfusion-Dependent Thalassaemia (NTDT) Ali Taher, MD, FRCP Professor Department of Internal Medicine American University of Beirut Medical Center Beirut, Lebanon

  2. Definition • Non–transfusion-dependent thalassaemia (NTDT) is a group of thalassaemias for which patients do not require regular red cell transfusions for survival • They may require occasional transfusions for growth failure, pregnancy, infections… • There are 5 NTDTs • β-Thalassaemia intermedia • Haemoglobin E β-thalassaemia • Haemoglobin H disease • Haemoglobin S β-thalassaemia • Haemoglobin C thalassaemia

  3. Varying Severity • These diseases form a spectrum, with 1 end being non–transfusion-dependent • Early recognition is vital to prevent placing children on lifelong transfusion therapy Mild Severe • Presentation at younger ages • Transfusion dependency • Completely asymptomatic until adult life • Non–transfusion-dependent TaherA, et al. Br J Haematol. 2011;152:512-523.

  4. β-ThalassaemiaIntermedia • “Highly diverse” group of β-thalassaemiasyndromes characterized by red blood cells that are sufficiently short-lived to cause anaemia, without patients necessarily requiring regular blood transfusions1 • The severity of the clinical phenotypes varies between those of β-thalassaemiaminor and β-thalassaemia major1 • Thalassaemiaintermedia arises from defective gene(s) leading to partial suppression of β-globin protein production1 • Occurs at low frequencies in all populations where β-thalassaemia is common, particularly in the Mediterranean and Middle East2 1. TaherA, et al. Br J Haematol. 2011;152:512-523. 2. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. 4th ed. Wiley-Blackwell; 2001.

  5. Determinants of Disease Severityin β-ThalassaemiaIntermedia Molecular factors1,2 Inheritance of a mild or silent β-chain mutation Presence of a polymorphism for the enzyme Xmn-1 in the G-promoter region, associated with increased fetal haemoglobin Coinheritance of -thalassaemia Increased production of -globin chains by triplicated or quadruplicated -genotype associated with β-heterozygosity; also from interaction of β- and δβ-thalassaemia Environmental factors may influence severity of symptoms2 Social conditions Nutrition Availability of medical care 1. TaherA, et al. Br J Haematol. 2011;152:512-523. 2. TaherA, et al. Blood Cell Mol Dis. 2006;37:12-20.

  6. Haemoglobin E β-Thalassaemia • Result of coinheritance of the structural variant haemoglobin E and 1 of the numerous β-thalassaemia alleles • Clinical severity varies with • The severity of the inherited β-allele • Genetic and environmental modifiers • Common in Southeast Asia, Bangladesh, and East India Olivieri NF, et al. Br J Haematol. 2008;141:388-397.

  7. β0- and β+-thal = 2%–5%1 HbE= 5%–50%2 HaemoglobinE β-Thalassaemia At least 20 million people have HbE traits worldwide1 Nearly 1 million are at risk of HbEβ-thalassaemia3 1. WeatherallDJ, Clegg JB. The Thalassaemia Syndromes. 4th ed. WileyBlackwell; 2001. 2.Vichinsky EP. Ann NY AcadSci. 2005;1054:18-24. 3.Vichinsky E. ASH Education Book. 2007:1:79-83.

  8. Haemoglobin H Disease • Result of inactivation of 3 out of 4 α-globin genes1 • Variable severity depending on molecular pathology2 • Deletional forms (-α/--) are mild and non–transfusion-dependent2 • 1deletional and 1nondeletional allele (αND/--) manifest a severe phenotype, sometimes requiring regular transfusion2 • Common in Southeast Asia2 1. Chui D, et al. Blood. 2003;101:791-800. 2. Higgs DR, Weatherall DJ. Cell Mol Life Sci. 2009;66:1154-1162. Chui D, et al. Blood. 2003; 101:791-800. Higgs DR, Weatherall DL. Cell Mol Life Sci. 2009;66:1154-1162

  9. Iron Overload in NTDT • Despite no regular transfusion therapy, NTDT patients accumulate iron with age • The mechanism is mainly increased iron absorption from the gastrointestinal tract • Occasional transfusion therapy can also increase iron loading • Due to variability, iron overload in NTDT requires regular monitoring and a tailored approach to management Taher A, et al. Br J Haematol. 2009;147:634-640.

  10. Mechanism of Iron Overload in Nontransfused Patients Ineffective erythropoiesis Chronic anaemia Hypoxia ↑ HIFs ↑ GDF15 ↑ Release of recycled iron from RES macrophages ↓ Hepcidin ↑Erythropoietin ↑ Duodenal iron absorption ↑ Ferroportin ↑ LIC ↓ Serum ferritin Abbreviations: GDF15, growth differentiation factor 15; HIF, hypoxia-inducible transcription factor; LIC, liver iron concentration; RES, reticuloendothelial system. With permission from Taher A, et al. Br J Haematol. 2011;152:512-523.

  11. GDF-15 Levels in 55 Untreated Patientswith β-ThalassaemiaIntermedia - - - GDF-15 (pg/mL - - - - - - β-TI (This report) Thal-trait α-Thal β-Thal CDA I RARS PKD SS HV Abbreviation: β-TI, beta thalassaemiaintermedia. With permission from Musallam KM, et al. Blood Cells Mol Dis. 2011;47:232-234.

  12. GDF-15 Levels Correlated with Clinical Severity Score in β-TI Mild Moderate Severe r = .830 P <.001 With permission from Musallam KM, et al. Blood Cells Mol Dis. 2011;47:232-234.

  13. Iron Overload in β-ThalassaemiaIntermedia • Iron overload occurs even in thalassaemiaintermedia (TI) patients who have not been transfused1,2 • Iron loading: 2–5 g Fe/year1; iron develops from age 5 years2 • It is much lower than in age-matched patients with transfusion-dependent thalassaemia major (TM)2 • Although the rate of iron loading differs between TM and TI, the consequences are apparent in both groups of patients and include liver, heart, and endocrine organs1,2 1. CappelliniMD, et al. “ThalassaemiaIntermedia.” In: ESH Handbook on Disorders of Erythropoiesis, Erythrocytes and Iron Metabolism. Beaumont C, et al, eds. ESH. 2009. 2. TaherA, et al. Br J Haematol. 2009;147:634-640.

  14. Iron Overload in β-TI Ferritin increases with age, indicating accumulation of iron with time despite transfusion naïvety Serum Ferritin Level Increases with Age (r = 0.653, P <.001) With permission from TaherA, et al. Br J Haematol. 2010;150:486-489.

  15. Complications vs Age Complications in 120 treatment-naïve patients with β-TI ≤10 years 11–20 years 21–32 years >32 years * * * * * * *Statistically significant trend. Abbreviations: ALF, abnormal liver function; DM, diabetes mellitus; EMH, extramedullaryhaematopoiesis; HF, heart failure; PHT, pulmonary hypertension. With permission from TaherA, et al. Br J Haematol. 2010;150:486-489.

  16. Iron Overload in HbEβ-Thalassaemia • Variable non–transfusional iron accumulation • Early studies found substantial iron overload and evidence of end-organ damage • Results of follow-up studies show highly variable rates of iron accumulation from periods ranging from 3 to 11 years Olivieri NF, et al. J PediatrHematolOncol. 2000;22:593-597.

  17. Iron Overload in HbH • High serum ferritin levels observed in older haemoglobin H α-thalassaemia patients1 • Serum ferritin levels increase with age and correlate with liver iron concentration2 1. Chui DH, et al. Blood. 2003;101:791-800. 2. Lal A, et al. N Engl J Med. 2011;364:710-718.

  18. Iron Overload in HbH Ferritin also positively correlated with age in HbH 85% of patients are iron overloaded Liver MRI showing a signal intensity of <1 (indicating iron overload) in 85% (51/60) of patients. This was significantly (P <.001) inversely correlated with serum ferritin levels Significant (P<.001) correlation between serum ferritin and age in 114 patients with HbH disease With permission from Chen FE, et al. N Eng J Med. 2000;343:544-550.

  19. Assessment of Iron Overload There are several methods to assess total body iron; each carrying their own advantages and disadvantages • Serum ferritin • SQUID • Liver iron concentration by biopsy or MRI Abbreviations: MRI, magnetic resonance imaging; SQUID, superconducting quantum interference device.

  20. Measuring and Interpreting Serum Ferritin Serial measurement of serum ferritin is a simple, reliable, indirect measure of total body iron Taher A, et al. SeminHematol. 2007;44(2 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.

  21. Measuring LIC by Liver Biopsy Taher A, et al. SeminHematol. 2007;44(2 Suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008. 3. BrittenhamGM, et al. Blood. 2003;101:15-19.

  22. Measuring LIC with MRI Taher A, et al. SeminHematol. 2007;44(2 Suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; 2008. 3. BrittenhamGM, et al. Blood. 2003;101:15-19.

  23. Correlation Between R2 MRI and Liver Biopsy R2 MRI has been studied, standardized, and validated in several iron loading states, including hereditary haemochromatosis, beta-thalassaemia, and HbE/beta-thalassaemia. It has been found to significantly correlate with liver biopsy value across all these diseases. Therefore, it has been approved for usage by the FDA, TGA, and EMEA.

  24. Serum Ferritin and LIC by SQUID Differences relative to the transfused group were tested using the U test. *P <.001; †P <.01; ‡P <.05. With permission from PakbazZ, et al. Pediatr Blood Cancer. 2007;49:329-332.

  25. Serum Ferritin and LIC by Liver Biopsy Serum ferritin was significantly lower in patients with TI than in those with TM, despite similar LIC by SQUID and liver biopsy *LIC normal range is .03–1.04 mg/g dry wt. With permission from OrigaR, et al. Haematologica. 2007;92:583-588.

  26. 10000 9000 8000 7000 6000 Serum Ferritin Level (μg/L) 5000 4000 3000 2000 1000 0 5 10 15 20 25 30 35 40 45 50 LIC (mg Fe/g dry wt) Serum Ferritin Underestimates Iron Burden by MRI in β-TI TI TM Linear (TI) Linear (TM) A significant positive correlation with serum ferritin levels was observed (R = 0.64; P <.001) LIC values measure by MRI were similar to those in patients with TM, but serum ferritin levels were significantly lower 0 LIC correlated with serum ferritin levels in patients with TI (R = 0.64;P <.001) With permission from TaherA, et al. Haematologica. 2008;93:1584-1586. Musallam KM, Taher AT. N Engl J Med. 2011;364:1476.

  27. LIC vs Morbidity in 168 Patients from Lebanon and Italy With permission from MusallamKM, et al. Haematologica. 2011;96:1605-1612.

  28. LIC and Vascular Morbidity With permission from MusallamKM, et al. Haematologica. 2011;96:1605-1612. Patients with an LIC ≥7 mg Fe/g dw had a significantly higher rate of vascular morbidity compared with patients with an LIC <7 mg Fe/g dw, in all groups of phenotype severity

  29. LIC andEndocrine and Bone Morbidity With permission from MusallamKM, et al. Haematologica. 2011;96:1605-1612. • Patients with an LIC ≥6 mg Fe/g dw had a significantly higher rate of endocrine morbidity compared with patients with an LIC <6 mg Fe/g dw, • in all groups of phenotype severity • A 1-mg increase in LIC was significantly associated with a significantly increased risk of developing thrombosis, pulmonary hypertension, hypothryroidism, hypogonadism, and osteoporosis

  30. Iron chelation

  31. Overview on Practices in ThalassaemiaIntermedia Management Aiming for Lowering Complication Rates Across a Region of Endemicity—The OPTIMAL CARE Study Retrospective review of 584 TI patients from 6 comprehensive care centers in the Middle East and Italy N = 127 N = 153 N = 200 N = 51 N = 12 N = 41 Taher AT, et al. Blood. 2010;115:1886-1892. Slidecourtesy of Dr. Taher.

  32. In the OPTIMAL CARE StudyChelated Patients: 336/584 With permission from TaherAT, et al.Blood. 2010;115:1886-1892.

  33. In the OPTIMAL CARE StudyChelated patients: 336/584 • Iron chelathion therapy was protective for hypogonadism, pulmonary hypertension, cholelithiasis, and osteoporosis. With permission from TaherAT, et al. Blood. 2010;115:1886-1892.

  34. Iron Chelation Therapy in ThalassaemiaIntermediaDesferrioxamine • Significant decline in serum ferritin after 6 months of desferrioxamine treatment • Significant urinary iron excretion (UIE) after 12 hours of continuous desferrioxamine(except in patients age <1 year) • In some patients, substantial UIE despite modest serum ferritin levels • Serum ferritin levels of no value in predicting UIE • No significant differences in excretion across doses CossuP, et al. Eur J Pediatr. 1981;137:267-271.

  35. Iron Chelation Therapy in ThalassaemiaIntermediaDeferiprone • Significant reductions seen in mean serum ferritin, hepatic iron, red-cell membrane iron, and serum NTBI levels • Serum ferritin ± SD • Initial 2168 ± 1142 μg/L • Final 418 ± 247 μg/L • Significant mean increase in serum erythropoietin also observed • Increase in Hb values in 3 patients; reduction in transfusion requirements in 4 patients Abbreviation: NTBI, non–transferrin-bound iron. PootrakulP, et al. Br J Hematol. 2003;122:305-310.

  36. Reduction in Iron Burden with Deferasirox at Year 1 in Patients with β-TI • Mean cardiac T2* and LVEF (both normal at baseline), serum creatinine, and cystatin C did not significantly change after 12 months of treatment with deferasirox Deferasirox can effectively reduce iron burden in patients with TI VoskaridouE, et al. Br J Haematol. 2010;148:332-334. Slide courtesy of Dr. Taher.

  37. Deferasirox for Nontransfusional Iron Overload in Patients with β-TI • 11 patients with thalassaemia intermedia • 6 male, 5 female • Mean age 31.7 years • 10 splenectomized • Deferasirox regimen • 1 year (n = 11), 2 years (n = 4) • 10 mg/kg/day (n = 7), 20 mg/kg/day (n = 4) • Dose adjustment after first year 1. Ladis V, et al. Haematologica. 2009;94(suppl 2):1-694. Abstr 1279. 2. LadisV, et al. Br J Haematol. 2010; 151:504-508.

  38. 1 patient, who was noncompliant, did not show decrease of iron overload and was excluded from graph Changes in LIC and ferritin levels were related to deferasirox dose, but even patients with severe iron load, treated with 10 mg/kg/day, responded well Serum ferritin at baseline Serum ferritin at 1 year Serum ferritin at 2 years 3000 LIC at baseline LIC at 1 year LIC at 2 years 2000 Serum Ferritin Levels (ng/mL) 1000 0 Patients Effect of Deferasirox on Serum Ferritin and LIC in Patients with β-TI and NontransfusionalIron Overload 40 30 LIC (mg Fe/g dw 20 10 0 Patients Ladis V, et al. Haematologica. 2009;94(suppl 2):1-694. Abstr 1279. With permission from Ladis V, et al. Br J Haematol. 2010;151:504-508.

  39. Safety of DeferasiroxDuring Treatment of Up to 2 Years Treatment was well tolerated No serious adverse events were noted Creatinine and cystatin C levels did not change during treatment Transaminase levels significantly decreased in year 1 (P = .0002) and year 2 (P = .024) of treatment This improvement probably due to decreased hepatic siderosis 1. LadisV, et al. Haematologica. 2009;94(suppl 2):1-694. Abstr 1279. 2. LadisV, et al. Br J Haematol. 2010;151:504-508.

  40. Deferasirox Significantly Reduces Liver Iron Concentration In Non–Transfusion-Dependent ThalassaemiaPatients with Iron Overload Results from the 1-Year Randomized, Double-Blind, Placebo-Controlled Phase II THALASSA Study

  41. Aim of the THALASSA Study Primary objective: To assess the efficacy of 2deferasirox regimens (starting doses 5 and 10 mg/kg/day) in patients with NTDT, based on the change in LIC from baseline after 1 year of treatment compared with placebo-treated patients Other objectives • To compare change from baseline in serum ferritin (SF) over 1 year of treatment between deferasirox and placebo treatment groups • To evaluate the safety of both regimens of deferasiroxvsplacebo • To evaluate the relationship between SF and LIC • To evaluate the iron accumulation rate based on LIC assessment in patients treated with placebo Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr902.

  42. Key Inclusion/Exclusion Criteria Inclusion criteria • Male or female age ≥10 years with NTDT • No transfusions within the previous 6 months prior to study entry • LIC ≥5 mg Fe/g dw by R2 MRI • SF >300 ng/mL Exclusion criteria • HbS variants of thalassaemiasyndromes • Anticipated regular transfusions during the study • Chelation within 1 month prior to study treatment • History of deferasirox exposure • Lab values–creatinineclearance ≤60 mL/min, serum creatinine >ULN and ALT >5 x ULN at screening Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. TaherAT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.

  43. Deferasirox Significantly Reduces LIC Compared with Placebo 1 StartingDeferasiroxDose 5 mg/kg/day 10 mg/kg/day 0.38 0 Placebo Study met its primary endpoint –1 LIC Change from Baseline to Week 52 Least Squares Mean (mg Fe/g dw) –1.95 –2 P = .001 –3 –3.80 P = .009 –4 P <.001 Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr902. Slide courtesy of Dr. Taher.

  44. Deferasirox Significantly Reduces SF Compared with Placebo 150 100 Starting deferasirox dose 50 5 mg/kg/day 10 mg/kg/day 115 0 Placebo SF Change from Baseline to Week 52 Least Squares Mean (ng/mL) –50 –100 –121 –150 P <.001 –200 –222 P = .088 –250 P <.001 Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr902. Slide courtesy of Dr. Taher.

  45. Most Common (≥3 Patients Overall) Drug-Related AEs Overall AE incidence comparable between deferasirox and placebo Most drug-related AEs were of mild-to-moderate severity and resolved without discontinuation of treatment Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902. Slide courtesy of Dr. Taher.

  46. THALASSA in Brief • THALASSA is the first multinational, randomized, double-blind, placebo-controlled study evaluating iron chelation therapy in NTDT patients • High baseline iron burden and increasing LIC and SF in placebo highlight the need for iron chelation therapy • Compared with placebo, deferasirox at starting doses 5 and 10 mg/kg/d with dose escalations up to 20 mg/kg/d in patients with high levels of iron overload significantly reduced LIC and SF • Deferasirox 10 mg/kg/d was superior to 5 mg/kg/d in reducing LIC • Lower dose range than required in transfusion-dependent thalassaemia patients (20–40 mg/kg/d) • Overall frequency of AEs with deferasirox in both dose groups was comparable with placebo • Based on benefit/risk profile of deferasirox in NTDT patients, chelation therapy should be considered when LIC >5 mg Fe/g dw Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.

  47. Conclusions • Despite being non–transfusion-dependent, NTDT patients are still at an increased risk of complications, including iron overload • Total body iron should be periodically assessed and chelation therapy tailored accordingly • In the THALASSA study, deferasirox was shown to be safe and efficacious in reducing iron in NTDT and is awaiting approval

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