Indications for Successful Iron Overload Treatment and Monitoring: Hereditary Haemochromatosis

1. Indications for Successful Iron Overload Treatment and Monitoring:Hereditary Haemochromatosis Pierre Brissot, MDProfessor of Medicine Liver Disease DepartmentUniversity Hospital PontchaillouRennes, France

2. Outline Iron overload treatment of • HFE-haemochromatosis • Type 1 or C282Y/C282Y HC • Non–HFE-haemochromatosis • Type 2 HC (juvenile HC) • Type 3 HC (TfR2 HC) • Type 4 HC (ferroportin disease) • Hereditary aceruloplasminaemia HC = haemochromatosis; TfR2 = transferrin receptor 2.

3. Principle Practical management Results Limitations HFE-Haemochromatosis Phlebotomy = Therapy of Choice Courtesy of P. Garo, Phanie Agency

4. Fe Fe Fe Fe Fe Fe RBC RBC RBC Phlebotomy HFE-HaemochromatosisPrinciple of Phlebotomy Hepatocyte Bone marrow 3 2 BLOOD 1 Courtesy of P. Brissot

5. HFE-HaemochromatosisPractical Management of Phlebotomies • Overall schedule1 • Start: grade 2 HC (ferritin level >300 µg/L for men,>200 µg/L for women) • Induction phase: 7 mL/kg body weight (<550 mL), weekly,until ferritin ≤50 µg/L (haemoglobin remaining ≥11 g/dL) • Maintenance phase: every 1–4 months to maintainferritin ≤50 µg/L (lifetime regimen) • Technical details • Nonfasting subject • In a half-recumbent position • Drinking an equivalent volume to that removed • Monitor blood pressure before and after the venesection 1. Brissot P, de Bets F.Hematology. Am Soc Hematol Educ Program. 2006:36.

6. HFE-HaemochromatosisResults of Phlebotomies • Good results on • General health • Hyperpigmentation • Hypertransaminasaemia and hepatic fibrosis (if moderate) • Cardiac symptoms • Mixed results on • Joint symptoms (may persist or even worsen) • Diabetes (remains insulin-dependent) Brissot P, de Bets F. Hematology. Am Soc Hematol Educ Program. 2006:36.

7. HFE-HaemochromatosisResults of Phlebotomies Two important notions • If cirrhosis was present prior to phlebotomies, the risk for hepatocellular carcinoma remains (requiring plasma alpha-feto-protein dosage and liver ultrasound every 6 months)1 • If cirrhosis or insulin-dependent diabetes was not present prior to phlebotomies, life expectancy returns to normal2 1. Brissot P, de Bels F. HematologyAm Soc Hematol Educ Program. 2006:36. 2. Dooley JS. Pract Res Clin Haematol. 2002;15:277.

8. HFE-HaemochromatosisLimitations of Phlebotomies—Conceptual Phlebotomies • By inducing marked iron release from hepatocytes(at the induction phase) and • By increasing intestinal absorption of iron (through enhancing hepcidin deficiency) May contribute to increase in plasma transferrin saturation (TfSat) and favour (whenever TfSat is ≥75%1) the appearance of labile plasma iron (LPI), which is the potentially toxic form of circulating iron 1. Le Lan C, et al. Blood. 2005;105:4527.

9. HFE-HaemochromatosisLimitations of Phlebotomies—Practical From the clinical viewpoint • Venous punctures may be (or become) difficult1 • Arthropathy may worsen2 • General lassitude in the long run • Efficacy may be insufficiently rapid in massive iron excess, especially with cardiomyopathy Adams PC. Lancet. 2007;370:1855. Dooley JS. Pract Res Clin Haematol. 2002;15:277.

10. HFE-HaemochromatosisLimitations of Phlebotomies—Practical From the societal viewpoint: • Time-consuming procedure (especially during professional activity) • Unsatisfactory health center network for venesections • Poorly defined procedure when performed at home (blood elimination process…)

11. HFE-HaemochromatosisIron Chelation—A Changing View Until recently: a very limited place • Desferrioxamine • Subcutaneous infusion (2 g/day; 12 hours/day;5 days/week; usually for several months) • Only • When phlebotomies are contraindicated or not feasible, or • In case of massive iron excess (with cardiac disease), and then combined with bloodletting • Efficient for iron depletion • But uncomfortable procedure and possibleside-effects (audiometry and eye exams annually)

12. HFE-HaemochromatosisIron Chelation—A Changing View • Until recently—a very limited place • Deferiprone • Oral chelator • Not advisable due to its very rare butunpredictable risk of agranulocytosis • Now—a promising perspective…

13. • Principle • Indications • Limitations HFE-Haemochromatosis Oral Chelation by Deferasirox—An Interesting Perspective

14. HFE-HaemochromatosisPrinciple of Oral Chelation—Deferasirox • Efficacy can be expected in type 1 haemochromatosis,due to • Its preferential hepatocytic target (as indicated by its very high degree of biliary elimination)1 • Its capacity for removing labile plasma iron (LPI) 1. Adams PC. Lancet. 2007;370:1855. 11

15. HFE-HaemochromatosisIndications of Oral Chelation—Deferasirox Could be used • Alone, as replacement for phlebotomies, in case of • Moderate or important iron excess • Technical impossibility for venesection1 • Contraindication for venesection (eg, anaemia)1,2 • In association with phlebotomies, in case of massive iron overload, especially with severe visceral (especially cardiac) damage 1. Adams PC. Lancet. 2007;370:1855. 2. Beutler E. Blood Cells Mol Dis. 2007;39:140.

16. HFE-HaemochromatosisLimitations of Oral Chelation Deferasirox will be used, provided it does not lead to significant side-effects This is the goal of an ongoing international safety trial 11

17. In Non–HFE-Haemochromatosis The respective place of phlebotomies and oral chelation depends greatly on the underlying pathophysiological mechanisms accounting for iron overload 11

18. Non–HFE-Haemochromatosis For type 2 HC (juvenile HC by haemojuvelin or hepcidin mutations), type 3 HC (TfR2 HC) or type 4-B HC (ferroportin disease with hepcidin resistance) • The therapeutic management for iron overload is very close to that of type 1 HC • In juvenile HC, massively damaging iron excess favors combining phlebotomy and oral chelation in order to accelerate iron removal

19. Non–HFE-Haemochromatosis For type 4-A HC (usual form of ferroportin disease), and hereditary aceruloplasminaemia, both characterized by an impairment of cellular iron release into the blood (= iron recycling defect) • Phlebotomies may be poorly tolerated (risk of anaemia)1in type 4-A HC, so that oral chelation may be, if well tolerated, a good indication • Phlebotomies are contraindicated in hereditary aceruloplasminaemia, due to pre-existing anaemia. • Parenteral desferrioxamine can be efficient,2 but oral chelation appears clearly an excellent indication • 1. Montosi GJ, et al. J Clin Invest. 2001;108:619. 2. Loreal OJ, et al. J Hepatol. 2002;36:851.

20. Long-Term Treatment Perspectives

21. Long-Term Treatment Perspectives For all forms of HC related to hepcidin deficiency (ie,Types 1, 2, and 3 haemochromatosis): The therapeutic approach will be either exogenous hepcidin supplementation or endogenous stimulation of hepcidin production

22. Long-Term Treatment Perspectives • For all forms of HC related to hepcidin deficiency, (ie, Types 1, 2, and 3 haemochromatosis), it is anticipated that: • The major indication of hepcidin upgrading will be during the maintenance phase, as it is expected that the use of hepcidin prior to restoration of normal iron stores by phlebotomies/iron chelation may hamper depletion of excess iron • Therefore, it might not be advisable for hepcidin supplementation to be done concurrently with phlebotomies/iron chelation

23. Conclusions • Phlebotomy remains the treatment of choice for HFE-haemochromatosis • Oral chelation by deferasirox may offer an alternative to phlebotomy or as an addition to phlebotomy in cases of massive iron overload and/or severe visceral damage • Respective roles of phlebotomy and iron chelation depend on the pathophysiologic mechanisms responsible for iron overload

24. Conclusions • Management of iron overload for types 2 and 3 HC is similar to that of type 1 • Oral chelation may be preferable in managing iron overload in type 4A HC and hereditary aceruloplasminaemia