1. 1 Indications for Successful Iron Overload Treatment and Monitoring: Sickle Cell Disease Mariane de Montalembert, MD Pediatrics Department University Hospital Necker Paris, France

2. 2 Underestimation of Iron Overload in Patients with Sickle Cell Disease (SCD) Iron overload in this population has long been underestimated 1 reason may be that transfusion is less frequent in SCD than in thalassaemia

3. 3 Frequency of Iron Overload in Adult Patients with SCD SCD-SSHb SC S-  -Thal No.2478242 Mean age (y)34 ± 1036 ± 1243 ± 13 Patients transfused (%) 622629 Ferritin ng/mL692 ± 117122 ± 45451 ± 318 Ferritin >1500 ng/mL (%) 23% SCD-SS = homozygous sickle cell anaemia; Hb SC = haemoglobin SC disease; S-  -thal = sickle beta thalassaemia. Ballas SK, Semin Hematol. 2001;38:30.

4. 4 Relationship Between Transfusions and Iron Overload in Patients with SCD

5. 5 Goals of Transfusion in Patients with SCD Increase oxygen-carrying capacity in severely anaemic patients –Acute simple transfusion Restore blood flow by replacing rigid sickle red cells with deformable red cells –Acute simple transfusion or exchange transfusion (phlebotomy + transfusion)

6. 6 Indications for Episodic Red Cell Transfusion in SCD Management of acute severe anaemia –Acute splenic sequestration –Transient red cell aplasia –Hyperhaemolysis (acute infection, acute chest syndrome) Management of other severe SCD sequelae –Stroke –Severe acute chest syndrome –Acute multiorgan failure –Prevention of potential acute episodes  Preparation to general anesthaesia and surgery Ohene-Frempong K, et al. Semin Hematol. 2001;38:5.

7. 7 Indications for Chronic Transfusion Therapy in SCD 1 Primary stroke prevention (STOP trial 2 ) Prevention of stroke recurrence Acute chest syndrome, chronic hypoxic lung disease, or pulmonary hypertension Chronic renal and heart failure Chronic debilitating pain Controversial indications –Recurrent priapism –Silent cerebral infarct –Short programs: leg ulcer, growth and developmental delay –Pregnancy 3 1. Ohene-Frempong, et al. Semin Hematol. 2001;38:5. 2. Adams RJ, et al. N Engl J Med.1998;339:5. 3. Driss F, et al. Transfus Clin Biol. 2007;14:386.

8. 8 Stroke Risk Increases with Transcranial Doppler Flow Rate* in Children with SCD 1. Adams RJ, et al. N Engl J Med. 1992;327:1062. 2. Adams RJ, et al. Control Clin Trials. 1998;19:110. 0.4 0.5 0.6 0.7 0.8 0.9 1 05101520253035 Time (months) Probability of Remaining Stroke-Free <170 cm/sec 170–199 cm/sec  200 cm/sec P =.0001 *Mean velocity measured in cm/sec.

9. 9 Prevention of a First Stroke in SCD Children with Cerebral Blood Flow >200 cm/sec STOP 1 Trial Adams RJ, et al. N Engl J Med. 1998;339:5.

10. 10 Discontinuation of Prophylactic Transfusions Used to Prevent Stroke in SCD Children STOP 2 Trial SCD children transfused for ≥30 months until normalisation of pathologic transcranial Doppler flow rate Randomisation –Stop transfusion (n = 41) –Continue transfusion (n = 38) 34% of patients in the transfusion-halted group reverted to high stroke risk, and 2 had strokes, compared with no patients who continued with transfusion Adams RJ, et al. N Engl J Med. 2005;353:2769.

11. 11 Frequency of Transfusion in Patients with SCD Cooperative Study of Sickle Cell Disease 1 –50% of all patients with SCD, 60% of patients with homozygous disease (SCD-SS) had received at least 1 transfusion at enrollment 2 –5.2% of SCD-SS were receiving chronic transfusion 2 Single-center, 20-year prospective study 3 –62% of SCD adult patients received blood transfusion; transfused patients received a mean of 10 units of RBC/year (= 2 g iron/year) Transcranial Doppler (TCD) studies 4,5 –An estimated 10% of SCD children will receive chronic transfusion for a pathologic TCD 1. Rosse WF, et al. Blood. 1990;76:1431. 2. Ohene-Frempong K, et al. Semin Hematol. 2001;38:5. 3. Ballas SK. Semin Hematol. 2001;38:30. 4. Adams RJ, et al. N Engl J Med. 1998;339:5. 5. Adams RJ, et al. N Engl J Med. 2005;353:2769.

12. 12 Simple Transfusion Manual Exchange Transfusion Erythrocyta- pheresis Easy to perform; 1 venous access Time-consuming; manual Expensive; requires 2 good venous access Iron overload+++Iron overload+No iron overload; good clinical tolerance Allo-immunization +++ Infections Chronic Transfusion Methods

13. 13 Iron Intake in Multitransfused SCD Patients Calculations –For simple transfusion: estimation of iron intake in mg = total volume (mL) of RBC transfused x 1.08 1 –For exchange transfusion: iron balance = iron intake – iron removed Iron intake data –From SCD patients: 0.22–0.23 mg/kg/d 2 –From thalassaemia patients: 0.39 mg/kg/d 1 1. Cappellini MD, et al. Blood. 2006;107:3455. 2. Vichinsky E, et al. Br J Haematol. 2007;136:501.

14. 14 Consequences of Iron Overload in Patients with SCD

15. 15 Platt O. In Sickle Cell Disease: Basic Principles and Clinical Practice, Embury SH, eds. New York, NY: Raven Press; 1994. Potential Worsening of Abnormal Membrane Protein Functions Related to Iron Overload and Oxidant Injury

16. 16 Does Iron Overload Have the Same Consequences in Patients with Sickle Cell Disease as in Patients with Thalassaemia?

17. 17 Cardiac Morbidity of Iron Overload SCD vs Thalassaemia Major (TM) SCD (n = 17) TM (n = 19) P Age (y) 17.6 ± 1.315.7 ± 1.4.23 Hepatic iron (mg/g dry weight) 19.3 ± 3.718.4 ± 3.8.997 Ferritin ( ng/mL) 5422 ± 8553648 ± 1378.37 Transfusion duration (y) 9.3 ± 1.312.2 ± 1.5.2 Chelation duration (y) 6.9 ± 1.29.8 ± 1.5.23 T2*, ms 38.1 ± 2.526.1 ± 4.6.005 LV ejection fraction % 71 ± 267 ± 2.14 Wood JC, et al. Blood. 2004;103:1934. T2* = Cardiac MRI relaxation parameter.

18. 18 SCD (n = 199) TM (n = 142) P Age (y) 24.9 ± 13.225.8 ± 8.1NS Transfusion duration (y) 9.9 ± 7.221.5 ± 8.9<.001 Hepatic iron (mg/g dry weight) 21.6 ± 10.419.4 ± 11.4NS Ferritin (ng/mL) 4344 ± 30373601 ± 2351<.001 Growth failure 14/198 (7%)47/142 (33%)<.001 Hypogonadism 7/166 (4%)53/133 (40%)<.001 Diabetes 4/199 (2%)18/141 (13%)<.001 Hypothyroidism 3/199 (1.5%)14/138 (10%)<.001 Any endocrinopathy 25/199 (13%)80/142 (56%)<.001 Duration of chronic transfusion = significant predictor of endocrine failure Fung EB, et al. Br J Haematol. 2006;135:574. Endocrine Morbidity of Iron Overload SCD vs Thalassaemia

19. 19 SCD (n = 43) TM (n = 30) P Age (y) 14.8 ± 1.018.4 ± 2.1NS Transfusion duration (y) 6.0 ± 0.612.2 ± 1.8.002 Ferritin (ng/mL) 2916 ± 2332122 ± 289.04 Hepatic iron (mg/g dry weight) 14.3 ± 1.414.8 ± 2.2NS Viral hepatitis 2%33%<.001 ALT >65 UL 7%37%.003 Abnormal fibrosis score 39%81%.02 Vichinsky E, et al. Am J Hematol. 2005;80:70. Hepatic Morbidity of Iron Overload SCD vs Thalassaemia

20. 20 It is not possible to conclude today that patients with SCD have a different risk of iron-related organ dysfunction than patients with thalassaemia –Low number of studies on patients with SCD transfused for >10 years –The duration of iron exposure seems to play a critical role in this risk –Chronic inflammation may also play a role 1 Prevention of neurologic complications leads 10% of children with SCD to be transfused monthly at young age, 2,3 which is a strong argument to predict that these patients will suffer from iron overload as much as patients with thalassaemia Does Iron Overload Have the Same Consequences in Patients with SCD as in Patients with Thalassaemia? 1. Vichinsky E, et al. Am J Hematol. 2005;80:70. 2. Adams RJ, et al. N Engl J Med. 1998;339:5. 3. Adams RJ, et al. N Engl J Med. 2005;353:2769.

21. 21 Management of Iron Overload in Patients with SCD

22. 22 Diagnosis of Iron Overload in SCD Patients Diagnosis of iron overload not easy to make! Liver biopsy –Invasive technique –Limited predictive value of a single biopsy 1 Ferritin –Ferritin levels influenced by infectious and inflammatory status and eventual liver disease –Ferritin trend may be more valuable Cardiac MRI-T2* –Low cardiac T2* = high cardiac iron 1. Telfer PT, et al. Br J Haematol. 2000;110:971.

23. 23 When to Begin Iron Chelation in SCD Rise in liver iron stores to 7 mg/g dry weight Cumulative transfusion of 120 cc of pure red cells/kg body weight Serum ferritin levels in steady-state >1000 ng/mL (easiest, but may under-or overestimate the iron content) NIH Guideline. The Management of Sickle Cell Disease, 4th ed. 2002.

24. 24 Goals of Iron Chelation Therapy in SCD Maintain iron balance Prevent iron accumulation and iron-mediated cellular injury Porter JB. Am J Hematol. 2007;82:1136.

25. 25 Iron Chelating Agents in SCD Desferrioxamine 1 –Short half-life (0.4 hours) and poor oral bioavailability (<2%) necessitates 8–12 hours subcutaneous infusion 5–7 days per week  Compliance an issue –Urinary and faecal excretion Deferasirox 2 –Long half-life (8–16 hours) and high oral bioavailability (70%) allows once-daily oral dosing –Faecal excretion Deferiprone –Licensed for thalassaemia only, not SCD 1. Desferal (desferrioxamine). International Package Leaflet. Basel, Switzerland; Novartis, 1998. 2. Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006.

26. 26 -10 -8 -6 -4 -2 0 2 4 Deferasirox Deferasirox 5 10 20 30 Desferrioxamine <25 25–35 35–50 ≥50 All doses in mg/kg 4 14 555 2041 1315 Patients (n) Mean Change in LIC ± SD (mg Fe/g dry weight) Deferasirox vs Desferrioxamine in the Treatment of Transfusional Iron Overload in SCD Mean Change in Liver Iron Concentration Vichinsky, et al. Blood. 2005;106:abstr 313. Desferrioxamine LIC = liver iron concentration.

27. 27 -5000 -4000 -3000 -2000 -1000 0 1000 2000 3000 Mean Change in Serum Ferritin ± SD (µg/L) DesferrioxamineDeferasirox 241142 11 10 29 7 Patients (n) Deferasirox* 5 10 20 30 Desferrioxamine* <25 25–35 35–50 ≥50 Deferasirox vs Desferrioxamine in the Treatment of Transfusional Iron Overload in SCD Mean Change in Serum Ferritin * All doses in mg/kg. Vichinsky, et al. Blood. 2005;106:abstr 313.

28. 28 Deferasirox Adverse Effects Generally well tolerated 1 –Mild to moderate transient gastrointestinal disturbance –Rash Renal tolerance –Mild nonprogressive creatinine elevation in patients with normal renal function 1 –Cases of renal insufficiency in postmarketing safety reports, primarily in patients with multiple co-morbidities 2 Hepatic tolerance –Occasional reversible increase in liver transaminase levels in patients with normal hepatic function 1 –Postmarketing reports of hepatic dysfunction 2 Haematologic tolerance –Postmarketing reports of cytopaenia, including agranulocytosis, neutropaenia, and thrombocytopaenia, mostly in patients with pre-existing haematologic disorders 2 1. Vichinsky, et al. Br J Haematol. 2006;136:501. 2. Exjade (deferasirox). Prescribing information. East Hanover, NJ: Novartis Pharmaceutical Corporation, 2007.

29. 29 Patients Eligibility for Deferasirox Treatment For SCD, desferrioxamine must be inadequate or contraindicated 1 Inclusion criteria 2 –>2 years of age –Iron overload from repeated blood transfusion  >20 units of packed red blood cells  Ferritin ≥1000 ng/mL Exclusion criteria 2 –Serum creatinine >ULN –Urinary protein/ creatinine ratio of ≥0.5 confirmed at 2 visits 1. Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006. 2. Vichinsky, et al. Br J Haematol. 2006;136:501.

30. 30 Deferasirox Dosage Dependent on –Iron intake: transfusional rate –Therapeutic goal: decrease or stabilization of iron overload Usual starting dose is 20 mg/kg/d (10–30 mg/kg/d) 1 1. Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006.

31. 31 Deferasirox should not be combined with other iron chelation therapies Monitoring Patients Taking Deferasirox Item to MonitorFrequency Blood intakeOngoing Serum ferritinMonthly with dose adjustment based on 3– to 6-month trends Renal function testsIn duplicate before initiating deferasirox therapy, weekly during the first month; monthly thereafter Liver function testsMonthly during therapy Auditory and ophthalmic testing Before the start of deferasirox therapy; annually thereafter Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006.

32. 32 Conclusions To prevent neurologic complication, more and more patients with SCD are going to be transfused early and regularly Consequences of iron overload in patients with SCD need to be clarified Prevention of iron overload has become an important therapeutic goal for patients with SCD