Mariane de Montalembert, MD Service de Pédiatrie Hospital Necker Paris, France

1. Mariane de Montalembert, MD Service de PédiatrieHospital NeckerParis, France Adjusting Chelator Dose in Response to Adverse Events in a Patient with Sickle Cell Disease

2. Patient Presentation • 14-year-old boy • Diagnosed through neonatal screening • No siblings • Acute chest syndrome (ACS) at age 2 and 6 years • 2–3 hospitalizations per year for vaso-occlusive crises (VOC) from age 5–7 years • Treatment with hydroxyurea initiated at age 7 years • Initial dosage 15 mg/kg/d • Progressive increase to 25 mg/kg/d • Initial success: no new VOC or ACS from age 7–12 years • ACS and repeated VOC at age 12 years • Progressive increase of dosage of hydroxyurea to 35 mg/kg/d with no subsequent reduction in frequency of pain crises

3. Decision Point 1What Is the Best Next Step?

4. Impact of Chronic Transfusion on Incidence of Pain and ACS in Compliant PatientsSTOP Trial Standard Care (n = 65) vs Transfusion (n = 59) aP = .0001; bP = .014.Abbreviations: ACS, acute chest syndrome; PY, patient-years; STOP, Stroke Prevention Trial.Miller ST, et al. J Pediatr. 2001;139:785-789.

5. Case Continues • Monthly transfusions initiated • 15 mL/kg/packed red blood cells • Routine monitoring of haemoglobin and serum ferritin levels Laboratory Data

6. Case Continues • Chelation therapy started 1 year after the beginning of transfusions • Deferasirox 20 mg/kg/d • Patient develops a rash after 2 weeks of treatment • moderate to severe rash

7. M8.19 Frequency of Adverse Effects of Deferasirox Treatmenta aNational Prescribing Information should be followed.Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; 2006. Graphic courtesy of Dr. Mariane de Montalembert.

8. Decision Point 2What Is the Best Next Step?

9. M8.7 Mild to moderate rash Severe rash • Interrupt treatment • After resolution of rash, reintroduce deferasirox at lower dose • Gradually escalate dose • Interrupt treatment • Reintroduce deferasirox at lower dose after resolution of rash • Gradually escalate dose • Interrupt treatment • After resolution of rash, reintroduce deferasirox at lower dose maybe in combination with oral steroid • Gradually escalate dose Skin Rash–Deferasirox Dose Modification Algorithma Continue treatment without interruption Moderate to severe rash aNational Prescribing Information should be followed. Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; 2006. Graphic courtesy of Dr. Mariane de Montalembert.

10. Case Continues • Deferasirox temporarily stopped • When rash resolved, deferasirox reintroduced at 10 mg/kg/d • After 1 month, dose reincreased up to 20 mg/kg/d, without recurrence of the rash

11. Case Continues • After 1 year of treatment, patient’s hepatic enzyme levels increase Laboratory Data

12. Decision Point 3What Is the Best Next Step?

13. M8.19 Frequency of Adverse Effects of Deferasirox Treatmenta aNational Prescribing Information should be followed.Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; 2006. Graphic courtesy of Dr. Mariane de Montalembert.

14. Managing Liver Function Test Abnormalitiesa 1. Discontinue deferasirox 2. Check for other causes of the liver function test abnormalities 3. When liver function tests return to baseline level, cautiously reintroduce deferasirox at 10 mg/kg/d 4. Check ALT and AST every week for 1 month 5. If no further increase, gradually increase dose to 20 mg/kg/d 6. Check ALT, AST, bilirubin, and alkaline phosphatase monthly aNational Prescribing Information should be followed. Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; 2006.

15. Case Continues • No other cause of abnormal liver function tests found (hepatitis B and C serologies negative, hepatic echo normal) • Deferasirox discontinued • Liver function tests returned to baseline level after 2 weeks • Then, deferasirox cautiously reintroduced at 10 mg/kg/d • ALT and AST checked every week for 1 month with no further increase • Deferasirox gradually increased to 20 mg/kg/d • ALT, AST, bilirubin, and alkaline phosphatase checked monthly

16. Case Continues Evolution of Urinary Markers of Renal Function

17. Case Continues Evolution of Urinary Markers of Renal Function

18. Decision Point 4What Is the Best Next Step?

19. M8.15 At 2 consecutive visits Dose reduction By 5–10 mg/kg in all cases Management of Increases in Serum Creatinine Serum Creatinine Increase in Adult Patients Serum Creatinine Increase in Paediatric Patients Nonprogressive increase of >33% above average of 2 pretreatment measurements and decrease of creatinine clearance to <90 mL/min that cannot be attributed to other cause Nonprogressive increase above age-appropriate ULN and/or decrease of creatinine clearance to <90 mL/min that cannot be attributed to other cause aNational Prescribing Information should be followed.Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; 2006.

20. Monitoring Patients Taking Deferasirox Deferasirox should not be combined with other iron chelation therapies Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; 2006. Graphic courtesy of Dr. Mariane de Montalembert.

21. Conclusion • Prevention of iron overload allows continuation of transfusion and its clinical benefit • Competency in chelation therapy • Knowing when to begin chelation therapy • Knowing when and how to adjust dosage in response to adverse events (eg, GI, rash, alterations in renal function) in order to maintain patients on therapy • Transfusional strategies may vary throughout the world but key principles are consistent