Dose Titration in a Paediatric Patient with Sickle Cell Disease

1. Dose Titration in a Paediatric Patient with Sickle Cell Disease

2. Background • There is a significant correlation between the number of transfusions a patient receives and the degree of iron overload in sickle cell disease (SCD) that is reflected in organ failure1 • To prevent neurologic complications, 10% of children with SCD begin monthly transfusions at a young age2,3 1. Ballas SK. Semin Hematol. 2001;38:30-36. 2. Adams RJ, et al. N Engl J Med.1998;339:5-11. 3. Adams RJ, et al. N Engl J Med. 2005; 353: 2769-2778.

3. Background • Mild, nonprogressive increases in serum creatinine >33% from baseline (at 2 consecutive visits) have been observed in 36% of patients receiving deferasirox in clinical trials • In most cases (71%), these increases resolved spontaneously; the remainder (29%) required dose adjustment Vichinsky E, et al. Br J Haematol. 2007;136:501-508.

4. Patient Presentation • 9-year-old African-American female patient diagnosed with sickle cell disease at birth • Patient experienced a stroke at 3 years of age and has been receiving transfusions of 1 unit of packed red blood cells per month since this event • Patient has never received chelation therapy • Patient presented with baseline liver iron concentration, assessed using a superconducting quantum interference device (SQUID), of 10.8 mg Fe/g dry weight and serum ferritin of 3210 ng/mL

5. Question Should chelation therapy be initiated atthis point? A. No, not until she is older B. Yes, with desferrioxamine C. Yes, with deferiprone D. Yes, with deferasirox

6. Treatment • Chelation therapy should be initiated • Serum ferritin is above the recommended level of 1,000 ng/mL for initiation of treatment • Deferiprone is not indicated for iron overload in patients with sickle cell disease (SCD) • The need for subcutaneous administration also makes it less suitable for paediatric use than orally administered deferasirox, especially in this patient, who has a fear of needles • Deferasirox is approved for children ≥2 years of age and for patients with SCD

7. Question Deferasirox was initiated at 20 mg/kg/d. After 3 months of treatment, serum ferritin levels remained unchanged at around 3200 ng/mL. What is the next step? A. Continue deferasirox at current dosage B. Increase dosage of deferasirox C. Consider switching to deferiprone

8. Response to Dose Increase • Deferasirox dose was increased to 30 mg/kg/d • 9 months later • Liver iron concentration had decreased from 10.8 to 8.2 mg Fe/g dry weight • Serum ferritin levels had decreased from 3210 to 2560 ng/mL

9. Increase in Serum Creatinine • With increase of deferasirox to 30 mg/kg/d, serum creatinine also increased, exceeding baseline by >33% at 2 consecutive visits • These increases were above the upper limit of normal appropriate for a 9-year-old • Deferasirox dose was therefore reduced to 20 mg/kg/d at month 10

10. Current Status • Patient remains on deferasirox 20 mg/kg/d and serum ferritin levels continue to fall • She has not experienced any further adverse events • Her growth and development are within normal limits

11. Conclusions • In some paediatric patients, 20 mg/kg/d may be sufficient to decrease serum ferritin levels • Deferasirox dose should be reviewed regularly at 3- to 6-month intervals and adjusted according to trends in serum ferritin levels • Increases in serum creatinine >33% above baselinea can be managed by dose reduction of 10 mg/kg/d a And above age-appropriate limit of normal in paediatric patients.