1 Rash and Low T2* MRI in a Paediatric Thalassaemia Patient

2 Patient Presentation 9 1/2-year-old male patient with  -thalassaemia Patient has been transfused with 1 unit every 3 weeks (0.46 mg/kg/d) since age 1 year At age 3 years, the patient began receiving desferrioxamine and is currently receiving desferrioxamine 40 mg/kg/d –Usually doses > 40 mg/kg/d are not recommended in paediatric patients

3 8–14 Thresholds for Parameters Used to Evaluate Iron Overload >250 <250Alanine aminotransferase (U/L) >0.4 0–0.4Labile plasma iron (μM) <1.2LIC (mg Fe/g dw) >5020–50Transferrin saturation (%) SevereModerateMild >20T2* (ms) <300Serum ferritin (ng/mL) Iron Overloaded State NormalParameter >73–7 >1000 to <2500 Increased risk of complications >15 <8 >2500 Increased risk of cardiac disease Courtesy of A. Taher, MD. 14–20

4 Response to Desferrioxamine Baseline Results ParameterValue Serum ferritin3940 ng/mL LIC16.7 mg/g dry weight T2*10.6 ms a a Indicating cardiac iron prevalence

5 Question What should the next step be? A. Continue on desferrioxamine at current dose B. Increase dose of desferrioxamine to >50 mg/kg/d C. Switch to deferiprone 100 mg/kg/d D. Switch to deferasirox 30 mg/kg/d

6 Choice of Chelator Patient is already on a high dose of desferrioxamine and a higher dose at his age is contraindicated Although deferiprone is approved for patients with thalassaemia when desferrioxamine is inadequate, starting dose is 75 mg/kg/d and doses >100 mg/kg/d are not recommended; TID dosing may pose difficulties for a patient his age Usual starting dose of deferasirox is 20 mg/kg/d, but 10 mg and 30 mg may also be used; once-daily oral administration makes deferasirox attractive for use in children

7 Deferasirox Dosing Recommended starting dose and modifications to treatment with deferasirox are the same in children and adults –In clinical studies, 20 or 30 mg/kg/d resulted in overall maintenance or reduction of liver iron concentration, respectively a –Starting dose of 10 mg/kg/d was not sufficient to achieve a negative iron balance in heavily transfused patients Patient began treatment with deferasirox 30 mg/kg/d a Study 107 Cappellini MD, et al. Blood. 2006;107:

8 Question At 1 month, patient developed a moderate-to-severe skin rash. How should this rash be managed? A.Reduce dose, then gradually increase dose to prior level when rash resolves B. Interrupt drug, then reintroduce at lower level when rash resolves, gradually escalating to target level C. Switch back to desferrioxamine or consider deferiprone

9 Resolution of Rash Drug treatment interrupted due to moderate- to-severe skin rash After 1 week, patient was restarted on reduced drug dose (20 mg/kg/d) and rash resolved After 2 months, dose was successfully increased to 30 mg/kg/d –Minor dose adjustments were made periodically over the next 3 years in response to serum ferritin levels

10 Skin Rash Treatment Algorithm Mild-to-moderate rash can be managed without treatment interruption More serious rash necessitates treatment interruption. Deferasirox should be reintroduced at a lower dosage after rash has resolved, with gradual dose escalation With severe rash, deferasirox should be interrupted, then reintroduced at a lower dose, possibly in combination with an oral steroid, after rash has resolved. Deferasirox dosage can then be gradually increased.

11 Response to Treatment Serum ferritin levels decreased steadily over next 3 years to <500 ng/mL Liver iron concentration decreased to 5.0 mg/g dry weight T2* readings increased steadily, from 10.6 ms to 17.0 ms Patient then received a successful bone marrow transplant

12 Dose Adjustments and Serum Ferritin Levels Serum ferritin levels during treatment with deferasirox Month Deferasirox Dose (mg/kg/d) Serum Ferritin (ng/mL)

13 Conclusions Deferasirox at appropriate doses results in continued reduction in serum ferritin levels Reduced cardiac iron burden in children, as measured by increased T2*, is also achieved with appropriate doses of deferasirox Skin rashes can be managed effectively, in many cases without interruption of treatment –In this patient, dose reduction to 20 mg/kg/d was sufficient for resolution of rash –Dose was then increased again to previous 30 mg/kg/d and serum ferritin levels fell continuously for the next 3 years