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Rash and Low T2* MRI in a Paediatric Thalassaemia

Patient

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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

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8–14

Thresholds for Parameters Used to Evaluate Iron Overload

>250<250Alanine aminotransferase (U/L)

>0.40–0.4Labile plasma iron (μM)

<1.2LIC (mg Fe/g dw)

>5020–50Transferrin saturation (%)

SevereModerateMild

>20T2* (ms)

<300 Serum ferritin (ng/mL)

Iron Overloaded StateNormalParameter

>7 3–7

>1000 to <2500

Increased risk of complications

>15

<8

>2500

Increased risk of cardiac disease

Courtesy of A. Taher, MD.

14–20

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Response to DesferrioxamineBaseline Results

Parameter Value

Serum ferritin 3940 ng/mL

LIC 16.7 mg/g dry weight

T2* 10.6 msa

aIndicating cardiac iron prevalence

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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

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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

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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, respectivelya

– 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

aStudy 107Cappellini MD, et al. Blood. 2006;107:3455-3462.

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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

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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

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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.

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Response to Treatment

• Serum ferritin levels decreased steadily over next 3 years to <500 ng/mL

• Liver iron concentration decreased to5.0 mg/g dry weight

• T2* readings increased steadily, from 10.6 ms to 17.0 ms

• Patient then received a successful bone marrow transplant

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Dose Adjustmentsand Serum Ferritin Levels

0

5

10

15

20

25

30

35

40

1 4 7 10 13 17 23 26 29

0

500

1000

1500

2000

2500

3000

3500

4000

4500Serum ferritin levels during treatment with deferasirox

Month

Def

eras

iro

x D

ose

(m

g/k

g/d

)

Ser

um

Fer

riti

n (

ng

/mL

)

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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