1. Mariane de Montalembert, MD
Adjusting Chelator Dose in Response to Adverse Events in a Patient with Sickle Cell Disease
Mariane de Montalembert, MD
Service de Pédiatrie Hospital Necker Paris, France 1

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 2 2

3. Decision Point 1 What Is the Best Next Step?
a. Transfusion
CORRECT: Chronic transfusion can decrease the incidence of VOC and ACS
b. Bone marrow transplant
INCORRECT: The patient has no sibling to serve as a potential donor
c. Increase dosage of hydroxyurea
INCORRECT: Hydroxurea dosage >35 mg/kg/d is not recommended

4. Standard Care (n = 65) vs Transfusion (n = 59)
Impact of Chronic Transfusion on Incidence of Pain and ACS in Compliant Patients STOP Trial
Standard Care (n = 65) vs Transfusion (n = 59)
ACS Events/ 100 PY
Standard care
15.7
Transfusion
2.2a
Pain Events/ 100 PY
Standard care
27.1
Transfusion
9.7b
aP = .0001; bP = Abbreviations: ACS, acute chest syndrome; PY, patient-years; STOP, Stroke Prevention Trial. Miller ST, et al. J Pediatr. 2001;139:

5. 1 Year After Start of Transfusions
Case Continues
Monthly transfusions initiated
15 mL/kg/packed red blood cells
Routine monitoring of haemoglobin and serum ferritin levels
Laboratory Data
Test
Result
Reference Range
Baseline
1 Year After Start of Transfusions
Haemoglobin
7.5 g/dL
7.9 g/dL
13.6–18.0 g/dL
Ferritin, serum
160 ng/mL
1300 ng/mL
24–273 ng/mL 5 5

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 6 6

7. Frequency of Adverse Effects of Deferasirox Treatmenta
Frequency (% patients)
Observations
Nonprogressive increase in serum creatinine 36
Mild, mostly within normal range; dose dependent, often resolves spontaneously; may sometimes be alleviated by dose reduction
GI disturbance (nausea, vomiting, diarrhaea, abdominal pain) 26
Dose-dependent, mostly mild to moderate, generally transient and self-limiting, even with continued therapy
Skin rash 7
Dose-dependent, mostly mild to moderate, generally transient and self-limiting with continued therapy
Elevation in liver transaminases 2
Most patients had elevated levels prior to deferasirox treatment
Elevations >10 x ULN were uncommon (0.3%)
High-frequency hearing loss and lenticular opacities ≤1
Uncommonly observed with patients taking deferasirox
aNational Prescribing Information should be followed. Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; Graphic courtesy of Dr. Mariane de Montalembert.

8. Decision Point 2 What Is the Best Next Step?
a. Continue deferasirox at same dose and apply over-the-counter steroid creme
INCORRECT: Inconsistent with guidelines for product use
b. Stop deferasirox until rash resolves, then restart
CORRECT: Consistent with guidelines for product use
c. Reduce deferasirox dose until rash resolves

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

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. At 1 Year After Start of Treatment
Case Continues
After 1 year of treatment, patient’s hepatic enzyme levels increase
Laboratory Data
Test
Result
Reference Range
At Start of Treatment
At 1 Year After Start of Treatment
ALT
100 U/L
330 U/L
7–40 U/L
AST
80 U/L
250 U/L
9–40 U/L
Bilirubin
29 mg/dL
30 mg/dL
0–17 mg/dL
Alkaline phosphatase
212 U/L
264 U/L
125–410 U/L 11 11

12. Decision Point 3 What Is the Best Next Step?
a. Increase deferasirox dosage
INCORRECT: Sudden hepatic cytolysis, evidenced by increased recent laboratory findings, is likely unrelated to iron overload
b. Stop deferasirox
CORRECT: Hepatic cytolysis may be an adverse event of deferasirox
c. Look for other causes of cytolysis, such as viral infection
CORRECT: Hepatic cytolysis may be caused by a viral infection

13. Frequency of Adverse Effects of Deferasirox Treatmenta
Frequency (% patients)
Observations
Nonprogressive increase in serum creatinine 36
Mild, mostly within normal range; dose dependent, often resolves spontaneously; may sometimes be alleviated by dose reduction
GI disturbance (nausea, vomiting, diarrhaea, abdominal pain) 26
Dose-dependent, mostly mild to moderate, generally transient and self-limiting, even with continued therapy
Skin rash 7
Dose-dependent, mostly mild to moderate, generally transient and self-limiting with continued therapy
Elevation in liver transaminases 2
Most patients had elevated levels prior to deferasirox treatment
Elevations >10 x ULN were uncommon (0.3%)
High-frequency hearing loss and lenticular opacities
≤ 1
Uncommonly observed with patients taking deferasirox
aNational Prescribing Information should be followed. Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; 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 Test
Results
Reference Range
Baseline
1 Year After Start of Deferasirox
2 Years After Start of Deferasirox
Creatinine
urine (mmol/L)
7.3
4.2
10.3
2.5–19
Creatinine clearance (mL/min)
110
120
>90
Total protein (g/L)
.082
.047
.117
<.15 g/L
Total protein/creatinine
ratio
.10
<.50 16 16

17. Case Continues Evolution of Urinary Markers of Renal Function Test
Results
Reference Range
Baseline
1 Year After Start of Deferasirox
2 Years After Start of Deferasirox
Creatinine
urine (mmol/L)
7.3
4.2
10.3
2.5–19
Creatinine clearance (mL/min)
110
120
>90
Total protein (g/L)
.082
.047
.117
<.15 g/L
Total protein/creatinine
ratio
.10
<.50 17 17

18. Decision Point 4 What Is the Best Next Step?
a. Discontinue chelator
INCORRECT: This action not warranted by urinary parameters
b. Decrease chelator dose
c. Maintain chelator dose
CORRECT: No significant proteinuria (urinary protein/creatinine ratio <.5) AND no increase of serum creatinine by >33% or decrease of creatinine clearance to <90 mL/min

19. 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
At 2 consecutive visits
Dose reduction
By 5–10 mg/kg in all cases
aNational Prescribing Information should be followed. Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; 2006.

20. Monitoring Patients Taking Deferasirox
Item to Monitor
Frequency
Blood intake
Ongoing
Serum ferritin
Monthly with dose adjustment based on 3- to 6-month trends
Renal function tests
In duplicate before initiating deferasirox therapy; weekly during the first month; monthly thereafter
Liver function tests
Every 2 weeks in the first month
then monthly during therapy
Auditory and ophthalmic testing
Before the start of deferasirox therapy; annually thereafter
Deferasirox should not be combined with other iron chelation therapies
Exjade [PI]. West Sussex, UK: Novartis Europharm Ltd; 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 21 21