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Mariane de Montalembert, MD

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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


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