Managing Iron Overload in Beta Thalassemia Major: Focus on Cardiac Iron

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Managing Iron Overload in Beta Thalassemia
Major Focus on Cardiac Iron
Ali Taher, MD American University of
Beirut Lebanon
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Baseline Patient Characteristics

• At presentation
• 22-year-old male patient diagnosed with beta
  thalassemia major at age 6 months
• Normal ECG
• Echocardiography showed LVEF of 70
• No history of hepatitis B
• Hepatitis C-positive by PCR
• Received peg-interferon and ribavirin from March
  2003 until March 2004, after which PCR was
  negative

ECG electrocardiogram LVEF left ventricular
ejection fraction PCR polymerase chain reaction
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Treatment History Iron Chelation Therapy

• Patient transfused for 21 years (since 1983)
  total of 14 blood transfusions/year
• Serum ferritin range 1823-4350 µg/L
• Received calcium and folic acid supplements
• Patient expressed dissatisfaction with burdensome
  subcutaneous regimen
• Was often noncompliant with treatment

Time Period Chelation Regimen
1984-2001 DFO 35-45 mg/kg/d 5x/wk
2001-2004 DFP 100 mg/kg/d (clinical trial)
2004 to mid-2005 DFO 35 mg/kg/d 5x/wk (clinical trial ended)
DFO deferoxamine DFP deferiprone
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Oral Chelators Potential to Improve Compliance
Oral Chelator Dosing Schedule Toxicity Profile
Deferiprone Thrice daily Neutropenia Agranulocytosis
Deferasirox Once daily Nausea, diarrhea

• ESCALATOR Study (N237) Compared pt ratings for
  satisfaction and convenience with prior tx (DFO
  or DFP) vs deferasirox1

Prior Therapy (baseline) Deferasirox (end of study)
Satisfied or very satisfied with therapy 23 91
Therapy convenient or very convenient 22 93
Time lost to therapy for daily activities (mean SD, hrs/month) 30.1 44.2 3.2 8.6
1. Taher A, et al. Acta Haematologica.
2010123220-225.
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Deferasirox Therapy

• Patient was willing to switch to deferasirox
• In year prior to starting deferasirox, patient
  received 14 transfusions, each 2 units PRBC (9530
  mL total) ? 2.3 units PRBC/mo

Baseline Measurement
Serum ferritin 3560 µg/L
LIC by MRI 12.4 mg Fe/g dry wt
Cardiac T2 by MRI 10.6 ms
Serum Cr and ALT Within normal range
ALT alanine aminotransferase Cr creatinine
LIC liver iron concentration MRI magnetic
resonance imaging PRBC packed red blood cells
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Iron Overload Assessment
Parameter Normal Iron-Overloaded State Iron-Overloaded State Iron-Overloaded State
Parameter Normal Mild Moderate Severe
LIC, mg Fe/g dry wt lt 1.2 37 gt 7 gt 15
Serum ferritin µg/L lt 300 gt 1000 to lt 2500 gt 1000 to lt 2500 gt 2500
Transferrin saturation, 2050 gt 50 gt 50 gt 50
T2, ms gt 20 1420 814 lt 8
Alanine aminotransferase, U/L lt 250 gt 250 gt 250 gt 250
Labile iron pool, µM 00.4 gt 0.4 gt 0.4 gt 0.4

• Patient has moderate-to-severe iron overload
  serum ferritin is 3560 µg/L LIC 12.4 mg Fe/g
  dry wt cardiac T2 10.6 ms

Jensen PD, et al. Blood. 20031014632-4639.
Data from Jensen PD, et al. Blood.
200310191-96. Olivieri NF, Brittenham GM.
Blood. 199789739-761.
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Deferasirox Dosing by Transfusion Requirements
and Therapeutic Goals
Starting dosages may also be modified as follows
Transfusion requirement
Therapeutic goal
Deferasirox dosage
30 mg/kg/d
Reduction of body iron
PRBCs gt 14 mL/kg/mo(4 adult units)
Maintenance of body iron
10 mg/kg/d
PRBCs lt 7 mL/kg/mo(2 adult units)
For patients well managed on DFO, suggested
starting dosage may be numerically half DFO
dosage, eg
EXJADE (deferasirox) Basic Prescribing
Information. Novartis Pharma AG. National
Prescribing Information should be followed.
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Serum Ferritin After 7 Mo Deferasirox 20 mg/kg/d
Serum Ferritin (µg/L)
Deferasirox 20 mg/kg/d
Months
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Case Study Details Response to Dosage Increase

• Patients dosage increased to 30 mg/kg/d
• Dosage further increased to 35 mg/kg/d after 4
  months because serum ferritin level was
  relatively unchanged
• Patient continued to receive 2.3 units PRBC/month

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Treatment and Assessments Serum Ferritin Over 2
Years
Serum ferritin levels decreased to 389 µg/L
Serum Ferritin (µg/L)
DFX 20
DFX 30
DFX 35
Months
DFX 20 deferasirox 20 mg/kg/dayDFX 30
deferasirox 30 mg/kg/dayDFX 35 deferasirox 35
mg/kg/day
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Treatment and AssessmentsSerum Creatinine and
ALT Over 2 Years
Serum Cr ULN
Serum Cr gt 33 above baseline
Creatinine (µmol/L)/ALT (U/L)
ALT ULN
DFX 20
DFX 30
DFX 35
Months
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Improvement in Cardiac T2 and LIC Over 2 Years
of Therapy
Cardiac T2 (ms)/LIC (mg Fe/g dry wt)
After 2 years Cardiac T2 improved by
60 LIC improved by 85
April 2005
April 2006
April 2007
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Successful Chelation Achieved Via Titration

• Although patient received deferasirox 20 mg/kg/d
  for almost 7 months, serum ferritin levels
  remained stable
• Dosage was increased to 30 mg/kg/d for 4 months
  and then to 35 mg/kg/d
• Patient did not experience any progressive
  increases in serum creatinine or liver enzyme
  levels

Variable Result After 2 Years Deferasirox Treatment
Serum ferritin Decreased to 389 µg/L
LIC Normalized to 1.3 mg Fe/g dry wt
Cardiac T2 Improved to 17 ms
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Deferasirox gt 30 mg/kg/d Safety
Most common drug-related adverse events, as
assessed by investigators (observed in gt 1
patient after dose escalation to gt 30 mg/kg/d)
Adverse event Frequency, n () Frequency, n ()
Adverse event Before dose escalation After dose escalation
Median exposure (weeks) 115.4 36.1
ALT increase 12 (5.4) 7 (3.1)
Vomiting 17 (7.6) 6 (2.7)
Abdominal pain 15 (6.7) 3 (1.3)
Abdominal pain (upper) 3 (1.3) 3 (1.3)
Nausea 24 (10.7) 3 (1.3)
Serum creatinine increase 13 (5.8) 3 (1.3)
Rash 19 (8.5) 2 (0.9)
Diarrhea 12 (5.4) 2 (0.9)
Taher A, et al. Br J Haematol. 2009147752-759.
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Follow-Up

• At this time, deferasirox treatment was stopped,
  because serum ferritin levels were lt 500 µg/L at
  2 consecutive study visits
• Deferasirox dosage lowered to 0 mg/kg/d as of 18
  May 2007 and later reinitiated when serum
  ferritin rose to gt 1000 µg/L

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Follow-Up Serum Ferritin lt 500 µg/L at 2
Consecutive Visits

• Prescribing information suggests temporary
  discontinuation of deferasirox when serum
  ferritin levels drop to lt 500 µg/L
• However, patient still had
• Continuous transfusion requirement and cardiac
  iron overload (cardiac T2 17 ms)
• No evidence of iron chelator-related toxicity
• Consider decreasing dose when serum ferritin
  levels drop to lt 1000 µg/L titrate to 500 µg/L
  instead of discontinuing treatment

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Safety Profile in Patients Who Achieved Serum
Ferritin Levels 1000 µg/L

• In total, 163 patients (25.0) achieved serum
  ferritin levels 1000 µg/L after a median of 1.2
  years on deferasirox
• Most common drug-related adverse events were
  transient and mild to moderate in severity
• 10 pts (6.1) had 2 consecutive serum creatinine
  increases of gt 33 above baseline and ULN most
  were only marginally gt ULN and none were gt 2x ULN
• All increases were nonprogressive and responded
  promptly to dose reduction

Drug-related adverse event Number of pts ()
Nausea 25 (15.3)
Diarrhea 17 (10.4)
Vomiting 11 (6.7)
Abdominal pain 10 (6.1)
Skin rash 9 (5.5)
ULN upper limit of normal
Porter J, et al. Poster presented at ASH 2007
poster 986.
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Successful Chelation AchievedKey Lessons

• Deferasirox effectively removes iron from the
  blood and organs
• Deferasirox at 30-40 mg/kg/d is effective in
  patients with liver and cardiac iron overload
• Adjustments should be made in steps of 5 or 10
  mg/kg/d andshould be tailored to individual
  patient response and therapeutic goals
  (maintenance or reduction of iron burden)
• Careful dose titration is necessary to avoid
  overchelation however, treatment should not be
  interrupted based on serum ferritin values alone