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Managing Iron Overload in Beta Thalassemia Major: Focus on Cardiac Iron. Ali Taher, MD American University of Beirut Lebanon. Baseline Patient Characteristics. At presentation 22-year-old male patient diagnosed with beta thalassemia major at age 6 months Normal ECG

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managing iron overload in beta thalassemia major focus on cardiac iron

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

Ali Taher, MD

American University of Beirut

Lebanon

baseline patient characteristics
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

treatment history iron chelation therapy
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

DFO = deferoxamine; DFP = deferiprone

oral chelators potential to improve compliance
Oral Chelators: Potential to Improve Compliance
  • ESCALATOR Study (N=237): Compared pt ratings for satisfaction and convenience with prior tx (DFO or DFP) vs deferasirox1

1. Taher A, et al. Acta Haematologica. 2010;123:220-225.

deferasirox therapy
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

ALT = alanine aminotransferase; Cr = creatinine; LIC = liver iron concentration; MRI = magnetic resonance imaging; PRBC = packed red blood cells

iron overload assessment

Increased risk of complications

Increased risk of cardiac disease

Iron Overload Assessment

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. 2003;101:4632-4639. Data from Jensen PD, et al. Blood. 2003;101:91-96. Olivieri NF, Brittenham GM. Blood. 1997;89:739-761.

deferasirox dosing by transfusion requirements and therapeutic goals
Deferasirox Dosing by Transfusion Requirements and Therapeutic Goals

Recommended initial deferasirox dosage

20 mg/kg/d

Starting dosages may also be modified as follows:

Deferasirox dosage

Transfusion requirement

Therapeutic goal

30 mg/kg/d

Reduction of body iron

PRBCs > 14 mL/kg/mo(~4 adult units)

Maintenance of body iron

10 mg/kg/d

PRBCs < 7 mL/kg/mo(~2 adult units)

For patients well managed on DFO, suggested starting dosage may be numerically half DFO dosage, eg:

Deferasirox 20 mg/kg/d

DFO 40 mg/kg/d 5 d/wk

EXJADE® (deferasirox) Basic Prescribing Information. Novartis Pharma AG. National Prescribing Information should be followed.

serum ferritin after 7 mo deferasirox 20 mg kg d
Serum Ferritin After 7 Mo Deferasirox 20 mg/kg/d

Serum Ferritin (μg/L)

Deferasirox 20 mg/kg/d

Months

case study details response to dosage increase
Case Study Details: Response to Dosage Increase
  • Patient’s 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
treatment and assessments serum ferritin over 2 years
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

treatment and assessments serum creatinine and alt over 2 years
Treatment and Assessments:Serum Creatinine and ALT Over 2 Years

Serum Cr ULN

Serum Cr > 33% above baseline

Creatinine (µmol/L)/ALT (U/L)

ALT ULN

DFX 20

DFX 30

DFX 35

Months

improvement in cardiac t2 and lic over 2 years of therapy

DFX 20

DFX 30

DFX 35

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

successful chelation achieved via titration
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
deferasirox 30 mg kg d safety
Deferasirox > 30 mg/kg/d: Safety

Most common drug-related adverse events, as assessed by investigators (observed in > 1 patient after dose escalation to > 30 mg/kg/d)

Taher A, et al. Br J Haematol. 2009;147:752-759.

follow up
Follow-Up
  • At this time, deferasirox treatment was stopped, because serum ferritin levels were < 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 > 1000 µg/L
follow up serum ferritin 500 g l at 2 consecutive visits
Follow-Up: Serum Ferritin < 500 µg/L at 2 Consecutive Visits
  • Prescribing information suggests temporary discontinuation of deferasirox when serum ferritin levels drop to < 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 < 1000 µg/L; titrate to 500 µg/L instead of discontinuing treatment
safety profile in patients who achieved serum ferritin levels 1000 g 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 > 33% above baseline and ULN; most were only marginally > ULN and none were > 2x ULN

All increases were nonprogressive and responded promptly to dose reduction

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

ULN = upper limit of normal

Porter J, et al. Poster presented at ASH 2007 [poster 986].

successful chelation achieved key lessons
Successful Chelation Achieved:Key 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