Sickle Cell Disease in the 21st Century

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Sickle Cell Disease in the 21st Century
James R. Eckman, MD Professor of Hematology,
Oncology, and Medicine Emory University School of
Medicine
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Disclosures
Dr. James Eckman, Personal/Professional
Financial Relationships with Industry
External Industry Relationships Company Name(s) Role
Equity, stock, or options in biomedical industry companies or publishers None
Board of Directors or officer None
Royalties from Emory or from external entity None
Industry funds to Emory for my research None
Other None
Consulting, scientific advisory board,
industry-sponsored CME, expert witness for
company, FDA representative for company,
publishing contract, etc. Does not include
stock in publicly-traded companies in retirement
funds and other pooled investment accounts
managed by others.
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AMERICAN DISCOVERYHerrick JB Arch Intern Med
6517-521, 1910
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OBJECTIVES

• Understand the change in prognosis in sickle cell
  disease
• Define the role of hydroxyurea in patients with
  sickle cell disease
• Understand the unique considerations for
  transfusion in sickle cell disease.

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SICKLE SURVIVALQuinn et al Blood 20101034023
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Improving Survival

• Sergeant et al. Int J Lab Hem 200931585-596.
• Cohort of 106 individuals with Hb SS over the age
  of 60.
• Female age and increased fetal hemoglobin
  associated with survival
• 40 were still alive ages 60 to 87
• Aging associated with decreased frequency of pain
  episodes, more anemia and renal insufficiency

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HYDROXYUREA
8

Van
der
Waerdens test.
Charache et al. N
Engl J
Med 3221317, 1995.
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Hydroxyurea Improves Survival
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Hydroxyurea Improves Survival
10 Year Predicted Survival
Adults 131 treated with Hydroxyurea and 199
usual care for up to 17 years (median 8 verses 5
years)
Group Hydroxyurea No Hydroxyurea P value
Overall 86 65
Hb SS 100 10 lt 0.001
Hb S ßo 87 54 lt0.001
Hb S ß 82 66 0.369
Voskaridou E et al. Blood 2010 115 2354-2363
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Hydroxyurea is Effective

• 312 North Carolina Medicaid enrollees 6/2000
  8/2008, 12 month follow-up
• 35 adherent MPR 80, mean 60
• Adherence associated with
• Reduced SCD hospitalizations (HR 0.65,
  p.03510)
• SCD related ER visits (HR 0.58, p .0079)
• All cause ER visits (HR 0.72, p .0388)
• Pain crisis ER visits (0.66, p .0130)

Candrilli et al. Am. J. Hematol. 201186273-277.
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Hydroxyurea may be Cost Effective
Cost Savings Sickle Related All Causes
Inpatient - 4,403 - 5,286
Ancillary Care - 836 - 1,336
Vaso-occlusive events - 5,793
Total Health Care - 5,329 - 6,529
Candrilli et al. Am. J. Hematol. 201186273-277.
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Hydroxyurea Dosing

• Starting dose 10 mg/kg/day
• Dose is increased by 5 mg/kg/day every 12
  weeks to toxicity or a maximum of 35
  mg/kg/day
• After toxicity, the dose is reduced 2.5
  mg/kg/day after counts recover
• If no further toxicity, this is the
  maximum tolerated dose ( MTD )
• Monitoring q 2 weeks to MTD then q 8 weeks

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Hydroxyurea Toxicity

• Predictable effects on bone marrow
• Increased pigmentation and hair breakage
• Azospermia in males
• Concerns about pregnancy while taking the drug
• No data or scientific basis for use in Hb SC
  disease

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Reasons For TransfusionSickle Cell Anemia

• Physiologic correction of symptomatic anemia
• Reduce the whole blood viscosity
• Suppress production of sickle cells
• Reduction in hemolysis
• Prevention of complications

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COMPLICATIONS OF TRANSFUSION

• Cardiovascular Complications
• Alloimmunization
• Delayed Transfusion Reactions
• Autoimmune Hemolytic Anemia
• Transmission of Infection
• Hepatitis
• Human Immunodeficiency Virus
• Other Agents - CMV, EB
• Bacterial Infections
• Iron Overload

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WHOLE BLOOD VISCOSITY
Erslev in Williams, Beutler, Erslev. Hematology
1990.
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WHOLE BLOOD VISCOSITY
Schmalzer et al. Transfusion 198727228 - 233
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SICKLE CELL DISEASEALLOANTIBODY RESPONSE
Reisner et al. Tissue Antigens 30161, 1987
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ALLOIMMUNIZATION 107 SICKLE CELL PATIENTS
Vichinsky et al. New Engl J Med 3221617, 1990
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ALLOIMMUNIZATION IN SICKLE CELL
Vichinsky et al. New Engl J Med 3221617, 1990
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TRANSFUSION IN SICKLE CELL

• Transfuse C, D, E, Kelly similar units
• Transfuse exclusively with phenotypically
  similar blood after the first alloantibody
• Some advocate phenotypically similar blood
  for all transfusions
• Recruit for blood donation from the African
  American population

Eckman and Reid, Charache, Lubin NIH Pub No.
95-2117, 1995.
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Transfusion Number Inati et al. Blood
2010115(14)2980
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Ferritin in Assessing Iron BurdenAdamiewicz et
al. Blood 2009114(21)4632
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MRI Assessment of LICWood et al. Blood 2005
106 1460-1465
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MAINTENANCE OF LOWER FERRITIN LEVEL PREDICTS
SURVIVAL AT UCLH
1.00
Ferritin lt2500 µ/L on more than two thirds of
occasions
0.75
Ferritin gt2500 µ/L on more than one thirdof
occasions
Survival probability
0.50
0.25
0
0
5
10
15
Years of follow-up
UCLH University College London
Hospital. Porter. Unpublished data.
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EXJADE (DEFERASIROX)A Novel Once-daily Oral
Iron Chelator

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