Leukoreduction Apheresis

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Leukoreduction Apheresis

• MCG Transfusion Medicine On-line
• James Fulcher, MD
• jfulcher_at_mcg.edu

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Case History

• Patient is a 12 year old boy with a 2 week
  history of fatigue and easy bruising
• ER physical exam shows widespread petechiae and
  several large bruises
• WBC in the ER is 180,000/µL but pathologist
  review of smear estimates a WBC of 600,000/µL

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Case History

• Examination of peripheral smear shows 85 blasts
  with very high nucleus/cytoplasm ratios
• Other important presentation data includes
  critically high serum uric acid, elevated lactate
  dehydrogenase, and increased liver enzymes

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Presentation Labs

• Test
  Patient Results Ref. Range
• WBC count, x103/?L (x 109/L) 186
  (186) 3.7-9.4
  (3.7-9.4)
• Hct
  24 37-49
• Platelets x 103/?L (x109/L)
  27(27) 134-357(134-357)
• Uric Acid mg/dL
  14.3
  4.5-8.5
• LDH U/L
  2827
  100-200
• AST U/L
  185
  lt40
• ALT U/L
  107
  lt48
• Alkaline Phosphatase IU/L
  223 20-130
• Protime seconds
  14.2
  10-14

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Presentation Blood Smear
40X
1000X
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Diagnosis and Treatment

• Patient has T-cell (by flow cytometric
  immunophenotype) ALL
• Candidate for leukoreduction apheresis (LRA)
• The patient received 3 apheresis procedures
  occurring on the evening of admission and
  hospital days 2 and 4

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Leukoreduction History

• Each pheresis procedure lasted several hours and
  removed between 589 cc and 465 cc of fluid of
  almost 100 leukemic blasts cells.
• The serial leukoreduction apheresis procedures
  greatly reduced WBC and Chemotherapy was safely
  begun on day 5

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Waste Bags from LRA showing WBC/Blast layer
Day 2
Day 1
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Time Frame of WBC Reduction
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Reduction of LDH and Uric Acid
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Day 5 Blood Smear
40X
40X
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Case Conclusion

• Patient WBC counts were dropped to levels safe
  enough to begin chemotherapy on day 5
• LDH and Uric acid level were also reduced (spike
  in LDH corresponded to start of chemotherapy
• Case illustrates the usefulness of leukoreduction
  apheresis before treatment with chemotherapy

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Leukoreduction Apheresis (LRA)

• The process of removing unwanted WBC or blasts
  from the circulation
• The procedure is indicated for the rapid
  correction of hyperleukocytosis, generally
  defined as a WBC count over 30-50K
• One procedure generally removes between 20-80 of
  WBC by processing 7-10 liters of blood

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The basic LRA Mechanics
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Indications for LRA

• Hyperleukocytosis
• Patients with significant hyperleukocytosis are
  reported in cases of
• acute myelogenous leukemia (AML) 5-25
• acute lymphoid leukemia (ALL) 10-30
• chronic myelogenous leukemia (CML) ?
• chronic lymphoid leukemia (CLL) ?
• chronic monomyelocytic leukemia (CMML) one
  reported case

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Complications of Hyperleukocytosis

• Leukostasis
• Hyperviscosity syndrome
• Tumor Lysis syndrome
• Disseminated intravascular coagulation (DIC)
• The goal of LRA is to reduce the incidence of
  these complications by physically removing blasts
  from the circulation

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Leukostasis

• Clinically significant when pulmonary or nervous
  system vascular blockage occurs causing
  hypoxemia, respiratory distress, and stroke
• Found at lower blast counts in AML (300-450K)
  than ALL (600-800K), this is related to blast
  size and expression of adhesion markers

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Myeloblast Interactions with Vessel Endothelial
Cells

• Myeloblasts have been shown to induce their own
  adhesion by secreting inflammatory cytokines
• Endothelial cells respond to the inflammation by
  releasing adhesion molecules-P/E -selectin,
  VCAM-1, ICAM-2
• This composes a cycle of inflammation and
  adhesion

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Hyperviscosity Syndrome

• Viscosity is the internal sheer force of a
  liquid, it can be thought of as thickness
• Leukocrit between 12-15 mL/dL will cause
  significant increases in viscosity, this is
  dependent on blast size and morphology
• Increased viscosity reduces the proper flow of
  blood in circulation

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Tumor Lysis Syndrome

• Tumor lysis syndrome is the release of
  intracellular chemicals
• Potassium, phosphate are important electrolytes
  that are released
• Potassium should be corrected quickly as fatal
  arrhythmia
• Purine and pyrimidine nucleotides are degraded to
  uric acid- this can damage the kidney

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Disseminated Intravascular Coagulation

• This is related to the release of intracellular
  contents
• There are many interfering substances described
  in hyperleukocytosis that may cause DIC, but few
  studies have been done
• More common presentation in ALL in combination
  with tumor lysis syndrome

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Procedural Complications

• Vascular Access- always better to have a central
  line, but large bore peripheral access can be
  used in emergencies
• Large volume of blood needs to be processed
• Machine must be primed with 250-300 cc of blood,
  important in small infants where is could
  represent their entire blood volume
• 6 hydroxyethyl starch (HES) is used as a red
  cell sedimentation agent, to facilitate blast and
  mature leukocyte removal

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Procedural Issues

• In cases of tumor lysis syndrome, pre-LRA
  treatment should include
• aggressive hydration
• urine alkalization
• allopurinol
• hydroxyurea

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Benefits of LRA in Leukemia

• Physical removal of blasts reduces burden on
  patient as chemotherapy destroys the blasts- LRA
  is an important pre-chemotherapy treatment
• Removal of circulating blasts, draws
  extra-vascular blasts into circulation
• Removal of blasts increases cells in S-phase,
  this improves response to some chemotherapy

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When is LRA Required in Hyperleukocytosis?

• No agreed upon initiation criteria or therapeutic
  goals
• Generally, LRA should be considered above
  peripheral blast counts above 50K
• Reduction of blast count by 30 or below 100K is
  recommended
• Patients should be considered on a case by case
  basis

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Complications/Disadvantages

• Expense
• Technical skill required
• Personal time required
• Citrate toxicity-be wary in small children
• In infants, measure serum Ca every 30-45 minutes
  and possibly start a Ca Drip

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Outcomes with LRA

• Short term survival advantage has been described
  but recent data on treatment with hydration,
  allopurinol, and hydroxyurea show similar
  survival
• No significant long-term survival advantage has
  been reported

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Conclusions

• LRA remains a useful tool in the acute setting of
  hyperleukocytosis
• It will require more studies to establish
  definitive LRA therapy guidelines
• The procedure is not without complications-physici
  ans should treat the patient not the numbers
• New research on molecular interactions between
  myeloblasts and endothelial cells might lead to
  additional treatment options

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Review Question 1

• In which of the following has hyperleukocytosis
  not been described?
• A) Acute Myelogenous Leukemia (AML) FAB type M4
• B) Acute Lymphocytic Leukemia (ALL)
• C) Chronic Lymphocytic Leukemia (CLL)
• D) Chronic Myelogenous Leukemia (CML), Blast
  Crisis
• E) Acute Megakaryocytic Leukemia

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Review Question 2

• 2. What is not a described complication of
  hyperleukocytosis?
• A) Disseminated intravascular coagulation (DIC)
• B) Leukostasis
• C) Renal infract
• D) Tumor lysis syndrome
• E) Hypoxemia

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Review Question 3

• What best describes the role of Hydroxyethyl
  starch (HES) in leukoreduction apheresis (LRA)
  procedures?
• A) Anticoagulant
• B) Erythrocyte sedimentation agent
• C) Alkalinization agent
• D) Leukocyte sedimentation agent
• E) Chelation agent

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Review Question 4

• What is the accepted therapeutic goal for LRA in
  cases of AML hyperleukocytosis?
• A) Reduction of blasts by 30
• B) Reduction of leukocrit to 12-15 ml/dL
• C) Amelioration of leukostasis symptoms
• D) No current consensus
• E) Reduction of WBC count to less than 100,000
  ?/L

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Review Question 5

• What cellular adhesion marker is not known to
  have a role in myeloblast and endothelial cell
  binding?
• A) ICAM-1
• B) P-Selectin
• C) VCAM-1
• D) E-Selectin
• E) E-cadherin

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References available upon request