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Hyperleukocytosis, Pediatric


Basics


Description


Hyperleukocytosis is a total white blood cell (WBC) count of ≥100,000/ Ž ¼L. ‚  

Risk Factors


  • Presentation with hyperleukocytosis depends on the type of leukemia.
  • Percent with hyperleukocytosis
    • Chronic myeloid leukemia (CML) especially in blast crisis ¢ ˆ ¼100%
    • Acute myeloid leukemia (AML) especially in infants 5 " “25%
    • ALL (especially with mediastinal mass) 8 " “13%
  • Factors associated with more severe clinical course:
    • Coagulopathy
    • Metabolic derangements
    • Presentation with clinical evidence of central nervous system (CNS) or pulmonary leukostasis

Alert
Children with trisomy 21 (Down syndrome) have an increased risk of developing transient leukemoid reactions and have an increased risk of developing acute leukemia, more commonly acute lymphoblastic leukemia (ALL). ‚  

Pathophysiology


The primary mechanism for symptoms is leukostasis due to increased viscosity and impaired blood flow. Contributory factors other than number of leukemic cells include their shape and size, which increases viscosity, as well as endothelial cell damage, which further impedes microcirculation. ‚  
  • WBCs lack the concave shape that enables reversible deformability of cellular contents of red blood cells (RBCs) to pass through the microvasculature. As compared to normal WBCs, blasts are much larger with less deformability.
  • Myeloblasts are twice the size of lymphoblasts, which are 25% larger than mature neutrophil granulocytes. Monoblasts are larger than myeloblasts. Aggregates of these large, undeformable cells cannot pass through capillaries.
  • In addition to increased cell-to-cell adhesions, leukemic blast cells have increased adhesion to the damaged endothelium, which promote additional cell aggregates through endothelial toxin and cytokine release.
  • Leukemic cells have a hypersensitive response to cytokines, which may account for clinical leukostasis at lower peripheral blast counts.
  • Leukostasis impairs blood flow and exacerbates hypoxemia; as expected, leukemic blasts have increased oxygen consumption due to a high rate of cell division.

Diagnosis


Differential Diagnosis


  • Hyperleukocytosis occurs primarily secondary to malignancy but may be seen with a leukemoid reaction secondary to infection or physiologic stress.
  • Malignancy
    • ALL
    • AML
    • CML
    • Transient myeloproliferative disorder (TMPD) is primarily associated with Down syndrome
  • Leukemoid reaction
    • Leukemoid reactions are WBC counts more than 50,000/ Ž ¼L and consist of myeloid precursor cells in the peripheral blood at all stages of maturity rather than proliferation of an immature WBC clonal population characteristic of malignancies.
    • Leukemoid reactions reflect a physiologic bone marrow response to cytokine secretion prompted by external stimuli such as infection or inflammation.
    • Nucleated RBCs (also seen in malignancy)

History


  • Symptoms and signs of hyperleukocytosis relate to the organ involved. Clinical evidence of leukostasis is most apparent in the CNS, lungs, retina, and penis.
  • CNS
    • Headache
    • Confusion
    • Blurred vision
    • Tinnitus
    • Paresis
    • Nausea/vomiting
  • Pulmonary
    • Dyspnea
    • Shortness of breath
    • Chest pain
  • Genitourinary (males)
    • Anuria/oliguria
    • Erection
  • Retina
    • Decreased visual acuity

Physical Exam


  • CNS
    • Coma
    • Somnolence
    • Altered mental status
    • Agitation
    • Seizures
    • Papilledema
    • Sluggish pupils
  • Pulmonary
    • Hypoxia
    • Tachypnea
  • Hematologic
    • Hemorrhage
    • Thrombosis
  • Reticuloendothelial system
    • Hepatomegaly
    • Splenomegaly
    • Enlarged lymph nodes
  • Genitourinary (males)
    • Priapism

Alert
  • Symptomatic hyperleukocytosis as a result of leukostasis represents an oncologic emergency.
  • Confused and/or hypoxic patients are at risk for severe late effects or death and require emergent intervention.

Diagnostic Tests & Interpretation


Lab
  • Peripheral blood analysis with morphology and flow cytometry aid in immediate diagnosis of acute leukemia.
  • Evaluate other cell lines. Concurrent presence of anemia and/or thrombocytopenia supports an underlying marrow disorder and may require inventions such as transfusions.
  • Tumor lysis laboratory evaluation includes the following:
    • Electrolytes
    • BUN, creatinine
    • Calcium
    • Phosphorous
    • Magnesium
    • Lactate dehydrogenase (LDH)
    • Uric acid

Alert
  • Confirm presence of leukemic blasts. Automated counting machines may mistake leukemic blasts for atypical/reactive lymphocytes or even monocytes.
  • Confirmation may require a manual differential and a pathologist or oncologist to review the peripheral smear.

Imaging
  • Obtain CXR, even if asymptomatic.
    • Evaluate for mediastinal mass.
    • Evaluate for pulmonary infiltrates.
  • If clinically indicated, obtain MRI or CT.

Procedures
Bone marrow aspirate may be required per clinical trial criteria, which includes cytogenetics for future prognostic/therapeutic decision making. ‚  

Treatment


  • The goal of treatment is to quickly make a correct diagnosis and implement definitive therapy while simultaneously identifying and addressing the potential complications of leukostasis secondary to hyperleukocytosis.
  • Leukoreduction refers to interventions that result in a rapid decline of the WBC. Leukoreduction is an absolute indication if a patient shows symptoms or signs of leukostasis. It is a relative indication in an asymptomatic patient with a WBC count ≥100,000 " “300,000/ Ž ¼L (depending on type of leukemia). Controversy exists about its impact on decreasing morbidity, risk of CNS hemorrhage, or mortality.
  • Induction chemotherapy
    • This is the definitive therapy for hyperleukocytosis secondary to malignancy.
    • Initiate chemotherapy as soon as malignant diagnosis is confirmed.
  • Management
    • Aggressive hydration at 2 " “4 ƒ — maintenance
    • Identify and correct metabolic abnormalities.
      • Tumor lysis syndrome
      • Hyperuricemia, indication for rasburicase
    • Identify and correct coagulopathies.
    • Transfuse for cytopenias.
      • Do not transfuse packed RBCs if hemodynamically stable due to increased blood viscosity.
      • Do not exceed hemoglobin 10 g/dL.
      • Transfuse platelets to maintain platelets >10,000/ Ž ¼L; will not affect blood viscosity
  • Cytoreduction
    • Leukapheresis
      • Benefit: Each pheresis session decreases the circulating WBC count by 20 " “50%. During pheresis, FFP may be administered to reduce risk of hemorrhage.
      • Limitation: availability of equipment, trained personnel, and anticoagulation
      • Caution: Leukapheresis only transiently decreases blast counts until definitive treatment can be initiated.
    • Exchange transfusion, including partial
      • Benefit: This technique is preferred over leukapheresis when (1) patient is an infant or <10 kg and (2) there is concurrent severe anemia and/or (3) need for concurrent administration of coagulation factors (i.e., FFP to treat CNS hemorrhage). Partial exchanges minimize volume overload and hyperviscosity.
      • Limitation: higher risk of infection
      • Caution: Patients are at high risk for tumor lysis syndrome (TLS).
    • Hydroxyurea (HU)
      • Mechanism of action: This antimetabolite inhibits ribonucleoside diphosphate reductase, which halts cells in the G1 phase and interferes with DNA repair.
      • Dose: 20 " “30 mg/kg/day
      • Benefit: HU is an oral medication and easily administered. It may be dissolved in water for NGT/OGT administration. Time to peak onset is only 1 " “4 hours.
      • Caution: may also worsen thrombocytopenia

Issues for Referral


Obtain immediate oncology consult. ‚  

Ongoing Care


Prognosis


  • Patients usually require treatment in a pediatric intensive care unit because they require rapid and continuous monitoring at presentation and during early phase of therapy due to complications of leukostasis and TLS.
  • Presence of organ failure or coagulopathy correlates with poor prognosis, specifically death, during induction chemotherapy, despite supportive care.

Alert
  • Early deaths are primarily due to intracranial and pulmonary complications.
  • Coagulopathy are most common in AML patients, in particular M3 or M4 subtypes.
  • The CNS and lungs are the two most common organs damaged by leukostasis.

Additional Reading


  • Blum ‚  W, Porcu ‚  P. Therapeutic apheresis in hyperleukocytosis and hyperviscosity syndrome. Semin Thromb Hemost.  2007;33(4):350 " “354. ‚  [View Abstract]
  • Jain ‚  R, Bansal ‚  D, Marwaha ‚  RK. Hyperleukocytosis: emergency management. Indian J Pediatr.  2013;80(2):144 " “148. ‚  [View Abstract]
  • Majhail ‚  N, Lichtin ‚  A. Acute leukemia with a very high leukocyte count: confronting a medical emergency. Cleveland Clin J Med.  2004;71(8):633 " “637. ‚  [View Abstract]
  • Porcu ‚  P, Cripe ‚  L, Ng ‚  EW, et al. Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management. Leuk Lymphoma.  2009;39(1 " “2):1 " “18. ‚  [View Abstract]
  • Sung ‚  L, Aplenc ‚  R, Alonzo ‚  TA, et al. Predictors and short-term outcomes of hyperleukocytosis in children with acute myeloid leukemia: a report from the Children 's Oncology Group. Haematologica.  2012;97(11):1770 " “1773.

Codes


ICD09


  • 288.60 Leukocytosis, unspecified
  • 204.00 Acute lymphoid leukemia, without mention of having achieved remission
  • 205.10 Chronic myeloid leukemia, without mention of having achieved remission
  • 205.00 Acute myeloid leukemia, without mention of having achieved remission

ICD10


  • D72.829 Elevated white blood cell count, unspecified
  • C91.00 Acute lymphoblastic leukemia not having achieved remission
  • C92.10 Chronic myeloid leukemia, BCR/ABL-positive, not having achieved remission
  • C92.00 Acute myeloblastic leukemia, not having achieved remission

SNOMED


  • 111583006 Leukocytosis (disorder)
  • 91857003 Acute lymphoid leukemia, disease (disorder)
  • 92818009 chronic myeloid leukemia, disease (disorder)
  • 91861009 Acute myeloid leukemia, disease (disorder)

FAQ


  • Q: Is there a linear relationship between the WBC count and the presence/severity of clinical disease and complications?
  • A: No. Clinically significant hyperleukocytosis usually occurs at WBC ≥200,000/ Ž ¼L or ≥300,000/ Ž ¼L in patients with AML or ALL and CML in blast crisis, respectively; however, symptoms may present with a WBC as low as 50,000/ Ž ¼L.
  • Q: Is there a linear correlation between the WBC count and presence of TLS?
  • A: Yes. Risk increases as the tumor burden increases. With high WBC counts and rapid cell turnover, the lysis/death of malignant cells release by-products, leading to electrolyte and metabolic abnormalities known as TLS. TLS is more common in ALL patients as compared to AML or CML. Components of TLS include hyperkalemia, hyperphosphatemia, hyperuricemia and hyperuricosuria, and hypocalcemia.
  • Q: Because transfusions for other cytopenias increase total blood viscosity, what are the current guidelines for transfusions?
  • A: For anemia, if hemodynamically unstable, transfuse to maintain hemoglobin 8 " “9 g/dL. Do not exceed hemoglobin levels >10 g/dL as increasing hematocrit increases blood viscosity. For thrombocytopenia, transfuse to maintain platelet >20,000/ Ž ¼L because platelet transfusions minimally increases blood viscosity. If CNS hemorrhage is present, maintain platelets at 75,000 " “100,000/ Ž ¼L.
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