What is the management of hyperleukocytosis in pediatric patients?

Management of Hyperleukocytosis in Pediatric Patients

Pediatric patients with hyperleukocytosis (WBC >100 × 10⁹/L) should be immediately started on aggressive intravenous hyperhydration (2.5-3 liters/m²/day) titrated to fluid balance and clinical status, combined with hydroxyurea (25-50 mg/kg/day in 2-3 divided doses), with leukapheresis or exchange transfusion reserved for emergency organ-threatening leukostasis (cerebral, pulmonary, or priapism). 1

Pathophysiology and Risk Stratification

Hyperleukocytosis causes life-threatening complications through distinct mechanisms:

• Rheological problems: Increased blood viscosity from excessive white cells leads to microvascular occlusion 1
• Intravascular micro-thrombosis: Despite high WBC counts, paradoxical thrombotic events occur 1
• Hemorrhage risk: Bleeding can occur despite normal or elevated platelet counts, particularly from acquired von Willebrand syndrome in patients with thrombocytosis 1
• Metabolic derangements: Tumor lysis syndrome from rapid cell turnover 1

Critical distinction by leukemia type: In acute myeloid leukemia (AML), particularly monocytic/myelomonocytic subtypes (FAB M4/M5), hyperleukocytosis carries significantly higher early mortality (23% vs 5% in ALL) due to intracerebral hemorrhage and pulmonary leukostasis 1, 2. In chronic myeloid leukemia (CML), despite median WBC counts of 240,000/µL in children, leukostasis occurs in only 16.5% of cases 1.

Immediate Management Algorithm

Step 1: Assess for Life-Threatening Complications

Organ-threatening leukostasis (requires emergency cytoreduction):

• Cerebral leukostasis: altered mental status, seizures, focal neurological deficits 1
• Pulmonary leukostasis: respiratory distress, hypoxemia, diffuse infiltrates 1
• Priapism in boys: painful sustained erection (occurs in 2.5-3.3% of boys with CML) 1

If any organ-threatening leukostasis is present: Proceed immediately to leukapheresis or exchange transfusion while simultaneously initiating other measures 1, 3

Step 2: Initiate Supportive Care

For all patients with hyperleukocytosis (WBC >100 × 10⁹/L):

• Intravenous hyperhydration: 2.5-3 liters/m²/day, titrated to fluid balance, clinical status, and WBC count 1
• Hydroxyurea: 25-50 mg/kg/day in 2-3 divided doses (achieves 50% WBC reduction in 1-2 weeks) 1
• Monitor for tumor lysis syndrome: Check uric acid, LDH, potassium, phosphate, calcium 1, 3

For patients without hyperleukocytosis or leukostasis:

• Oral hydration is sufficient 1

Step 3: Tumor Lysis Syndrome Prevention

Allopurinol indications (rasburicase NOT routinely needed):

• Deranged TLS parameters at presentation 1
• Increased plasma uric acid after starting cytoreductive therapy 1
• Note: TLS is rare in pediatric CML-CP; hydration alone is usually sufficient 1

In AML with hyperleukocytosis: Rasburicase may be necessary with careful monitoring 1. However, recent data show that when resources are limited, rasburicase should be reserved for patients presenting with or developing hyperuricemia and/or renal dysfunction 4.

Step 4: Cytoreduction Strategy Based on Clinical Urgency

Emergency cytoreduction (for organ-threatening leukostasis):

• Leukapheresis or exchange transfusion: Achieves 30-80% WBC reduction within hours 1
• Exchange transfusion preferred in infants and younger children due to lower blood volume 1, 5
• Critical caveat: Avoid leukapheresis in acute promyelocytic leukemia (APL) due to fatal hemorrhage risk 3
• Potential complications: Bleeding, electrolyte disturbances 1

Faster-acting cytoreduction (for symptomatic leukostasis without organ threat):

• Low-dose cytarabine: 100 mg/m²/day IV (achieves 50% reduction in 3-5 days) 1
• Low-dose cytarabine plus thioguanine: 1 mg/kg/day maximum 40 mg once daily (achieves 50% reduction in 3 days) 1

Standard cytoreduction (for asymptomatic hyperleukocytosis):

• Hydroxyurea: 50 mg/kg/day (achieves 50% reduction in 1-2 weeks) 1
• Tyrosine kinase inhibitors (for CML): Start once Ph chromosome or BCR::ABL1 fusion confirmed (achieves 50% reduction in 1-2 weeks) 1

Step 5: Initiate Definitive Chemotherapy

Do not delay chemotherapy initiation 1. Start induction chemotherapy as soon as diagnosis is confirmed, even while managing hyperleukocytosis 1, 4.

Management of Specific Complications

Priapism (Emergency - 24-48 hour window)

Simultaneous interventions required:

• Rapid leukoreduction: Exchange transfusion or leukapheresis 1
• Urological emergency management: Penile puncture and blood aspiration from cavernous tissue, followed by saline flushing 1
• If detumescence not achieved: Epinephrine injection 1
• Alternative: Dissociative sedation with low-dose ketamine has shown prompt detumescence 1
• Last resort: Spongio-cavernous shunt operation if priapism persists 1

Bleeding Despite Normal/Elevated Platelets

Mechanism: Acquired von Willebrand syndrome (AVWS) in patients with high platelet counts 1

Management:

• Desmopressin for mild bleeding 1
• For severe bleeding: Fresh frozen plasma, von Willebrand factor concentrates, intravenous immunoglobulin, or recombinant factor VIIa 1
• Emergency imaging: Rule out intracerebral hemorrhage if CNS symptoms appear 1
• Definitive treatment: TKI therapy results in AVWS remission within 2-4 weeks 1

Critical caveat: Low-dose aspirin cannot be recommended in children due to Reye syndrome risk and platelet dysfunction 1

Coagulopathy Management

Maintain hemostatic parameters:

• Platelet count: Above 30-50 × 10⁹/L 3
• Fibrinogen: Above 100-150 mg/dL 3

Evidence-Based Outcomes and Caveats

Leukapheresis effectiveness: Marked cytoreduction achieved within 24 hours in all patients without procedure-related adverse events in single-center experience 6. However, the exact impact on short and long-term outcomes requires further multicenter evaluation 6.

Management without leukapheresis: Recent data demonstrate that patients with hyperleukocytosis can be successfully treated without leukapheresis using hyperhydration, allopurinol, strict monitoring, and early chemotherapy initiation 4. In this approach, laboratory TLS developed in 54% of ALL and 77% of AML patients, but no patient required dialysis 4.

Early death risk stratification:

• AML with WBC ≥400,000/µL: Highest risk for cerebral leukostasis/coagulopathy-related early death (7.7%) 4
• ALL with WBC ≥400,000/µL: Increased intracerebral hemorrhage risk even with normal coagulation 2
• WBC >300 × 10⁹/L in ANLL: Significantly increased early death risk 2

Intracerebral hemorrhage: Main cause of early death, especially in patients already presenting with this complication 4. In AML, this occurs in 11% of hyperleukocytosis patients and accounts for most early deaths, usually associated with coagulopathy 2.

Key Clinical Pitfalls to Avoid

• Do not transfuse red blood cells in hyperleukocytosis without concurrent cytoreduction, as this increases blood viscosity and worsens leukostasis 1
• Avoid invasive procedures (central venous catheterization) in severe neutropenia due to hemorrhagic complication risk 3
• Do not use azole antifungals during anthracycline chemotherapy due to drug interactions increasing toxicity 3
• Never delay chemotherapy for cytoreduction procedures; both should proceed simultaneously 1, 4