What are the causes, diagnosis, and management of Tumor Lysis Syndrome (TLS) in patients with leukemia or lymphoma undergoing chemotherapy?

Tumor Lysis Syndrome: Causes, Diagnosis, and Management

Definition and Pathophysiology

Tumor lysis syndrome is a metabolic emergency caused by massive release of intracellular contents (potassium, phosphorus, nucleic acids, proteins) into the bloodstream following rapid tumor cell lysis, leading to hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. 1

The pathophysiologic cascade occurs as follows:

• Released nucleic acids are catabolized through hypoxanthine and xanthine to uric acid by xanthine oxidase, precipitating in renal tubules and causing acute kidney injury 2
• Intracellular potassium floods the circulation, exacerbated by concurrent renal failure that impairs excretion 3
• Phosphate release leads to calcium-phosphate precipitation in tissues, worsening renal injury and causing symptomatic hypocalcemia 3

Diagnostic Criteria

Laboratory TLS requires two or more abnormal metabolic values within 3 days before or 7 days after chemotherapy initiation: 1, 2

• Hyperuricemia: >8 mg/dL in adults and children 3, 2
• Hyperkalemia: ≥6 mmol/L (life-threatening threshold) 3
• Hyperphosphatemia: >1.62 mmol/L 3
• Hypocalcemia: Below normal range 3

Clinical TLS requires laboratory TLS plus one or more of the following complications: 1, 2

• Renal insufficiency (creatinine ≥1.5 times upper normal limit or creatinine clearance <60 mL/min) 2
• Cardiac arrhythmias or sudden death 1
• Seizures 1

Critical distinction: The Cairo-Bishop classification system addresses shortcomings of earlier systems by not requiring a 25% increase from baseline (accounting for pre-existing abnormalities) and extending the timeframe to 3 days before through 7 days after treatment initiation 1

High-Risk Features and Incidence

The highest-risk malignancies are B-cell acute lymphoblastic leukemia (26.4% TLS rate) and Burkitt's lymphoma, followed by acute myeloid leukemia with WBC >100 × 10⁹/L. 2

Risk stratification by malignancy type: 1, 2

• B-ALL: 26.4% TLS development rate
• Burkitt's lymphoma: 8.4% overall, with metabolic abnormalities in 27%
• High-grade NHL: 6.1% TLS rate, though laboratory abnormalities occur in 42%
• AML: 17% overall (12% laboratory TLS, 5% clinical TLS)
• CLL: Lowest risk at 0.33-0.42%

Additional high-risk factors requiring aggressive prophylaxis: 3, 2

• Bulky disease (lymph nodes >5 cm or large tumor burden)
• Elevated LDH >2 times upper normal limit
• WBC count >50,000-100,000/mm³
• Pre-existing renal impairment
• Baseline hyperuricemia (>8 mg/dL in children, >10 mg/dL in adults)

Clinical TLS carries 83% mortality in AML versus 24% in those without TLS, underscoring the critical importance of prevention. 1, 2

Prevention Strategy: Risk-Stratified Approach

High-Risk Patients

Administer rasburicase 0.20 mg/kg/day IV over 30 minutes plus aggressive hydration (3 L/m²/day) in an inpatient setting, starting at least 4 hours before chemotherapy. 1, 2, 4

• Rasburicase achieves uric acid ≤2 mg/dL in 96% of patients within 4 hours 3, 4
• Continue for 3-5 days as needed 2
• Do NOT administer rasburicase concurrently with allopurinol to avoid xanthine accumulation and substrate depletion 2
• Maintain urine output ≥100 mL/hour in adults 3, 2

Intermediate-Risk Patients

Provide aggressive hydration plus either allopurinol 300 mg orally once daily OR rasburicase based on clinical judgment. 1, 2

Low-Risk Patients

Administer oral allopurinol 100 mg/m² three times daily (maximum 800 mg/day) plus vigorous hydration (≥2 L/m²/day). 1, 2

Critical timing: Start aggressive hydration 48 hours before tumor-specific therapy when possible 2

Monitoring Protocol

High-risk patients require laboratory monitoring every 12 hours for the first 3 days, then every 24 hours: 2

• Uric acid, sodium, potassium, phosphorus, calcium
• Creatinine, BUN, LDH
• Vital signs and urine output

Patients with established TLS require intensified monitoring every 6 hours for the first 24 hours, then daily. 2

Hyperkalemic patients require continuous ECG monitoring. 3, 2

Pre-treatment evaluation must include: 2

• Creatinine clearance or estimated GFR
• Baseline electrolytes, uric acid, LDH
• Renal ultrasound in all patients undergoing chemotherapy

Management of Established TLS

Immediate Interventions

All patients with clinical TLS or worsening laboratory TLS should receive rasburicase immediately plus aggressive IV hydration through central venous access. 2

For severe hyperkalemia (≥6 mmol/L), administer sequentially: 3

• Calcium carbonate 100-200 mg/kg/dose IV to stabilize cardiac membranes
• Rapid insulin 0.1 units/kg IV plus 25% dextrose 2 mL/kg IV to shift potassium intracellularly
• Continuous ECG monitoring

For hyperphosphatemia with symptomatic hypocalcemia: 3

• Calcium gluconate 50-100 mg/kg IV over 2-5 minutes

Loop diuretics may be required to maintain urine output, except in obstructive uropathy or hypovolemia. 2

Alkalinization Controversy

Urine alkalinization is NOT recommended. 1 This represents a shift from older practices, as alkalinization can worsen calcium-phosphate precipitation.

Indications for Emergency Hemodialysis

Initiate hemodialysis urgently when: 3, 2

• Oliguria or anuria persists despite aggressive hydration
• Severe refractory hyperkalemia unresponsive to medical management
• Symptomatic hypocalcemia refractory to treatment
• Severe hyperphosphatemia with calcium-phosphate precipitation
• Hyperuricemia unresponsive to rasburicase
• Severe volume overload or symptomatic uremia

Hemodialysis achieves uric acid clearance of 70-100 mL/min, reducing plasma uric acid by approximately 50% with each 6-hour treatment. 3, 2

Critical Safety Considerations

Rasburicase Contraindications and Warnings

Rasburicase is absolutely contraindicated in G6PD deficiency and can cause fatal hemolysis. 4

Screen patients at higher risk for G6PD deficiency (African or Mediterranean ancestry) before starting rasburicase. 4

Additional rasburicase warnings: 4

• Can cause serious and fatal hypersensitivity reactions including anaphylaxis (<1% incidence)
• Can result in methemoglobinemia
• Immediately and permanently discontinue if hemolysis, methemoglobinemia, or severe hypersensitivity occurs
• Indicated only for a single course of treatment (dosing beyond 5 days not recommended)

Laboratory Sample Handling

Rasburicase enzymatically degrades uric acid in blood samples at room temperature, causing falsely low readings. 4

Collect blood samples in pre-chilled tubes containing heparin, immediately immerse in ice water bath, and assay within 4 hours. 4

Special Clinical Scenarios

Spontaneous TLS

TLS can occur spontaneously without chemotherapy in tumors with high proliferative rates (Burkitt's lymphoma, B-ALL) and large tumor burden, though this is rare. 5

Patients with bulky disease should be monitored even before starting treatment, as pre-existing renal dysfunction significantly worsens prognosis 5

Corticosteroid-Induced TLS

Patients receiving dexamethasone for high-grade NHL (particularly Burkitt's or lymphoblastic lymphoma) with bulky disease require TLS prophylaxis. 5

For patients with extremely high tumor load, consider prednisone 100 mg orally for several days as "prephase" treatment before intensive therapy to avoid severe TLS 5

Common Pitfalls to Avoid

• Failing to identify high-risk patients before initiating therapy (including corticosteroids alone) 5
• Inadequate hydration or prophylaxis in high-risk patients 5
• Delaying chemotherapy without addressing TLS risk first (mortality approaches 83% with clinical TLS) 2
• Concurrent administration of allopurinol with rasburicase 2
• Improper blood sample handling leading to falsely low uric acid measurements 4
• Administering rasburicase to patients with G6PD deficiency 4
• Underestimating TLS risk in solid tumors (mortality approaches 35% due to delayed recognition) 3