What is the treatment approach for a patient at risk of or diagnosed with tumor lysis syndrome (TLS), particularly those with high-grade hematologic malignancies?

Treatment of Tumor Lysis Syndrome

High-risk patients with high-grade hematologic malignancies should receive aggressive IV hydration plus rasburicase 0.20 mg/kg/day IV over 30 minutes for 3-5 days in an inpatient setting, while low-risk patients require hydration (≥2 L/m²/day) plus oral allopurinol 100 mg/m² three times daily (maximum 800 mg/day). 1, 2

Risk Stratification: The Critical First Step

Before initiating any treatment, you must stratify TLS risk based on three categories of factors:

Disease-Related High-Risk Features:

• Burkitt's lymphoma and B-cell ALL (26.4% TLS rate) represent the absolute highest-risk malignancies 2
• AML with WBC > 100 × 10⁹/L (83% mortality if clinical TLS develops versus 24% without TLS) 2
• High-grade lymphomas, particularly T-cell lymphoblastic NHL 2
• Bulky disease with elevated LDH >2 times upper normal limit 2
• Extensive bone marrow involvement 2

Host-Related High-Risk Features:

• Pre-existing renal impairment (creatinine ≥1.5 times upper normal limit or creatinine clearance <60 mL/min) 1, 2
• Baseline hyperuricemia (>8 mg/dL in adults, >10 mg/dL in children) 2
• Dehydration, hyponatremia, or obstructive uropathy 3, 2

Pre-Treatment Evaluation: Mandatory Baseline Assessment

Before starting any anticancer therapy, obtain:

• Creatinine clearance or estimated GFR 2
• Serum uric acid, potassium, phosphate, calcium 2
• Serum LDH 2
• Renal ultrasound in all patients undergoing chemotherapy 2
• G6PD screening is mandatory before rasburicase administration (contraindicated in G6PD deficiency due to risk of life-threatening hemolysis and methemoglobinemia) 1

Treatment Algorithm Based on Risk Level

High-Risk Patients: Aggressive Prophylaxis Required

Initiate immediately, ideally 48 hours before chemotherapy:

• Aggressive IV hydration at 3 L/m²/day through central venous access to maintain urine output ≥100 mL/hour in adults or 3 mL/kg/hour in children <10 kg 2, 4
• Rasburicase 0.20 mg/kg/day IV over 30 minutes for 3-5 days 1, 2, 5
• The first rasburicase dose must be given at least 4 hours before starting chemotherapy 1
• After completing rasburicase (days 3-5), transition to oral allopurinol 1

Critical Safety Point: Never administer rasburicase and allopurinol concurrently—this causes xanthine accumulation (lower solubility than uric acid) and eliminates rasburicase's substrate, potentially causing xanthine crystal deposition in renal tubules and acute obstructive uropathy 1, 2

Rasburicase Contraindications (Absolute):

• G6PD deficiency 1, 5
• History of anaphylaxis to rasburicase 1
• Methemoglobinemia or hemolytic reactions 1
• Pregnancy and lactation 1

Intermediate-Risk Patients

Initiate 48 hours before chemotherapy when possible:

• Aggressive IV hydration at 3 L/m²/day 2
• Either allopurinol 100 mg/m² three times daily (maximum 800 mg/day) OR rasburicase 0.20 mg/kg/day 1, 2
• The choice depends on baseline uric acid levels and renal function 2

Low-Risk Patients

Standard prophylaxis:

• Vigorous hydration ≥2 L/m²/day 1, 2
• Oral allopurinol 100 mg/m² three times daily (maximum 800 mg/day) 1, 2
• Start 1-2 days before chemotherapy and continue for 3-7 days afterward 1

Allopurinol Dosing Caveat: Reduce dose by 50% or more in renal insufficiency, as allopurinol and its metabolites accumulate renally 1

Mechanism of Action: Why These Agents Work

Rasburicase converts existing uric acid to allantoin (5-10 times more soluble than uric acid), providing immediate reduction of pre-existing hyperuricemia with median time to uric acid control of 4 hours 1, 2. In pooled analyses, 92% of patients maintained uric acid control by 4 hours, and 100% by 96 hours 5. Among patients with baseline uric acid ≥8 mg/dL, the median decrease was 9.1 mg/dL by 4 hours after the first dose 5.

Allopurinol blocks xanthine oxidase enzyme activity, preventing conversion of xanthine and hypoxanthine to uric acid, but does not reduce existing uric acid levels 1, 4. Time to uric acid control with allopurinol alone is 27 hours versus 4 hours for rasburicase 1.

Treatment of Established TLS: Immediate Intervention Required

If clinical TLS develops or laboratory TLS worsens despite prophylaxis:

• Admit to inpatient setting with continuous monitoring 2
• Aggressive IV hydration at 3 L/m²/day through central venous access 2
• Rasburicase 0.20 mg/kg/day IV immediately (even if patient was on allopurinol—stop allopurinol first) 2, 4
• Loop diuretics (furosemide) to maintain urine output, but only after confirming adequate hydration and ruling out obstructive uropathy 2, 4

Do NOT use urine alkalinization—it increases calcium phosphate precipitation risk without improving outcomes 4

Electrolyte Management: Specific Interventions

Hyperkalemia Management:

• Mild (<6 mmol/L, asymptomatic): Hydration, loop diuretics, sodium polystyrene 1 g/kg orally or by enema 4
• Severe (≥6 mmol/L): Immediate intervention required:
  • Insulin 0.1 units/kg plus 25% dextrose 2 mL/kg 4
  • Calcium carbonate 100-200 mg/kg/dose to stabilize myocardial membranes 4
  • Sodium bicarbonate to correct acidosis 4
  • Continuous ECG monitoring is mandatory 2, 4

Monitoring Protocol: Frequency Matters

High-Risk Patients (prophylaxis):

• Every 12 hours for first 3 days, then every 24 hours 2, 4
• Monitor: vital signs, uric acid, potassium, phosphorus, calcium, creatinine, BUN, LDH, urine output 2, 4

Established TLS:

• Every 6 hours for first 24 hours, then daily 2
• Same parameters as above 2

Critical Laboratory Handling: Place blood samples immediately on ice to prevent continued ex vivo enzymatic degradation by rasburicase, which falsely lowers measured uric acid levels 1

Indications for Renal Replacement Therapy

Initiate dialysis for:

• Severe oliguria or anuria unresponsive to medical management 2, 4
• Persistent hyperkalemia despite medical therapy 2, 4
• Hyperphosphatemia with symptomatic hypocalcemia 2, 4
• Hyperuricemia not responding to rasburicase 2, 4
• Severe volume overload or symptomatic uremia 2, 4

Hemodialysis effectively removes uric acid (clearance 70-100 mL/min) with plasma uric acid falling approximately 50% per 6-hour treatment 2

Common Pitfalls to Avoid

The concurrent allopurinol-rasburicase error: This is the most dangerous mistake—administering both agents simultaneously causes xanthine accumulation and potential xanthine nephropathy 1, 2. Always stop allopurinol before starting rasburicase, and only restart allopurinol after completing rasburicase therapy (typically day 3-5) 1.

Failure to screen for G6PD deficiency: Rasburicase causes life-threatening hemolysis in G6PD-deficient patients—this screening is mandatory before first dose 1, 5.

Inadequate hydration before diuretics: Loop diuretics worsen outcomes if given to hypovolemic patients or those with obstructive uropathy—confirm adequate hydration first 2, 4.

Underestimating solid tumor TLS risk: The TLS-related fatality rate is surprisingly high (nearly 35%) in adults with solid tumors compared to hematologic malignancies, likely due to delayed prophylaxis initiation 3.