When should allopurinol be initiated for tumour lysis syndrome prophylaxis in intermediate- or high-risk patients, and what are the essential management steps including aggressive hydration, dosing, rasburicase use, electrolyte correction, and renal support?

Tumor Lysis Syndrome: Allopurinol Initiation and Management

When to Initiate Allopurinol

Allopurinol should be reserved for intermediate-risk patients only, started 1-2 days before chemotherapy at 100 mg/m² orally every 8 hours (maximum 800 mg/day), while high-risk patients require rasburicase instead. 1, 2

Risk Stratification Determines Agent Selection

Intermediate-risk patients receive allopurinol prophylaxis combined with aggressive hydration:

• Dose: 100 mg/m² every 8 hours orally (maximum 800 mg/day) or 200-400 mg/m²/day IV in divided doses (maximum 600 mg/day) 1
• Start 1-2 days before chemotherapy and continue for 3-7 days afterward 2
• Reduce dose by ≥50% in renal impairment due to drug and metabolite accumulation 1, 2

High-risk patients require rasburicase as first-line prophylaxis, NOT allopurinol:

• High-risk features include: pre-existing renal impairment (creatinine elevation, malignant infiltration), dehydration or obstructive uropathy, hyperuricemia >8 mg/dL (children) or >10 mg/dL (adults), bulky disease (high-grade lymphoma, Burkitt lymphoma, T-cell lymphoblastic NHL), LDH >2× upper limit of normal, rapidly rising blast counts, or intensive polychemotherapy 2
• Only 2.6% of patients receiving rasburicase required dialysis versus 16% receiving allopurinol in retrospective pediatric data 2

Essential Management Steps

1. Aggressive Hydration (All Risk Levels)

Initiate vigorous IV hydration at least 48 hours before chemotherapy when feasible:

• Pediatric: 2-3 L/m²/day (or 200 mL/kg/day if <10 kg) of quarter-normal saline/5% dextrose 1
• Target urine output: 80-100 mL/m²/h in children (4-6 mL/kg/h if <10 kg) or ≥100 mL/hour in adults 1, 3
• Withhold potassium, calcium, and phosphate from initial hydration fluids due to concurrent risks of hyperkalemia, hyperphosphatemia, and calcium phosphate precipitation 1
• Loop diuretics (not thiazides) may be required to achieve target output if no obstructive uropathy or hypovolemia present 1, 3
• Maintain urine-specific gravity at 1.010 1

2. Rasburicase for High-Risk Patients

Rasburicase dosing and administration:

• 0.20 mg/kg/day IV over 30 minutes for 3-5 days 2, 3
• First dose must be given at least 4 hours before starting chemotherapy 2, 3
• Converts existing uric acid to allantoin (5-10 times more soluble), providing immediate reduction of pre-existing hyperuricemia 2, 4
• Achieves 86% reduction in plasma uric acid within 4 hours 2

Critical contraindications:

• G6PD deficiency (risk of life-threatening hemolysis and methemoglobinemia) 2, 3
• History of anaphylaxis, hypersensitivity reactions, hemolytic reactions, or methemoglobinemia to rasburicase 1, 2
• Pregnancy and lactation 2

3. Drug Sequencing: Never Concurrent Use

Allopurinol and rasburicase must NEVER be administered concurrently:

• Concurrent use causes xanthine accumulation and risk of xanthine crystal deposition in renal tubules leading to acute obstructive uropathy 2
• After completing rasburicase (3-5 days), transition to oral allopurinol 2, 3
• A phase III trial demonstrated rasburicase followed by allopurinol achieved 78% response rate with uric acid control in 4 hours (versus 27 hours for allopurinol alone) 2

4. Electrolyte Correction

Monitor and correct electrolyte abnormalities aggressively:

• Check LDH, uric acid, sodium, potassium, creatinine, BUN, phosphorus, and calcium every 6 hours for first 24 hours, then every 12 hours for first 3 days, then daily until stable 3
• Do NOT correct mild hypocalcemia with calcium gluconate as it increases tissue and renal precipitation of calcium phosphate 3
• Treat hyperkalemia and hyperphosphatemia per standard protocols 1

5. Renal Support Indications

Prepare for potential dialysis in high-risk patients:

• Prophylaxis should be delivered in an inpatient setting with immediate access to dialysis 2
• Coordinate treatment plan with nephrology service before initiating chemotherapy 2
• Consult nephrology before restarting therapy in patients with previous clinical TLS 5

Critical Monitoring Requirements

Place blood samples immediately on ice to prevent continued ex vivo enzymatic degradation by rasburicase, which falsely lowers measured uric acid levels 2

Monitor vital parameters (heart rate, blood pressure, urine output, respiratory rate), serum uric acid, electrolytes, and renal function every 6 hours for first 24 hours, then daily 3

Common Pitfalls to Avoid

• Using allopurinol in high-risk patients: Allopurinol only prevents NEW uric acid formation; it does not reduce pre-existing hyperuricemia and has inferior renal protection compared to rasburicase 2, 6
• Failing to reduce allopurinol dose in renal impairment: Leads to drug accumulation and toxicity 1, 2
• Urine alkalinization is NOT recommended: No unequivocal evidence of efficacy, and it increases risk of calcium phosphate crystal precipitation 1
• Concurrent 6-mercaptopurine or azathioprine: Reduce doses by 65-75% when used with allopurinol due to drug interactions 1
• Premature chemotherapy resumption: Ensure uric acid <8 mg/dL, creatinine <141 μmol/L, pH ≥7.0, and normalized electrolytes before restarting 5

Pre-Treatment Evaluation

Obtain baseline creatinine clearance (or estimated GFR), serum LDH, electrolytes (potassium, phosphorus, calcium), and renal ultrasound in every patient scheduled for chemotherapy 2

Perform mandatory G6PD screening before initiating rasburicase 2