What is the management of Tumor Lysis Syndrome (TLS)?

Management of Tumor Lysis Syndrome

The management of TLS is fundamentally risk-stratified: high-risk patients require rasburicase (0.20 mg/kg/day IV for 3-5 days) plus aggressive hydration in an inpatient setting, while low-risk patients receive oral allopurinol (100 mg/m² three times daily, maximum 800 mg/day) with hydration and close monitoring. 1

Risk Stratification Framework

Before initiating any therapy, patients must be stratified into risk categories based on specific criteria 1:

High-Risk Factors (Any One Present)

Host-related factors:

• Pre-existing renal impairment (including renal infiltration by malignancy) 1
• Dehydration 1
• Obstructive uropathy 1
• Hyperuricemia (>8 mg/dL in children, >10 mg/dL in adults) 1

Disease-related factors:

• Bulky disease (especially bulky SCLC or massive liver metastases) 1
• High-grade lymphomas (particularly Burkitt's lymphoma and T-cell lymphoblastic NHL) 1
• Acute lymphoblastic leukemia in adults or advanced T-cell ALL in pediatric patients 1
• Elevated serum LDH (>2× upper normal limit) 1
• Metastatic germ cell tumors 1

Therapy-related factors:

• Intensive polychemotherapy including cisplatin, cytosine arabinoside, etoposide, or methotrexate 1

Pre-Treatment Evaluation

All patients require the following assessments before starting prophylaxis 1:

• Creatinine clearance or estimated GFR 1
• Serum LDH levels 1
• Renal ultrasound in all patients undergoing chemotherapy 1

Management Algorithm by Risk Category

Low-Risk Patients

Treatment regimen:

• Oral allopurinol 100 mg/m² three times daily (maximum 800 mg/day) 1
• Vigorous hydration (≥2 L/m²/day) 2
• Urine alkalinization 1
• Close monitoring 1

Critical dosing adjustment: Reduce allopurinol dose by 50% or more in patients with renal insufficiency, as the drug and its metabolites accumulate 2

High-Risk Patients

Treatment regimen:

• Rasburicase 0.20 mg/kg/day IV infused over 30 minutes 1, 3
• First dose administered at least 4 hours before starting tumor-specific therapy 1, 3
• Continue for 3-5 days 1, 3
• Aggressive hydration with target urine output ≥100 mL/hour in adults (3 mL/kg/hour in children <10 kg) 1
• Inpatient setting required 1

After completing rasburicase: Transition to oral allopurinol 1

Critical contraindication: Never administer allopurinol concurrently with rasburicase to avoid xanthine accumulation and lack of substrate for the enzyme 1, 2

Rasburicase Contraindications

Rasburicase is absolutely contraindicated in 1, 3:

• G6PD deficiency (risk of hemolysis) 1, 3
• Methemoglobinemia 1, 3
• History of anaphylaxis to rasburicase 3
• Other metabolic disorders causing hemolytic anemia 1
• Pregnancy and lactation 2

For these patients: Use oral allopurinol, hydration, and urine alkalinization instead 1

Management of Established TLS

Clinical or Laboratory TLS

Rasburicase should be administered to all patients with clinical TLS or laboratory TLS (defined as ≥2 metabolic abnormalities), regardless of whether hyperuricemia is present. 4

Treatment approach:

• Rasburicase with hydration for all clinical TLS cases 4
• Identical treatment for laboratory TLS in adults 4
• Children with rapidly worsening biochemical parameters require rasburicase 4
• Aggressive hydration and diuresis 1

Hydration Protocol

Timing and targets:

• Initiate hydration at least 48 hours before tumor-specific therapy when possible 1, 5
• Maintain urine output ≥100 mL/hour in adults 1, 5
• Loop diuretics may be required to achieve target urine output 5

Important note: Rasburicase allows for earlier administration of chemotherapy if needed due to rapid uric acid degradation 1

Alkalinization Controversy

Alkalinization is not recommended in current guidelines. 1 This represents a shift from older practices, as alkalinization can worsen calcium phosphate precipitation.

Monitoring Requirements

Frequency Based on Risk

High-risk patients or established TLS:

• Every 6 hours for the first 24 hours 5, 4
• Every 12 hours for days 2-3 5
• Daily monitoring until stable 5

Parameters to monitor:

• Uric acid (even if not initially elevated) 4
• Potassium 5
• Phosphate 5
• Calcium 5
• Creatinine 5

Critical Sample Handling

Blood samples must be placed immediately on ice to prevent continued ex vivo enzymatic degradation by rasburicase, which falsely lowers measured uric acid levels. 2, 3

Management of Specific Metabolic Derangements

Hyperkalemia

• Sodium polystyrene sulfonate 6
• Hypertonic glucose and insulin 6
• Loop diuretics 6
• Bicarbonate 6

Hyperphosphatemia

• Reduce dietary phosphate intake 6
• Phosphate binders (aluminum hydroxide, aluminum carbonate) 6

Hypocalcemia

• Continuous IV calcium gluconate infusion for recurrent hypocalcemia 6

Indications for Dialysis

Hemodialysis should be considered for 6:

• Excessively elevated uric acid unresponsive to medical management 6
• Severe hyperkalemia or hyperphosphatemia 6
• Acute renal failure requiring volume control 6
• Management of uremia 6

Resuming Chemotherapy After TLS

Laboratory Thresholds for Safe Resumption

Before restarting chemotherapy, ensure 5:

• Uric acid <475 μmol/L (8 mg/dL) 5
• Creatinine <141 μmol/L 5
• pH ≥7.0 5
• All electrolytes normalized (potassium, phosphate, calcium) 5

Management Protocol

Mandatory steps:

• Obtain nephrology consultation for all patients with previous clinical TLS 1, 5
• Initiate aggressive hydration 48 hours before chemotherapy resumption 5
• Implement prophylactic rasburicase for all subsequent chemotherapy cycles 5
• Enhanced monitoring: every 6 hours for first 24 hours after resumption, then daily until stable 5

Rasburicase allows for earlier and safer chemotherapy resumption compared to allopurinol alone. 5

Common Pitfalls to Avoid

Concurrent allopurinol and rasburicase administration: This causes xanthine accumulation and removes the substrate for rasburicase 1, 2

Inadequate allopurinol dose adjustment in renal impairment: Failure to reduce dose by 50% leads to drug accumulation and potential xanthine crystal deposition in renal tubules 2

Premature chemotherapy resumption: Restarting before metabolic abnormalities are corrected increases risk of recurrent TLS 5

Improper sample handling: Failure to place blood samples on ice results in falsely low uric acid measurements 2, 3

Underestimating risk in solid tumors: While less common, TLS can occur with bulky solid tumors (especially SCLC with liver metastases) and metastatic germ cell tumors 1

Evidence Quality Note

The 2008 consensus guidelines from both the Journal of Clinical Oncology and Haematologica 1 provide the foundational framework for TLS management. A retrospective pediatric study demonstrated the superiority of urate oxidase (rasburicase) over allopurinol, with only 2.6% requiring dialysis versus 16% with allopurinol 1. The FDA-approved dosing for rasburicase is 0.20 mg/kg/day, which achieved uric acid control in 100% of patients by 96 hours in clinical trials 3.