What are the diagnosis and management strategies for Tumor Lysis Syndrome (TLS) in patients with hematological malignancies, particularly those at high risk?

Diagnosis and Management of Tumor Lysis Syndrome

The best management of TLS is prevention through risk stratification, with high-risk patients requiring aggressive IV hydration plus rasburicase 0.20 mg/kg/day, intermediate-risk patients receiving hydration plus allopurinol or rasburicase, and low-risk patients needing close monitoring with hydration alone. 1

Definition and Diagnostic Criteria

TLS is classified into two categories that guide management decisions 2:

Laboratory TLS (LTLS) is defined by two or more of the following metabolic abnormalities occurring within 3 days before or 7 days after initiating anticancer therapy 2:

• Uric acid >8 mg/dL in adults or increase >25% from baseline 1, 3
• Potassium elevation above normal limits 2
• Phosphorus elevation above normal limits 2
• Calcium below normal limits 2

Clinical TLS (CTLS) requires laboratory TLS plus at least one of the following complications 1, 2:

• Renal insufficiency (creatinine ≥1.5 times upper normal limit or creatinine clearance <60 mL/min) 2
• Cardiac arrhythmias (ranging from minor to life-threatening with CHF, hypotension, syncope, or shock) 2
• Seizures (from brief generalized to status epilepticus) 2

The distinction between laboratory and clinical TLS is critical because clinical TLS carries an 83% mortality rate in AML compared to 24% in those without TLS, requiring immediate aggressive intervention 2.

Risk Stratification

Risk stratification must be performed before initiating chemotherapy to determine prophylaxis intensity 4, 2:

High-Risk Factors 4, 2:

• Burkitt's lymphoma or B-cell acute lymphoblastic leukemia (B-ALL shows 26.4% TLS rate) 2
• AML with WBC >100 × 10⁹/L 2
• High-grade lymphomas, particularly T-cell lymphoblastic NHL 2
• Bulky disease (tumor mass >10 cm or extensive disease burden) 4, 2
• Elevated LDH >2 times upper normal limit 4, 2
• Pre-existing hyperuricemia (>8 mg/dL in children, >10 mg/dL in adults) 2
• Pre-existing renal impairment, dehydration, or obstructive uropathy 4

Intermediate-Risk Factors 1:

• Diffuse large B-cell lymphoma with moderate tumor burden (overall NHL TLS rate approximately 6.1%) 2
• Acute leukemias without extreme leukocytosis 1

Low-Risk Factors 2:

• Chronic lymphocytic leukemia (TLS occurs in only 0.42% of patients) 2
• Solid tumors without bulky disease 1

Prevention Strategies

High-Risk Patients

High-risk patients require the most aggressive prophylaxis in an inpatient setting 4, 2:

• Rasburicase 0.20 mg/kg/day IV over 30 minutes, with the first dose given at least 4 hours before starting chemotherapy 4, 5
• Aggressive IV hydration starting 48 hours before chemotherapy at 2-3 L/m²/day (or 3 L/m²/day for established TLS) 4, 2
• Target urine output ≥100 mL/hour in adults or 3 mL/kg/hour in children <10 kg 4
• Loop diuretics may be needed to maintain urine output, but only after confirming adequate hydration and ruling out obstructive uropathy or hypovolemia 4

Intermediate-Risk Patients

Intermediate-risk patients receive hydration plus either allopurinol or rasburicase 1:

• Hydration at ≥2 L/m²/day 4
• Allopurinol 100 mg/m² three times daily (maximum 800 mg/day) OR rasburicase 0.20 mg/kg/day 4, 2
• Monitor every 24 hours 3

Low-Risk Patients

Low-risk patients require less intensive prophylaxis 4, 2:

• Oral allopurinol 100 mg/m² three times daily (maximum 800 mg/day) 4, 2
• Vigorous hydration ≥2 L/m²/day 4
• Close monitoring but may not need pharmacological prophylaxis in some cases 3

Critical Pitfalls to Avoid

DO NOT give allopurinol concurrently with rasburicase - this causes xanthine accumulation and eliminates substrate for rasburicase activity 4, 2

DO NOT alkalinize urine in patients receiving rasburicase - this increases calcium-phosphate precipitation risk and reduces xanthine solubility 1, 4

DO NOT use rasburicase in patients with G6PD deficiency - this can cause severe hemolysis 3

DO NOT use calcium gluconate to correct mild hypocalcemia - this can worsen calcium-phosphate precipitation 3

Monitoring Protocol

Pre-Treatment Baseline Assessment

Before starting prophylaxis, obtain 4, 2:

• Creatinine clearance or estimated GFR 4, 2
• Serum LDH 4, 2
• Baseline electrolytes (uric acid, potassium, phosphorus, calcium) 4, 2
• Renal ultrasound 4

High-Risk Patient Monitoring

Monitor every 12 hours for the first 3 days, then every 24 hours 3, 4, 2:

• Vital signs 2
• LDH, uric acid, sodium, potassium 3, 4
• Creatinine, BUN 3, 4
• Phosphorus, calcium 3, 4

Established TLS Monitoring

Monitor every 6 hours for the first 24 hours, then daily 3, 4, 2:

• All parameters listed above 3, 4
• Continuous ECG monitoring for hyperkalemic patients 2

Management of Established TLS

All patients with clinical TLS or laboratory TLS with worsening parameters require immediate aggressive intervention 2:

Immediate Interventions

• Rasburicase 0.20 mg/kg/day IV over 30 minutes for 3-5 days 2, 5
• Aggressive IV hydration at 3 L/m²/day through central venous access 2
• Maintain urine output ≥100 mL/hour in adults 2
• Loop diuretics as needed (except in obstructive uropathy or hypovolemia) 2

Rasburicase Efficacy

Rasburicase rapidly reduces uric acid levels 5:

• Among patients with baseline uric acid ≥8 mg/dL (median 10.6 mg/dL), the median decrease by 4 hours was 9.1 mg/dL 5
• 72% of hyperuricemic patients achieved uric acid control by 4 hours, 98% by 72 hours, and 100% by 96 hours 5
• In the randomized adult study, 87% of rasburicase-treated patients achieved uric acid response versus 66% with allopurinol alone 5

Allopurinol Alternative

For patients who cannot receive rasburicase 2:

• Allopurinol 300 mg orally once daily (or 100 mg/m² three times daily, maximum 800 mg/day) 2
• Note: Allopurinol blocks xanthine oxidase but does not reduce existing elevated uric acid levels 4

Indications for Renal Replacement Therapy

Dialysis should be initiated early in TLS because the threshold is lower than other clinical situations, as cell breakdown is ongoing and rapid electrolyte increases cannot be predicted 2, 6:

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

Hemodialysis effectively removes uric acid (clearance 70-100 mL/min) and phosphate, with plasma uric acid falling approximately 50% with each 6-hour treatment 2. In high-risk cases, cytotoxic chemotherapy should be given in facilities with ready access to dialysis and a treatment plan discussed with the nephrology team 6.