Tumour Lysis Syndrome Pharmacology

Tumour lysis syndrome is the metabolic emergency that follows rapid tumour cell death, which releases potassium, phosphate and nucleic acids. Purines are converted to uric acid, and the resulting hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia can cause acute kidney injury, arrhythmias and seizures. It is most common in high-grade lymphoma (Burkitt), acute leukaemia with high white cell count, and bulky chemosensitive tumours, and after venetoclax, rituximab or high-dose steroids.

Classification. Hydration; xanthine oxidase inhibitors (allopurinol, febuxostat); recombinant urate oxidase (rasburicase); treatment of electrolyte abnormalities; renal replacement therapy.

Pharmacokinetics. Allopurinol is converted to oxypurinol (half life up to 24 hours in kidney impairment); rasburicase converts uric acid to allantoin and acts within hours.

• Intravenous fluids 2 to 3 litres/m2 daily (about 3 litres/m2 in children) to maintain urine output of 80 to 100 mL/m2 hourly (at least 100 mL/hour in adults); use isotonic saline or dextrose-saline without potassium or calcium.
• Allopurinol 300 mg orally daily (10 mg/kg daily in children, in 2 or 3 divided doses), starting 1 to 2 days before chemotherapy and continued for 7 days or until risk resolves; reduce to 100 mg daily in severe kidney impairment.
• Febuxostat 120 mg orally daily as an alternative.
• Rasburicase 0.2 mg/kg intravenously over 30 minutes once daily for up to 5 days; a single 3 mg or 6 mg fixed dose may be effective and is used to save cost.
• Hyperkalaemia: calcium gluconate 10 percent, 10 to 20 mL intravenously over 5 to 10 minutes; insulin 10 units with 25 g glucose; salbutamol 10 to 20 mg nebulised; furosemide if volume overloaded; dialysis for refractory hyperkalaemia.
• Hyperphosphataemia: aluminium-free phosphate binders (calcium carbonate or sevelamer) when levels are high; avoid when calcium-phosphate product is high.
• Hypocalcaemia: treat only if symptomatic (tetany, seizures, arrhythmia) with calcium gluconate.

Differences. Allopurinol only prevents new uric acid; rasburicase destroys existing uric acid and is preferred when uric acid is already high or in high-risk patients.

• Diagnosis: laboratory tumour lysis syndrome when 2 or more of the following occur within 3 days before or 7 days after chemotherapy: uric acid 476 micromol/L (8 mg/dL) or more, potassium 6 mmol/L or more, phosphate 1.45 mmol/L or more, and calcium 1.75 mmol/L or less (or a 25 percent change from baseline); clinical syndrome adds creatinine rise, arrhythmia or seizure.
• Risk stratification: high risk (Burkitt lymphoma, acute lymphoblastic leukaemia with white cell count over 100 x 10^9/L, bulky lymphoma, acute myeloid leukaemia with white cell count over 50 x 10^9/L, abnormal kidney function): hydration plus rasburicase; intermediate: hydration plus allopurinol; low: monitoring and oral fluids.
• Rasburicase safety: test for G6PD deficiency before giving (it causes haemolysis and methaemoglobinaemia); G6PD deficiency is common in East Africa, so use allopurinol instead if testing is unavailable; collect uric acid samples on ice and send promptly because the enzyme continues to work in the tube.
• Do not routinely alkalinise urine: it adds risk of calcium phosphate precipitation.
• Avoid: nephrotoxins (NSAIDs, aminoglycosides, intravenous contrast), potassium and phosphate supplements, and calcium infusions in asymptomatic patients.
• Start cytoreduction carefully: in very high-risk disease, delay or give low-dose pre-phase chemotherapy (prednisolone with or without cyclophosphamide) for several days while hydrating.
• Venetoclax: dose ramp-up over 5 weeks with hydration, uric acid-lowering drugs and frequent laboratory checks.
• Dialysis indications: refractory hyperkalaemia, volume overload, severe acidosis, uraemic complications, or persistent hyperphosphataemia with hypocalcaemia.

Selection. Combine hydration with the uric acid drug by risk, and begin before the first dose of chemotherapy.

Contraindications. Rasburicase: G6PD deficiency, haemolytic reaction or methaemoglobinaemia with prior exposure, hypersensitivity. Allopurinol: previous severe hypersensitivity (HLA-B*58:01 carriers at risk of Stevens-Johnson syndrome).

Adverse effects. Allopurinol: rash, hypersensitivity syndrome, xanthine nephropathy, marrow suppression. Rasburicase: haemolysis, methaemoglobinaemia, anaphylaxis, interference with uric acid assay. Fluid overload with heart or kidney disease.

Interactions. Allopurinol raises mercaptopurine and azathioprine levels (reduce those doses by two thirds to three quarters), increases rash with ampicillin and amoxicillin, and increases cyclophosphamide marrow toxicity; thiazide diuretics and ACE inhibitors increase hypersensitivity risk.

Special groups.

• Pregnancy: allopurinol and rasburicase are used when essential.
• Breastfeeding: allopurinol is acceptable; avoid rasburicase.
• Children: rasburicase 0.2 mg/kg daily; allopurinol by weight.
• Older adults: monitor fluid balance carefully.
• Kidney impairment: reduce allopurinol; consider early dialysis.
• Liver impairment: caution with allopurinol.

Monitoring. For high-risk patients, measure potassium, phosphate, calcium, uric acid, creatinine and lactate dehydrogenase before treatment and every 4 to 6 hours for the first 24 to 48 hours, then every 8 to 12 hours until stable; check urine output hourly, fluid balance, and ECG if potassium is high.

Referral and escalation. Potassium over 6 mmol/L, arrhythmia, oliguria, rising creatinine, seizures, or symptomatic hypocalcaemia need critical care and nephrology involvement.