Approach

Optimal management of TLS involves identifying all patients at risk of TLS, and preventing the development of TLS.[8][37]

Treatment is required if TLS develops despite preventive interventions. This involves correction of biochemical and clinical abnormalities, and avoidance of potentially life-threatening complications (e.g., cardiac arrhythmia or seizures).

Patients should be managed by a multidisciplinary team including haematologists, oncologists, nephrologists, and intensive care physicians.

Prevention

Prevention relies on early recognition of patients at risk of developing TLS and initiation of appropriate preventive measures.[2]

Patients can be categorised as low, intermediate, or high risk depending on the type of malignancy, treatment sensitivity (of the tumour), disease stage, white blood cell (WBC) count, tumour burden (bulk), lactate dehydrogenase (LDH) levels, and pre-existing renal impairment/renal abnormality.[37]

Nephrotoxic agents (e.g., non-steroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents) should be avoided in all patients with haematological malignancy undergoing chemotherapy. Drugs that increase the levels of uric acid, potassium, and phosphate (e.g., thiazide or potassium-sparing diuretics) should be avoided if possible.

Prophylaxis: low-risk patients

Low-risk patients include those with:[37]

  • Solid tumours, except rare solid tumours that are chemosensitive (e.g., neuroblastoma, germ cell tumours, small cell lung cancer), or others with bulky or advanced disease

  • Chronic myeloid leukaemia: chronic phase

  • Chronic lymphocytic leukaemia when treated exclusively with alkylating agents

  • Multiple myeloma

  • Hodgkin's lymphoma

  • Acute myeloid leukaemia with WBC count <25 × 10⁹/L (<25,000/microlitre) and LDH <2 times the upper limit of normal (ULN)

  • Indolent/low proliferating non-Hodgkin's lymphoma (e.g., small lymphocytic lymphoma, follicular lymphoma, marginal B-cell lymphoma, MALT lymphoma, mantle cell lymphoma [non-blastoid], cutaneous T-cell lymphoma, and anaplastic large cell lymphoma [adults])

Patients with low-risk disease who have renal dysfunction/involvement should be categorised as intermediate risk.[37]

Low-risk patients can be observed with regular monitoring of blood biochemistry (including uric acid, phosphate, potassium, calcium, urea, creatinine, and LDH) and regular assessment of fluid balance and vital signs.[1]

Allopurinol (a xanthine oxidase inhibitor) may be considered for the management of hyperuricaemia in low-risk patients, if required (e.g., if there are signs of metabolic changes, bulky and/or advanced disease, and/or high proliferative disease).[4][8][37]​​​​[41]​ Allopurinol reduces uric acid production by preventing the degradation of purine (from nucleic acids) to uric acid, but it has no effect on uric acid already present.[1][2]​​ It has been shown to reduce the incidence of urate nephropathy related to uric acid crystal precipitation.[38][39]

When allopurinol is used in combination with a purine-based chemotherapeutic agent (e.g., mercaptopurine or azathioprine), dose reduction of the purine-based agent is required to prevent toxicity. Co-administration of allopurinol and capecitabine should be avoided due to the risk of decreased efficacy with capecitabine.

If allopurinol is unsuitable (e.g., due to allergy or intolerance), febuxostat (a non-purine selective xanthine oxidase inhibitor) can be used in adult patients.[40] The safety and efficacy of febuxostat in children is unclear.

The US National Comprehensive Cancer Network (NCCN) recommends starting allopurinol or febuxostat 2 to 3 days prior to initiation of cancer treatment and continuing for 10 to 14 days.[4]​​[41]

Prophylaxis: intermediate-risk patients

Intermediate-risk patients include those with:[37][41]

  • Rare solid tumours that are chemosensitive (e.g., neuroblastoma, germ cell tumours, small cell lung cancer), or others with bulky or advanced-stage disease

  • Early-stage Burkitt's lymphoma with LDH <2 times the ULN

  • Early-stage lymphoblastic lymphoma with LDH <2 times ULN

  • Acute lymphoblastic leukaemia with WBC count <100 × 10⁹/L (<100,000/microlitre) and LDH <2 times ULN

  • Acute myeloid leukaemia with WBC count ≥25 × 10⁹/L (≥25,000/microlitre) to <100 × 10⁹/L (<100,000/microlitre), or WBC count <25 × 10⁹/L (<25,000/microlitre) and LDH ≥2 times ULN

  • Chronic lymphocytic leukaemia with WBC count ≥50 × 10⁹/L (≥50,000/microlitre) and/or treated with fludarabine or targeted agents (e.g., rituximab, lenalidomide, obinutuzumab, venetoclax)

Patients with intermediate-risk disease who have renal dysfunction/involvement, or uric acid, potassium, and/or phosphate levels above the normal range, should be categorised as high risk.

Intermediate-risk patients should have regular (at least daily) checks of their blood pressure, heart rate, and respiratory rate. Blood biochemistry (including uric acid, phosphate, potassium, calcium, urea, creatinine, and LDH) should be determined before preventive interventions, and then 1 to 2 times daily for the first 3 days of therapy and once daily thereafter. Guidelines for monitoring and assessment may differ depending on region and centre; therefore, referral to local guidance is advised.

Two days before the initiation of cancer treatment, patients at intermediate risk should receive intravenous hydration with isotonic saline to maintain a urinary output of 100 mL/m²/hour (3 mL/kg/hour in children <10 kg body weight). Aggressive hydration improves intravascular volume and enhances renal blood flow.[1][2]​ A high glomerular filtration rate helps eliminate potassium, uric acid, and phosphate from the bloodstream.

If urine output is not satisfactory despite volume repletion, then loop diuretics may be used.[2] Loop diuretics may, however, cause precipitation of uric acid and calcium phosphate in the tubules and should be avoided in patients with renal obstruction or volume depletion.[42]

Allopurinol or febuxostat (if allopurinol is unsuitable) is recommended for the management of hyperuricaemia.[4][41]​[43]​​

Rasburicase (a recombinant form of the urate oxidase enzyme) should be used if hyperuricaemia is inadequately managed by allopurinol or febuxostat.[1] Rasburicase transforms uric acid into allantoin. Allantoin is more soluble in urine than uric acid, and more easily eliminated by the kidney.[44] Rasburicase has been shown to reduce the median uric acid concentration from 577 to 60 micromol/L within 4 hours of treatment.[45] One systematic review (of controlled trials for the prevention or management of TLS) concluded that there is insufficient evidence to determine whether rasburicase improves clinical outcomes in adults compared with alternatives.[46]

Rasburicase may be considered for initial management of hyperuricaemia in paediatric patients.[1]

Approximately 1% of recipients develop hypersensitivity reactions to rasburicase.

Rasburicase is contraindicated in patients with:

  • Glucose-6-phosphate dehydrogenase deficiency (screening should be performed in all patients before starting treatment)

  • A history of haemolytic anaemia or methaemoglobinaemia.

Alkalinisation of urine (to eliminate uric acid) is no longer routinely recommended, although some centres still use this approach.[1] If desired, sodium bicarbonate can be given to raise urinary pH. There is a lack of evidence to support its superiority over volume repletion alone in preventing urate nephropathy, and in the presence of hyperphosphataemia it may induce calcium crystal precipitation and worsen renal function.

Phosphate-binding agents (e.g., aluminium hydroxide) may be considered to reduce bowel absorption of phosphate, but they are rarely used.[1][2]​ Aluminium hydroxide may cause constipation, but its use with magnesium hydroxide may reduce colonic adverse effects.

Prophylaxis: high-risk patients

High-risk patients include those with:[37][41]

  • Certain high-grade non-Hodgkin's lymphoma (e.g., advanced-stage Burkitt's lymphoma or lymphoblastic lymphoma) and bulky high-grade non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma)

  • Acute lymphoblastic leukaemia with WBC count ≥100 × 10⁹/L (≥100,000/microlitre), or WBC count <100 × 10⁹/L (<100,000/microlitre) and LDH ≥2 times ULN

  • Acute myeloid leukaemia with WBC count ≥100 × 10⁹/L (≥100,000/microlitre)

  • Chronic lymphocytic leukaemia treated with venetoclax if there is a high tumour burden (lymph node ≥10 cm or lymph node ≥5 cm and absolute lymphocyte count [ALC] ≥25,000/microlitre) or a medium tumour burden (lymph node 5 cm to <10 cm; or ALC ≥25 × 10⁹/L [≥25,000/microlitre]) in those with creatinine clearance <1.34 mL/s (<80 mL/min).

High-risk patients should have regular (at least daily) checks of their blood pressure, heart rate, and respiratory rate. Blood biochemistry (including uric acid, phosphate, potassium, calcium, urea, creatinine, and LDH) should be determined before preventive interventions, and then monitored frequently thereafter (e.g., 3 to 4 times daily).[3] Guidelines for monitoring and assessment may differ depending on region and centre; therefore, referral to local guidance is advised.

Intravenous hydration is the same as that for intermediate-risk patients. Rasburicase is used in preference to allopurinol or febuxostat for the management of hyperuricaemia in high-risk patients.[1][4][41]​ Allopurinol can be used if rasburicase is unsuitable (e.g., due to glucose-6-phosphate dehydrogenase deficiency).[4][37]​​[41]

Treatment: laboratory TLS

Initial treatment of patients with laboratory TLS involves:

  • Aggressive hydration to optimise renal function

  • Use of rasburicase to manage hyperuricaemia

  • Consideration of phosphate-binding agents to manage hyperphosphataemia.

Treatment for other underlying biochemical abnormalities should be initiated.

Management of hyperkalaemia

Hyperkalaemia requires specific therapy:[1][2]

  • Potassium levels ≤6 mmol/L (≤6 mEq/L): treatment includes hydration, a loop diuretic, and sodium polystyrene sulfonate.

  • Potassium levels >6 mmol/L (>6 mEq/L): treatment includes calcium gluconate given as a slow bolus (to counterbalance the effects of high potassium on the heart), followed by an insulin plus glucose infusion to force potassium back into the cells. Sodium polystyrene sulfonate is then subsequently given.[34]

Sodium polystyrene sulfonate is used to bind potassium and promote elimination through the bowel. However, it potentially binds to other oral drugs. Therefore, orally administered drugs should be taken at least 3 hours before or 3 hours after sodium polystyrene sulfonate. This should be increased to 6 hours for patients with gastroparesis or other conditions resulting in delayed emptying of food from the stomach into the small intestine.

Management of hypocalcaemia and/or hyperphosphataemia

Asymptomatic hypocalcaemia does not require treatment.

Early treatment of hyperphosphataemia (e.g., with phosphate-binding agents) may help to prevent development of hypocalcaemia. However, phosphate-binding agents are rarely used.

Renal dialysis

Renal dialysis is indicated if biochemical abnormalities are resistant to medical management, there is persistent volume overload or uncontrolled hypertension, severe acidosis, and/or uraemia with central nervous system toxicity.

Treatment: clinical TLS

If clinical TLS develops, then immediate management of the complication is required. Cardiac arrhythmias and seizures can be rapidly life threatening. Treatment of underlying biochemical abnormalities should continue.

Cardiac arrhythmia

  • ECG changes are characteristic, and continuous cardiac monitoring is necessary when any cardiac arrhythmia is diagnosed and throughout treatment.

  • Treatment depends on the type of arrhythmia and may include pharmacological therapy or cardioversion.

  • Recognition of early ECG changes and prompt treatment of electrolyte abnormalities (e.g., correction of underlying hyperkalaemia, hyperphosphataemia, or hypocalcaemia) is crucial.

Seizures

  • Seizures are usually secondary to severe hypocalcaemia or hyperphosphataemia.

  • Symptomatically, seizures may be managed with anticonvulsants in a similar manner to seizures of any other aetiology.

  • Development of seizures is a definitive indication for treatment of underlying hypocalcaemia with calcium gluconate.

Acute kidney injury

  • Attention to fluid balance and adequate hydration is essential if acute kidney injury develops.

  • Renal dialysis may be required in some patients but the need for this seems to have reduced since the introduction of rasburicase.[55]

  • Phosphate-binding agents (e.g., aluminium salts) have no place in the management of TLS if acute kidney injury develops.[56][57]

Monitoring and assessment of established TLS

Close monitoring is essential following the diagnosis of TLS. Vital signs, urine output, urine pH, and blood biochemistry (including uric acid, phosphate, potassium, calcium, urea, creatinine, and LDH) should be performed every 6 hours in the first 24 hours after diagnosis, and 2 to 4 times daily subsequently, depending on the response to treatment.[1][2][58]

Hourly urine output should also be performed for the first 6 hours after diagnosis.

Guidelines for monitoring and assessment may differ depending on region and centre; therefore, referral to local guidance is advised.

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