Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

low risk

1st line – regular monitoring and assessment

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INITIAL
|
low risk
1st line – 

regular monitoring and assessment

Low-risk patients include those with:

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

chronic myeloid leukemia: chronic phase;

chronic lymphocytic leukemia when treated exclusively with alkylating agents;

multiple myeloma;

Hodgkin lymphoma;

acute myeloid leukemia with WBC count <25,000/microliter and lactate dehydrogenase (LDH) <2 times the upper limit of normal (ULN);

indolent/low proliferating non-Hodgkin 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]).[35] 

Patients with low-risk disease who have renal dysfunction/involvement should be categorized as intermediate risk.[35]

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

Nephrotoxic agents (e.g., nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents) should be avoided in all patients with hematologic 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.

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

Consider – allopurinol or febuxostat

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INITIAL
|
low risk
Consider – 

allopurinol or febuxostat

Treatment recommended for SOME patients in selected patient group

Allopurinol (a xanthine oxidase inhibitor) may be considered for the management of hyperuricemia 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][35][36]

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.[37][38]

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.

Coadministration 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 nonpurine selective xanthine oxidase inhibitor) can be used in adult patients.[39] The safety and efficacy of febuxostat in children is unclear.

The 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.[36][40][41]​​​

Primary options

allopurinol: children: consult specialist for guidance on dose; adults: 600-800 mg/day orally given in 2-4 divided doses; adults: 200-400 mg/square meter of body surface area/day intravenously given in divided doses every 6-24 hours, maximum 600 mg/day

Secondary options

febuxostat: adults: 120 mg orally once daily

intermediate risk

1st line – intravenous hydration (before initiating cancer treatment)

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INITIAL
|
intermediate risk
1st line – 

intravenous hydration (before initiating cancer treatment)

Intermediate-risk patients include those with:

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

early-stage Burkitt lymphoma with lactate dehydrogenase (LDH) <2 times the upper limit of normal (ULN);

early-stage lymphoblastic lymphoma with LDH <2 times ULN;

acute lymphoblastic leukemia with WBC count <100,000/microliter and LDH <2 times ULN;

acute myeloid leukemia with WBC count ≥25,000/microliter to <100,000/microliter, or WBC count <25,000/microliter and LDH ≥2 times ULN;

chronic lymphocytic leukemia with WBC count ≥50,000/microliter and/or treated with fludarabine or targeted agents (e.g., rituximab, lenalidomide, obinutuzumab, venetoclax).[35][41]

Patients with intermediate-risk disease who have renal dysfunction/involvement, or uric acid, potassium, and/or phosphate levels above the normal range, should be categorized as high risk.[35]

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.

Plus – regular monitoring and assessment

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INITIAL
|
intermediate risk
Plus – 

regular monitoring and assessment

Treatment recommended for ALL patients in selected patient group

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, blood urea nitrogen, creatinine, and lactate dehydrogenase) should be determined before preventive interventions, and then 1 to 2 times daily for the first 3 days of therapy and once daily thereafter.

Nephrotoxic agents (e.g., nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents) should be avoided in all patients with hematologic 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.

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

Plus – allopurinol, febuxostat, or rasburicase

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INITIAL
|
intermediate risk
Plus – 

allopurinol, febuxostat, or rasburicase

Treatment recommended for ALL patients in selected patient group

Allopurinol (a xanthine oxidase inhibitor) is recommended for the management of hyperuricemia.[36][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.[37][38]

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.

Coadministration 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 nonpurine selective xanthine oxidase inhibitor) can be used in adult patients.[39] The safety and efficacy of febuxostat in children is unclear.

The 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.[36][40][41]​​​

Rasburicase (a recombinant form of the urate oxidase enzyme) should be used if hyperuricemia 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.[43] Rasburicase has been shown to reduce the median uric acid concentration from 577 to 60 micromol/L within 4 hours of treatment.[44] 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.[45]

Rasburicase may be considered for initial management of hyperuricemia in pediatric 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); and, patients with a history of hemolytic anemia or methemoglobinemia.

Generally one dose of rasburicase is adequate; however, certain patients may need re-dosing.

Primary options

allopurinol: children: consult specialist for guidance on dose; adults: 600-800 mg/day orally given in 2-4 divided doses; adults: 200-400 mg/square meter of body surface area/day intravenously given in divided doses every 6-24 hours, maximum 600 mg/day

Secondary options

febuxostat: adults: 120 mg orally once daily

Tertiary options

rasburicase: children and adults: 0.2 mg/kg intravenously every 24 hours for up to 5 days

Consider – loop diuretic

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INITIAL
|
intermediate risk
Consider – 

loop diuretic

Treatment recommended for SOME patients in selected patient group

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]

Primary options

furosemide: children: 1-3 mg/kg orally/intravenously once daily, maximum 40 mg/day; adults: 40 mg orally/intravenously once daily

OR

bumetanide: children: 0.015 to 0.1 mg/kg orally/intravenously once daily; adults: 0.5 to 2 mg orally/intravenously once daily

Consider – sodium bicarbonate

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INITIAL
|
intermediate risk
Consider – 

sodium bicarbonate

Treatment recommended for SOME patients in selected patient group

Alkalinization of urine (to eliminate uric acid) is no longer routinely recommended, although some centers 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 hyperphosphatemia it may induce calcium crystal precipitation and worsen renal function.

Adjust dose according to urinary pH.

Primary options

sodium bicarbonate: children: 84-840 mg/kg/day orally given in divided doses every 4-6 hours; adults: 3900 mg orally as a single dose, followed by 975-1950 mg every 4 hours, maximum 15.6 g/day (<60 years of age) or 7.8 g/day (>60 years of age)

Consider – phosphate binder

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INITIAL
|
intermediate risk
Consider – 

phosphate binder

Treatment recommended for SOME patients in selected patient group

Phosphate-binding agents (e.g., aluminum hydroxide) may be considered to reduce bowel absorption of phosphate, but they are rarely used.[1][2]

Aluminum hydroxide may cause constipation, but its use with magnesium hydroxide may reduce colonic adverse effects.

Primary options

aluminum hydroxide: children: 50-150 mg/kg/day orally given in divided doses every 4-6 hours; adults: 300-600 mg orally three times daily

high risk

1st line – intravenous hydration (before initiating cancer treatment)

Back
INITIAL
|
high risk
1st line – 

intravenous hydration (before initiating cancer treatment)

High-risk patients include those with:

certain high-grade non-Hodgkin lymphoma (e.g., advanced-stage Burkitt lymphoma or lymphoblastic lymphoma) and bulky high-grade non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma);

acute lymphoblastic leukemia with WBC count ≥100,000/microliter, or WBC count <100,000/microliter and lactate dehydrogenase (LDH) ≥2 times the upper limit of normal (ULN);

acute myeloid leukemia with WBC count ≥100,000/microliter;

chronic lymphocytic leukemia treated with venetoclax if there is a high tumor burden (lymph node ≥10 cm or lymph node ≥5 cm and absolute lymphocyte count [ALC] ≥25,000/microliter) or a medium tumor burden (lymph node 5 cm to <10 cm; or ALC ≥25,000/microliter) in those with creatinine clearance <80 mL/min.[35][41]

Two days before the initiation of cancer treatment, patients should receive intravenous hydration with isotonic saline to maintain a high 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.

Plus – regular monitoring and assessment

Back
INITIAL
|
high risk
Plus – 

regular monitoring and assessment

Treatment recommended for ALL patients in selected patient group

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, blood urea nitrogen, creatinine, and lactate dehydrogenase) should be determined before preventive interventions, and then monitored frequently thereafter (e.g., 3 to 4 times daily).[28]

Nephrotoxic agents (e.g., nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents) should be avoided in all patients with hematologic 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.

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

Plus – rasburicase

Back
INITIAL
|
high risk
Plus – 

rasburicase

Treatment recommended for ALL patients in selected patient group

Rasburicase is used in preference to allopurinol or febuxostat for the management of hyperuricemia in high-risk patients.[1][36][41]

Rasburicase transforms uric acid into allantoin. Allantoin is more soluble in urine than uric acid, and more easily eliminated by the kidney.[43] Rasburicase has been shown to reduce the median uric acid concentration from 577 to 60 micromol/L within 4 hours of treatment.[44] 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.[45]

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) and in patients with history of hemolytic anemia or methemoglobinemia.

Generally one dose of rasburicase is adequate; however, certain patients may need re-dosing.

Primary options

rasburicase: children and adults: 0.2 mg/kg intravenously every 24 hours for up to 5 days

Consider – loop diuretic

Back
INITIAL
|
high risk
Consider – 

loop diuretic

Treatment recommended for SOME patients in selected patient group

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]

Primary options

furosemide: children: 1-3 mg/kg orally/intravenously once daily, maximum 40 mg/day; adults: 40 mg orally/intravenously once daily

OR

bumetanide: children: 0.015 to 0.1 mg/kg orally/intravenously once daily; adults: 0.5 to 2 mg orally/intravenously once daily

Consider – sodium bicarbonate

Back
INITIAL
|
high risk
Consider – 

sodium bicarbonate

Treatment recommended for SOME patients in selected patient group

Alkalinization of urine (to eliminate uric acid) is no longer routinely recommended, although some centers 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 hyperphosphatemia it may induce calcium crystal precipitation and worsen renal function.

Adjust dose according to urinary pH.

Primary options

sodium bicarbonate: children: 84-840 mg/kg/day orally given in divided doses every 4-6 hours; adults: 3900 mg orally as a single dose, followed by 975-1950 mg every 4 hours, maximum 15.6 g/day (<60 years of age) or 7.8 g/day (>60 years of age)

Consider – phosphate binder

Back
INITIAL
|
high risk
Consider – 

phosphate binder

Treatment recommended for SOME patients in selected patient group

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

Primary options

aluminum hydroxide: children: 50-150 mg/kg/day orally given in divided doses every 4-6 hours; adults: 300-600 mg orally three times daily

ACUTE

laboratory or clinical TLS

1st line – urgent treatment of cardiac arrhythmia or seizure

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ACUTE
|
laboratory or clinical TLS
1st line – 

urgent treatment of cardiac arrhythmia or seizure

Cardiac arrhythmias are the most serious manifestation of clinical TLS. 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 pharmacologic therapy or cardioversion.

Recognition of early ECG changes and prompt treatment of electrolyte abnormalities (e.g., correction of underlying hyperkalemia, hyperphosphatemia, or hypocalcemia) is crucial.

Seizures are usually secondary to severe hypocalcemia or hyperphosphatemia. Symptomatically, seizures may be managed with anticonvulsants in a similar manner to seizures of any other etiology. Development of seizures is a definitive indication for treatment of underlying hypocalcemia with calcium gluconate.

Primary options

calcium gluconate: children: 100-200 mg/kg intravenously as a single dose, may repeat every 6-8 hours until response; adults: 1-3 g intravenously as a single dose, may repeat until response

Plus – intensive fluid resuscitation with or without loop diuretic

Back
ACUTE
|
laboratory or clinical TLS
Plus – 

intensive fluid resuscitation with or without loop diuretic

Treatment recommended for ALL patients in selected patient group

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]

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

Primary options

furosemide: children: 1-3 mg/kg orally/intravenously once daily, maximum 40 mg/day; adults: 40 mg orally/intravenously once daily

OR

bumetanide: children: 0.015 to 0.1 mg/kg orally/intravenously once daily; adults: 0.5 to 2 mg orally/intravenously once daily

Plus – regular monitoring and assessment

Back
ACUTE
|
laboratory or clinical TLS
Plus – 

regular monitoring and assessment

Treatment recommended for ALL patients in selected patient group

Close monitoring is essential following the diagnosis of TLS.

Vital signs, urine output, urine pH, and blood biochemistry (including uric acid, phosphate, potassium, calcium, blood urea nitrogen, creatinine, and lactate dehydrogenase) 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][53]

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 center; therefore, referral to local guidance is advised.

Plus – rasburicase

Back
ACUTE
|
laboratory or clinical TLS
Plus – 

rasburicase

Treatment recommended for ALL patients in selected patient group

Rasburicase (a recombinant form of the urate oxidase enzyme) should be used to manage hyperuricemia in patients with established TLS.

Rasburicase transforms uric acid into allantoin. Allantoin is more soluble in urine than uric acid, and more easily eliminated by the kidney.[43]

Rasburicase has been shown to reduce the median uric acid concentration from 577 to 60 micromol/L within 4 hours of treatment.[44] 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.[45]

Approximately 1% of recipients develop hypersensitivity reactions.

Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency (screening should be performed in all patients before starting treatment) and in patients with a history of hemolytic anemia or methemoglobinemia.

Generally one dose of rasburicase is adequate; however, certain patients may need re-dosing.

Primary options

rasburicase: children and adults: 0.2 mg/kg intravenously every 24 hours for up to 5 days

Consider – correction of hyperkalemia

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ACUTE
|
laboratory or clinical TLS
Consider – 

correction of hyperkalemia

Treatment recommended for SOME patients in selected patient group

Hyperkalemia 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 dextrose infusion to force potassium back into the cells. Sodium polystyrene sulfonate is then subsequently given.[31]

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.

Primary options

furosemide: children: 1-3 mg/kg orally/intravenously as a single dose; adults: 40 mg orally/intravenously as a single dose

and

sodium polystyrene sulfonate: children: 1 g/kg orally every 6 hours; adults: 15 g orally once to four times daily

OR

calcium gluconate: (10%) children: 60-100 mg/kg intravenously as a single dose, maximum 3000 mg/dose; adults: 500-3000 mg intravenously as a single dose

and

insulin regular: children: 0.1 units/kg intravenously in dextrose, may repeat in 30-60 minutes; adults: 10 units intravenously in dextrose

and

dextrose: children: 0.5 g/kg (25%) intravenous infusion over 30 min; adults: 500 mL (20%) intravenous infusion over 1-2 hours

and

sodium polystyrene sulfonate: children: 1 g/kg orally every 6 hours; adults: 15 g orally once to four times daily

Consider – sodium bicarbonate

Back
ACUTE
|
laboratory or clinical TLS
Consider – 

sodium bicarbonate

Treatment recommended for SOME patients in selected patient group

Alkalinization of urine (to eliminate uric acid) is no longer routinely recommended, although some centers 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 hyperphosphatemia it may induce calcium crystal precipitation and worsen renal function.

Adjust dose according to urinary pH.

Primary options

sodium bicarbonate: children: 84-840 mg/kg/day orally given in divided doses every 4-6 hours; adults: 3900 mg orally as a single dose, followed by 975-1950 mg every 4 hours, maximum 15.6 g/day (<60 years of age) or 7.8 g/day (>60 years of age)

Consider – phosphate binder

Back
ACUTE
|
laboratory or clinical TLS
Consider – 

phosphate binder

Treatment recommended for SOME patients in selected patient group

Early treatment of hyperphosphatemia may help prevent development of hypocalcemia.

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

Phosphate-binding agents (e.g., aluminum salts) have no place in the management of TLS if acute kidney injury develops.[51][52]

Primary options

aluminum hydroxide: children: 50-150 mg/kg/day orally given in divided doses every 4-6 hours; adults: 300-600 mg orally three times daily

Consider – renal dialysis

Back
ACUTE
|
laboratory or clinical TLS
Consider – 

renal dialysis

Treatment recommended for SOME patients in selected patient group

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

May also be required if acute kidney injury develops, but the need for this seems to have reduced since the introduction of rasburicase.[50]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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