Tumor lysis syndrome: Prevention and treatment

INTRODUCTION — 

Tumor lysis syndrome (TLS) is an oncologic emergency caused by massive tumor cell lysis with the release of potassium, phosphate, and nucleic acids into the systemic circulation.

TLS most often occurs when treating lymphomas, leukemias, and solid tumors with high proliferative rates, large tumor burdens, or high sensitivity to cytotoxic or targeted therapy. The frequency and severity of TLS have increased with the use of effective targeted anticancer drugs, whether used alone or in combination with conventional cytotoxic agents. TLS can occur spontaneously in some settings.

Hyperuricemia and hyperphosphatemia from TLS can cause acute kidney injury. Hyperuricemia arising from catabolism of nucleic acids can precipitate in renal tubules and cause renal vasoconstriction, impaired autoregulation, decreased renal blood flow, and inflammation.

Hyperphosphatemia and hyperuricemia can also increase the precipitation of calcium phosphate and/or coprecipitation in renal tubules, exacerbating the risk of acute kidney injury.

TLS is defined by laboratory criteria and clinical features. Methods to prevent TLS should be implemented when there is a high likelihood of occurrence, and prompt treatment of TLS is important to preserve kidney and other organ function.

This topic discusses the prevention and treatment of TLS.

The pathogenesis, risk factors, and clinical presentation of TLS are discussed in greater detail separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

The risk of TLS in association with specific diseases and treatments is discussed in disease-specific topics.

OVERVIEW — 

TLS is an oncologic emergency caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation.

●Clinical presentation – Symptoms associated with TLS include nausea, vomiting, diarrhea, anorexia, lethargy, hematuria, heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and possible sudden death [1]. These symptoms largely reflect metabolic abnormalities, such as hyperkalemia, hyperphosphatemia, and hypocalcemia. Flank pain may occur when uric acid or calcium phosphate deposition causes renal pelvic or ureteral stone formation.

●Diagnosis – TLS is a clinical syndrome defined by increased serum uric acid, potassium, and phosphorus and/or decreased calcium (table 1). The severity of TLS is graded according to the level of serum creatinine and the occurrence of heart arrhythmias and/or seizures (table 2).

●Risk factors – The risk of TLS varies with the type of malignancy (table 3) and the type of treatment.

TLS most often occurs when treating a malignancy with a high proliferative rate, a large tumor burden, or high sensitivity to cytotoxic or targeted therapy. Prominent examples include certain lymphomas (eg, Burkitt lymphoma, mantle cell lymphoma with bulky disease), leukemias (eg, T cell acute lymphoblastic leukemia, chronic lymphocytic leukemia), multiple myeloma, or solid tumors (eg, hepatocellular carcinoma, lung cancer). In some cases, TLS can occur spontaneously.

The risk of TLS is increased with treatment that includes effective targeted agents. It is most common with venetoclax (BCL2 inhibitor), monoclonal antibodies (eg, obinutuzumab, bispecific antibodies), chimeric antigen receptor T cell therapy, and various targeted agents, such as dinaciclib, carfilzomib, or alvocidib, with or without cytotoxic chemotherapy.

Further details of clinical manifestations, diagnostic criteria, severity grading, and risk factors for TLS are discussed separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

CLINICAL IMPACT — 

The potential severity of complications from TLS necessitates preventive measures in patients who are at high or intermediate risk (table 3) and require prompt treatment when TLS occurs. Our approach to the prevention and management of TLS is consistent with published guidelines [1,2].

TLS is associated with increased mortality and treatment-related complications, as described in the following studies:

●Mortality

•A retrospective series of 772 consecutive patients receiving induction chemotherapy along with standard prophylaxis (ie, hydration, allopurinol) for acute myeloid leukemia (AML) reported TLS in 17 percent of patients (12 percent laboratory-based diagnosis; 5 percent clinical TLS) [3]. Compared with 23 percent early mortality in patients without clinical TLS, death occurred in 79 percent of patients diagnosed with clinical TLS (ie, oliguric kidney failure, hemodialysis, electrocardiographic signs of hyperkalemia, cardiac arrhythmia/sudden death, tetany, or seizures). Laboratory-based diagnosis, alone, was not associated with increased mortality.

•Increased mortality was also reported in adults with clinical TLS in the setting of acute lymphoblastic leukemia (ALL), refractory or relapsed (r/r) multiple myeloma treated with chimeric antigen receptor (CAR)-T cell therapy, and critically ill patients needing urgent chemotherapy [4-6].

●Treatment-related complications and costs

•Analysis of 600,000 patients treated for a hematologic malignancy from the Health Care Utilization project reported that patients who developed acute kidney failure requiring dialysis had longer hospital stays (21 versus 7 days) and fivefold higher total cost per discharge compared with those who did not develop renal failure [7].

•A multicenter analysis of 788 patients undergoing induction therapy for newly diagnosed or recurrent ALL, AML, or non-Hodgkin lymphoma (NHL) reported that costs incurred by patients with hyperuricemia and TLS were higher than those in patients with hyperuricemia but without TLS [8].

•Prevention of hyperuricemia and TLS using prophylactic rasburicase was associated with decreased cost per life-year saved in both children and adults [9]. A retrospective study of patients from more than 400 hospitals reported that, compared with allopurinol, rasburicase was associated with shorter hospitalization and treatment in an intensive care unit and lower total health care costs per hospitalization [10].

TLS PROPHYLAXIS — 

Patients with an intermediate or high risk for TLS (table 3) should receive intravenous hydration plus a hypouricemic agent to lessen the complications and possible mortality associated with TLS.

The choice of hypouricemic agent is guided by the risk for TLS, which depends on malignancy, disease burden, planned treatment, and patient comorbidities.

Our approach to the prevention of TLS is consistent with published guidelines [1,2].

High risk — For patients with high risk for TLS (table 3), we suggest intravenous hydration plus rasburicase, rather than hydration plus allopurinol. This suggestion is based on more effective control of hyperuricemia and some evidence of better TLS-related outcomes with rasburicase.

Rasburicase should not be given to patients with glucose-6 phosphate dehydrogenase (G6PD) deficiency, or patients who had anaphylaxis, hypersensitivity, hemolysis, or methemoglobinemia when previously treated with rasburicase. Rasburicase administration, contraindications, toxicity, and outcomes are discussed below. (See 'Rasburicase' below.)

Intravenous hydration is discussed below. (See 'Intravenous hydration' below.)

In certain circumstances, initial management should take place in an intensive care unit (ICU), or in a setting where the patient can be readily transferred to an ICU if needed. For example, patients with kidney dysfunction; elevated pretreatment uric acid, potassium, or phosphate; other significant comorbidities; and Burkitt leukemia or advanced-stage Burkitt lymphoma (BL) require close monitoring and care that can be best provided in an ICU. Laboratory and clinical findings associated with TLS must be closely monitored for all patients. (See 'Monitoring' below.)

Rasburicase more effectively controls uric acid than allopurinol, but it has not been consistently proven to be associated with less clinical TLS, kidney injury, or death.

●In a phase 3 trial, rasburicase controlled uric acid and other laboratory-based abnormalities better than allopurinol, but it did not reduce clinical TLS [11]. Treatment was randomly assigned to 280 adults with hematologic malignancies at risk for TLS as follows: rasburicase alone (0.2 mg/kg daily on days 1 to 5), rasburicase (0.2 mg/kg daily on days 1 to 3) plus oral allopurinol (300 mg daily on days 3 to 5), or allopurinol alone (300 mg daily on days 1 to 5). Compared with allopurinol alone, rasburicase was associated with less laboratory-based TLS (21 versus 41 percent) and more normalization of serum uric acid at days 3 to 7 (87 versus 66 percent), but there was no difference in clinical TLS (3 versus 4 percent, respectively). There were trends toward better efficacy with rasburicase plus allopurinol compared with allopurinol alone that did not reach statistical significance. Rasburicase reduced serum uric acid more quickly (median time, 4 hours with rasburicase with or without allopurinol, versus 27 hours with allopurinol alone). There were no treatment-related life-threatening events or deaths in the trial.

●Rasburicase more effectively reduced uric acid than allopurinol in a phase 3 trial of 52 children with a high-risk lymphoma or leukemia, or with any lymphoma or leukemia with pretreatment serum uric acid ≥8 mg/dL [12]. Rasburicase reduced uric acid within four hours in 86 percent, compared with 12 percent for children receiving allopurinol. One child receiving allopurinol required dialysis, compared with none receiving rasburicase.

●A Cochrane analysis (>1000 children in 7 studies, including 1 randomized trial) reported that urate oxidase (either rasburicase or a nonrecombinant product) was more effective than allopurinol for reducing uric acid, but it did not clearly reduce clinical TLS, kidney failure, or mortality [13]. Urate oxidase more effectively controlled uric acid at various time points, but the seven studies could not be directly compared because they measured different outcomes. Pooled results from three studies found that urate oxidase was associated with lower mortality from TLS (relative risk [RR] 0.05 [95% CI 0.00-0.89]), and pooled results from five studies reported less kidney failure with urate oxidase (RR 0.26 [95% CI 0.08-0.89]). Pooled results from three studies showed a higher frequency of adverse effects (AEs) with urate oxidase (RR 9.10 [95% CI 1.29-64.00]).

●In children receiving chemotherapy for advanced-stage BL, TLS occurred in 9 percent of 98 patients receiving rasburicase, compared with 26 percent of 101 patients who received allopurinol [14]. The corresponding rates of patients requiring dialysis were 3 and 15 percent, respectively.

Following are examples of conditions associated with high risk for TLS [2] (table 3).

●Chronic lymphocytic leukemia (CLL) – CLL treated with venetoclax and lymph node(s) ≥10 cm, or lymph nodes ≥5 cm with absolute lymphocyte count (ALC) ≥25 x 10⁹/L and elevated baseline uric acid.

●Acute myeloid leukemia (AML) – AML with white blood cell (WBC) ≥100 x 10⁹/L.

●Acute lymphoblastic leukemia (ALL) – WBC ≥100 x 10⁹/L and/or lactate dehydrogenase (LDH) ≥2 x upper limit of normal (ULN).

●Lymphomas

•BL – BL stage III/IV and/or LDH ≥2 x ULN.

•Burkitt leukemia

•Lymphoblastic lymphoma (LBL) – LBL stage III/IV and/or LDH ≥2 x ULN.

•Childhood non-Hodgkin lymphoma (NHL) – Childhood diffuse large B cell lymphoma (DLBCL) stage III/IV with LDH ≥2 x ULN.

•Other lymphomas – Adult T cell leukemia/lymphoma (ATLL), DLBCL, transformed lymphoma, or mantle cell lymphoma (MCL) with bulky disease or LDH ≥2 x ULN.

●Solid tumors – Highly chemotherapy-sensitive solid tumors, such as neuroblastoma, germ cell tumor, or small-cell lung cancer with bulky or advanced-stage disease.

Intermediate risk — For patients with intermediate risk of TLS, we suggest intravenous hydration plus allopurinol, rather than hydration plus rasburicase, based on comparable clinical outcomes, but lower cost and greater convenience with allopurinol.

Conditions associated with intermediate risk for TLS [2] (table 3) are listed below. However, the risk may increase with kidney dysfunction, other significant comorbidities, and certain cancer treatments. Patients with these conditions or elevated pretreatment uric acid, potassium, or phosphate should be treated as discussed above. (See 'High risk' above.)

The administration of allopurinol is discussed below. Note that allopurinol is not a suitable hypouricemic agent for patients with elevated pretreatment uric acid, certain medications, or heightened risk for AEs of allopurinol. (See 'Allopurinol' below.)

Intravenous hydration is discussed below. (See 'Intravenous hydration' below.)

The patient should be closely monitored for laboratory and clinical findings associated with TLS. (See 'Monitoring' below.)

Following are examples of conditions associated with intermediate risk for TLS [2] (table 3). However, pre-existing kidney dysfunction; elevated pretreatment uric acid, potassium, and/or phosphate; or tumor involvement of the kidneys increase the risk for TLS and require an alternative method of prophylaxis.

●CLL – CLL treated with fludarabine, rituximab, lenalidomide, or venetoclax and lymph node ≥5 cm or ALC ≥25 x 10⁹/L and/or WBC count ≥50 x 10⁹/L.

●AML – AML with WBC 25 to ≤100 x 10⁹/L or WBC <25 x 10⁹/L and LDH ≥2 x ULN.

●ALL – ALL with WBC <100 x 10⁹/L and LDH <2 x ULN.

●Lymphomas

•BL – BL with LDH <2 x ULN

•LBL – LBL stage I/II with LDH <2 x ULN

•Childhood anaplastic large cell lymphoma (ALCL) – Stage III/IV

•Childhood NHL – Intermediate grade NHL stage III/IV with LDH >2 x ULN

•Other lymphomas – Nonbulky adult ATLL, DLBCL, transformed lymphomas, and MCL with LDH >ULN

●Solid tumors – Highly chemotherapy-sensitive solid tumors, such as neuroblastoma, germ cell tumor, or small-cell lung cancer with bulky or advanced-stage disease.

MONITORING — 

Monitoring for TLS should begin before initiating cancer treatment, regardless of the pretreatment risk of TLS.

Baseline values and ongoing monitoring include urine output, potassium, phosphate, uric acid, calcium, creatinine, blood urea nitrogen, and lactate dehydrogenase (LDH). Note that for patients receiving rasburicase, the blood specimen for uric acid should be collected in a prechilled tube, immediately placed on ice, and the assay completed within four hours, whenever possible. (See 'Possible spurious uric acid levels' below.)

The need for an electrocardiogram and/or continuous cardiac monitoring depends on the presence of kidney dysfunction, hyperkalemia, or hypocalcemia; other comorbidities; cardiac risk factors; and the TLS risk category.

●High risk – Laboratory and clinical parameters should be assessed every four to six hours after beginning cancer treatment; the intervals can increase as serum LDH and uric acid normalize and the risk of TLS decreases.

Patients at high risk should begin cancer treatment and monitoring for TLS as inpatients. Management in an intensive care unit (ICU; or with ready access to an ICU) should be considered for selected patients with a very high risk for TLS, as discussed above. (See 'High risk' above.)

●Intermediate risk – The frequency of monitoring is individualized, with consideration of risk factors and comorbidities. Monitoring can generally take place once or twice daily until the serum LDH and uric acid normalize and the risk of TLS decreases.

Selected patients at intermediate risk for TLS may benefit from inpatient monitoring (eg, one-night hospital stay), according to kidney function and urine output; levels of uric acid, phosphate, and potassium; other comorbidities; and the type of cancer, tumor burden, and cancer treatment.

MANAGEMENT OF TLS — 

The acute effects of TLS, including treatment of hyperkalemia, hyperuricemia, hypocalcemia, and kidney dysfunction, require immediate management. Consultation with a nephrologist is advisable for patients with clinical TLS and a potential need for dialysis.

Despite appropriate preventive measures, approximately 3 to 5 percent of patients develop laboratory and/or clinical evidence of TLS. TLS can also occur spontaneously (ie, prior to the cancer treatment), primarily in patients with non-Hodgkin lymphoma (NHL) or acute leukemia. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Spontaneous TLS'.)

While TLS itself may not directly impact long-term quality of life, reduced kidney function from TLS can have lasting effects on a patient's overall health. TLS can increase the risk of acute kidney injury and worsening kidney damage when patients are exposed to additional nephrotoxic agents, such as antibiotics, cancer treatments, and supportive care medications.

●Patients who develop TLS require close monitoring, including urine output, electrolytes, creatinine, and uric acid evaluation every four to six hours, and attention to dysrhythmias and other cardiac adverse effects (AEs). (See 'Monitoring' above.)

●Patients should receive intravenous hydration and prompt correction of electrolyte abnormalities. Treatment with a loop diuretic may be needed to maintain adequate urine output. (See 'Intravenous hydration' below.)

●Hyperuricemia should be controlled with rasburicase if it was not previously given. Further treatment with rasburicase is guided by the level of serum uric acid. (See 'Rasburicase' below.)

●A kidney specialist should be consulted to consider kidney replacement therapy if needed. (See 'Kidney replacement therapy' below.)

Electrolyte abnormalities — Our approach to managing electrolyte abnormalities in patients with TLS is summarized in the table (table 4).

Patients should limit potassium and phosphate intake during the risk period for TLS.

●Potassium – Hyperkalemia can cause sudden death from heart dysrhythmias.

Serum potassium should be monitored every four to six hours, and continuous cardiac monitoring should be implemented.

Oral potassium-lowering binders (eg, sodium zirconium cyclosilicate, patiromer, or sodium polystyrene sulfonate), glucose plus insulin, beta-agonists, and/or calcium gluconate can be used as temporizing measures to limit cardiac dysrhythmias. (See "Treatment and prevention of hyperkalemia in adults".)

Hemodialysis and hemofiltration can be used to control persistent hyperkalemia, if needed. (See 'Kidney replacement therapy' below.)

●Phosphate – Hyperphosphatemia remains a major problem in TLS and can cause acute kidney injury.

The ability of oral phosphate binders (eg, sevelamer, lanthanum, calcium-based binders, iron-based binders) to rapidly lower serum phosphorus is limited due to the intracellular origin of phosphorus (rather than dietary intake), and their efficacy in this setting is not proven [15]. Strategies to lower serum phosphate levels should be used in conjunction with aggressive hydration and control of uric acid.

●Calcium – Hypocalcemia caused by hyperphosphatemia can cause severe, life-threatening AEs.

To avoid calcium-phosphate precipitation, symptomatic hypocalcemic patients with hyperphosphatemia (particularly if the calcium phosphate product is >60 mg²/dL² [16]) should not be treated with calcium until hyperphosphatemia is corrected.

However, patients with severe symptoms related to hypocalcemia (eg, tetany or cardiac arrhythmia) should receive a calcium replacement regardless of the phosphate level. Symptomatic hypocalcemia should be treated with calcium at the lowest doses required to relieve symptoms. Adults with hyperkalemia who have electrocardiogram changes related to hypocalcemia are generally given 1000 mg of calcium gluconate, while children are typically treated with 100 to 200 mg/kg. Treatment can be repeated after 5 to 10 minutes if symptoms or electrocardiogram changes persist.

Asymptomatic patients with hypocalcemia do not require treatment.

Specific management issues pertaining to hyperkalemia, hyperphosphatemia, and hypocalcemia in adults are discussed in detail separately. (See "Treatment and prevention of hyperkalemia in adults" and "Overview of the causes and treatment of hyperphosphatemia" and "Treatment of hypocalcemia".)

Kidney replacement therapy — Despite optimal care, severe acute kidney injury develops in some patients and may require kidney replacement therapy. However, the need for dialysis due to TLS has declined since the introduction of rasburicase.

Indications for kidney replacement therapy are like those for other causes of acute kidney injury, but lower thresholds may be applied for TLS-associated kidney injury because of potentially rapid potassium release and accumulation, particularly if urine output is low. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose" and "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy".)

●Indications – Kidney replacement therapy may be required in patients with oliguria/anuria, for intractable fluid overload, to manage electrolyte abnormalities, and other indications, as discussed separately. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)

Hyperuricemia is seldom an indication for dialysis from TLS in settings where rasburicase is available [17,18]. However, despite the use of rasburicase, one study reported that 1.5 percent of children and 5 percent of adults required dialysis during induction therapy [18].

●Methods – Depending on the dialyzer and blood flow, phosphate clearance usually ranges from 60 to 100 mL/min with hemodialysis. The phosphate burden in these patients can vary from 2 to 7 grams per day; as a result, it is frequently necessary to perform hemodialysis at 12- to 24-hour intervals.

Continuous renal replacement therapies, such as continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), may be better tolerated and are also effective in cases of acute kidney injury from TLS [19-22]. Phosphorus clearance with continuous arteriovenous hemodialysis (CAVHD), for example, can reach 40 mL/min at a dialysate flow rate of four liters per hour [20]. This can lead to the removal of up to 10 grams of phosphorus per day without the rebound hyperphosphatemia often seen after intermittent hemodialysis. (See "Continuous kidney replacement therapy in acute kidney injury".)

Oliguria due to acute uric acid nephropathy responds quickly to hemodialysis, with diuresis usually beginning as the serum uric acid concentration falls below 10 mg/dL (595 micromol/L) [23]. Hemodialysis efficiently removes uric acid; the clearance is approximately 70 to 100 mL/min, and serum uric acid levels fall by approximately 50 percent with each six-hour treatment [23]. Peritoneal dialysis is much less efficient with uric acid clearances below 10 mL/min.

The prognosis for complete recovery of renal function is excellent if dialysis is initiated early to rapidly reduce serum uric acid and phosphate concentrations.

In a retrospective series, only 2 of 57 children undergoing induction therapy for Burkitt lymphoma or B cell acute lymphoblastic leukemia who received prophylactic urate oxidase therapy required dialysis during induction therapy, and none died from acute kidney injury or other metabolic complications [24]. This compares favorably with 21 percent of children requiring hemodialysis and 5 percent mortality from metabolic/kidney complications in an earlier study in which allopurinol, hydration, and urinary alkalinization were used for TLS prophylaxis [25].

●Long-term effects of TLS – While TLS itself may not directly impact long-term quality of life, reduced kidney function from TLS can have lasting effects on a patient's overall health.

TLS can increase the risk of acute kidney injury and worsening kidney damage when patients are exposed to additional nephrotoxic agents, such as antibiotics, cancer treatments, and supportive care medications.

Incomplete kidney recovery after acute kidney injury can lead to premature onset of clinically significant chronic kidney disease [26].

HYPOURICEMIC AGENTS

Rasburicase — Rasburicase (recombinant urate oxidase) catalyzes the oxidation of uric acid to the more water-soluble compound, allantoin (figure 1).

Rasburicase is generally well tolerated, rapidly lowers serum uric acid, and can effectively prevent and treat hyperuricemia and TLS-associated findings [12,17,18,27-32]. The rapid reduction of serum uric acid with rasburicase contrasts with the effect of allopurinol, which decreases the formation of uric acid but does not acutely reduce pre-existing elevated serum uric acid. (See 'Allopurinol' below.)

Contraindications — Rasburicase should not be used for patients with glucose-6 phosphate dehydrogenase (G6PD) deficiency or who had anaphylaxis, severe hypersensitivity, hemolysis, or methemoglobinemia when previously treated with rasburicase.

G6PD is an X-linked gene. Patients, especially males, with prior drug-induced hemolytic anemia or a racial/ethnic background more often associated with G6PD deficiency (eg, African American, Mediterranean, individuals of Southeast Asian descent) should undergo definitive quantitative enzyme assay or genetic testing followed by quantitative enzyme assay (if appropriate), as discussed separately. (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Administration — We suggest a single rasburicase infusion (with additional treatments given according to levels of uric acid), rather than successive daily treatments to reduce treatments and cost.

The possibility of G6PD deficiency should be considered before beginning rasburicase.

For most patients, rasburicase can be started when cancer treatment begins. However, it should be started before cancer therapy if the baseline serum uric acid is markedly elevated. Rasburicase is also generally started before treatment of Burkitt leukemia or advanced-stage Burkitt lymphoma; in such cases, low-dose chemotherapy may be used as initial therapy to prevent massive tumor lysis. (See "Treatment of Burkitt leukemia/lymphoma in adults".)

Serum uric acid should be closely monitored to determine the duration of treatment. Note that spuriously low values can occur unless the specimen is properly handled, as discussed below. (See 'Possible spurious uric acid levels' below.)

We discontinue rasburicase when serum uric acid has normalized, and then begin allopurinol. (See 'Allopurinol' below.)

●Emergency use if G6PD status is unknown – If emergency administration is required and G6PD results are not available, we administer a single low-dose treatment of 0.02 to 0.05 mg/kg (≤3 mg total) as a 30-minute intravenous (IV) infusion.

Hemodialysis must be readily available in the event of significant hemolysis.

Further doses, if needed, should only be given if there was no evidence of hemolysis or methemoglobinemia.

●Other settings – Rasburicase is generally given as a single infusion, with further treatments guided by close monitoring of serum uric acid.

•Flat-dose therapy – A flat dose of rasburicase 3 mg is commonly used for treating adults, with the number of treatments guided by the response.

We test serum uric acid four to six hours after the infusion and administer another dose if it remains elevated.

•Weight-based dosing – We generally round the dose (typically up) to the closest number of full vials (1.5 or 7.5 mg vials), so that the drug is not wasted.

-Rasburicase 0.2 mg/kg is given as a 30-minute IV infusion.

-For patients with intermediate risk for TLS and pretreatment serum uric acid <8 mg/dL, rasburicase 0.15 mg/kg can be given.

Some clinicians administer daily rasburicase infusions until serum uric acid has normalized.

Rasburicase is approved for up to five days by the US Food and Drug Administration (FDA) and up to seven days by the European Medicines Agency (EMA).

Adverse effects — The rasburicase label carries a boxed warning about the risks of hemolysis, hemoglobinuria, methemoglobinemia, interference with serum uric acid measurements, and anaphylaxis.

●Hemolysis in patients with G6PD deficiency – Rasburicase should not be given to patients with G6PD deficiency because hydrogen peroxide, a byproduct of uric acid breakdown, can cause severe hemolysis in this setting [33].

Patients, especially males, with prior drug-induced hemolytic anemia and/or a racial/ethnic background associated with G6PD deficiency (eg, African American, Mediterranean, or individuals of Southeast Asian descent) should undergo definitive quantitative enzyme assay or genetic testing followed by quantitative enzyme assay (if appropriate) [34], preferably before administration of rasburicase. Details of testing for G6PD deficiency are presented separately. (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Emergency use of rasburicase before G6PD results are available is discussed above. (See 'Administration' above.)

If hemolysis occurs, rasburicase should be immediately and permanently discontinued. An alternative hypouricemic agent, such as allopurinol or febuxostat together with saline hydration, should be used. Rarely, an individual with mild G6PD deficiency (eg, activity 50 to 60 percent of normal) may be treated with rasburicase if the risk of TLS is high and alternatives to rasburicase are not available.

●Anaphylaxis – Rasburicase can cause severe hypersensitivity reactions. Anaphylaxis may occur with the initial dose but is more common with repeated courses of rasburicase.

Among 97 patients who required repeated courses of rasburicase, no patient experienced anaphylaxis during the first course, but six patients developed anaphylaxis during a subsequent course of treatment [35].

Treatment for anaphylaxis should be readily available when administering a repeated course of rasburicase several months or longer after the initial course.

●Methemoglobinemia – Rasburicase can cause severe methemoglobinemia. If this occurs, the drug should be immediately and permanently discontinued.

Details of the management of methemoglobinemia are presented separately. (See "Methemoglobinemia", section on 'Management (acquired/toxic)'.)

●Teratogenicity – Rasburicase has not been studied in pregnant or lactating patients and the risk for teratogenicity is uncertain.

Rasburicase should only be used in pregnant or lactating females if the perceived benefits outweigh the uncertain potential for teratogenicity.

Possible spurious uric acid levels — Ex vivo degradation of uric acid by rasburicase can yield spuriously low serum uric acid levels, with resultant failure to detect TLS.

In patients receiving rasburicase, blood samples for assaying uric acid should be collected in a prechilled tube, immediately placed on ice, and the assay should be completed within four hours, if possible. (See 'Monitoring' above.)

Outcomes — Rasburicase effectively and rapidly decreases serum uric acid and reduces the risk for complications of TLS.

●A meta-analysis of 19 studies reported that a single 3 mg dose of rasburicase is sufficient to normalize and sustain the uric acid level in adults with a pretreatment level <12 mg/dL [36]. In another meta-analysis, a single dose of rasburicase was as effective as daily administration and was considerably less expensive [37].

●A systematic review reported that rasburicase effectively reduced serum uric acid levels in adults with TLS or at risk for TLS [11,38].

●Treatment with rasburicase in 100 adults with aggressive non-Hodgkin lymphoma at high risk for TLS (including 11 percent with hyperuricemia at presentation) reported effective control of uric acid within four hours in all patients that was maintained throughout the period of observation [28].

Allopurinol — Allopurinol is a hypoxanthine analog that competitively inhibits xanthine oxidase, thereby blocking the metabolism of hypoxanthine and xanthine to uric acid (figure 1).

Allopurinol can decrease the formation of uric acid and reduce the incidence of obstructive uropathy, but it does not reduce pre-existing serum uric acid [12]. Allopurinol is orally administered, inexpensive, and well tolerated.

Administration of allopurinol — Allopurinol should not be given to patients with pretreatment uric acid ≥8 mg/dL (476 micromol/L). Rasburicase should instead be used in patients with elevated pretreatment uric acid. (See 'Rasburicase' above.)

Allopurinol should start 24 to 48 hours before beginning chemotherapy and continue until serum uric acid normalizes and laboratory evidence of tumor lysis (eg, elevated serum lactate dehydrogenase) is resolving (eg, three to seven days after beginning cancer treatment).

The usual allopurinol dose is:

●Adults – Allopurinol 100 mg/m² every eight hours, to a maximum of 800 mg per day.

The dose must be reduced by 50 percent in the setting of acute kidney injury to avoid the accumulation of allopurinol and its metabolites.

The dose should be reduced to 200 mg daily for creatinine clearance 10 to 20 mL/minute, ≤100 mg daily for creatinine clearance 3 to 10 mL/minute, and ≤100 mg/dose at extended intervals for creatinine clearance <3 mL/minute.

When azathioprine or mercaptopurine is given concurrently with allopurinol, the thiopurine dose should be reduced to one-third to one-fourth of the usual dose because allopurinol can increase the patient's plasma concentrations and cause severe toxicity [39,40].

●Children – Allopurinol 50 to 100 mg/m² every eight hours, to a maximum of 300 mg/m² per day, or 10 mg/kg per day in divided doses every eight hours [1].

For patients who are unable to take oral medications, IV allopurinol 200 to 400 mg/m² per day in one to three divided doses (maximum dose 600 mg per day) can be used [41,42].

Cautions and toxicity — Allopurinol is generally well tolerated, but caution is advised in several circumstances:

●Allopurinol should not be given to patients with elevated pretreatment uric acid ≥8 mg/dL.

●Caution is advised when considering allopurinol therapy in patients of Han Chinese, Thai, or Korean ancestry because of a strong association between inheritance of the human leukocyte antigen (HLA)-B*58:01 allele and severe cutaneous adverse effects (AEs). Given the time needed for HLA testing, some experts advise using rasburicase instead of allopurinol in Asian patients at moderate or high risk of TLS who require urgent chemotherapy [43]. (See 'Rasburicase' above.)

●Allopurinol increases serum levels of the purine precursors hypoxanthine and xanthine, which may lead to xanthinuria, deposition of xanthine crystals in the renal tubules, and acute kidney injury. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Xanthinuria'.)

●Allopurinol can interact with other drugs, including cyclophosphamide, bendamustine, high-dose methotrexate, ampicillin, amoxicillin, carbamazepine, loop diuretics, and thiazide diuretics.

●Allopurinol has been associated with hypersensitivity reactions, including vasculitis and Stevens-Johnson syndrome.

When allopurinol is contraindicated, either rasburicase or febuxostat can be used instead.

Febuxostat — Febuxostat is a hypouricemic drug that inhibits xanthine oxidase.

Febuxostat differs from allopurinol because it is not a purine analog. It inhibits both reduced and oxidized forms of xanthine oxidase, and it has minimal effects on other enzymes involved in purine and pyrimidine metabolism [44-46].

Febuxostat is contraindicated in patients receiving azathioprine or mercaptopurine. These agents are metabolized by xanthine oxidase, and febuxostat can increase plasma concentrations of these thiopurines, resulting in severe toxicity.

Febuxostat can be used for patients with hyperuricemia who cannot tolerate allopurinol and for whom rasburicase is contraindicated or not available. Febuxostat is more expensive than allopurinol, which is widely available as a generic formulation.

●Administration – Febuxostat 40 mg is taken once daily.

Dose adjustment is not needed in patients with mild to moderate kidney function impairment, and there are fewer drug-drug interactions with febuxostat than with allopurinol [47].

If a gout flare occurs after initiating treatment, febuxostat should not be discontinued; rather, a nonsteroidal anti-inflammatory drug or colchicine can be used to treat the gout flare.

Febuxostat is approved by the FDA and the EMA for treating hyperuricemia.

●Toxicity – Febuxostat can cause severe AEs, including cardiovascular death, effects on the liver, and serious skin reactions.

●Outcomes – Only limited studies of febuxostat for the prevention of TLS are available.

•A trial that randomly assigned febuxostat versus allopurinol to 346 adults with intermediate or high risk for TLS reported comparable toxicity and preservation of kidney function [48].

•A meta-analysis of 6 studies (659 patients, most with hematologic malignancies), including the phase 3 trial above, reported no difference in TLS incidence, control of uric acid, or toxicity between febuxostat and allopurinol for TLS prophylaxis [49].

•Retrospective analysis of 45 children with hematologic malignancies reported comparable control of serum uric acid using either febuxostat or allopurinol [50].

•Two long-term studies of patients with gout produced conflicting results about a potential association between febuxostat and higher all-cause and cardiovascular mortality compared with allopurinol [51,52].

Further discussion of febuxostat is presented separately. (See "Gout: Pharmacologic urate-lowering therapy and treatment of tophi", section on 'Febuxostat'.)

INTRAVENOUS HYDRATION — 

Aggressive intravenous (IV) hydration is the cornerstone of TLS prophylaxis. Hydration allows for dilution of potentially harmful levels of byproducts from tumor lysis.

IV hydration can minimize the likelihood of uric acid or calcium phosphate precipitation in kidney tubules by improving renal perfusion, glomerular filtration, and inducing high urine output [1,2,53]. However, IV hydration can lead to potentially dangerous fluid overload in patients with underlying acute kidney injury or cardiac dysfunction, particularly if the patient is in an edematous state.

Reversible causes of acute kidney injury, such as urinary tract obstruction, should be corrected prior to initiating aggressive hydration.

●Administration – Children and adults at risk for TLS should initially receive IV fluid 2 to 3 L/m²/day (or 200 mL/kg per day in children weighing ≤10 kg) [1].

The duration of IV hydration is individualized, with consideration of the tumor burden and drug sensitivity, the patient's ability to drink, and kidney function. IV hydration should continue at least until the tumor burden is largely resolved (ie, indicated by decreased blast count and size of liver and spleen in patients with leukemia or reduced tumor size and/or serum lactate dehydrogenase [LDH] with solid tumors), there is no evidence of significant tumor lysis (eg, normalization of uric acid and phosphorus), and the patient can produce good urine output with oral fluids.

●Hydration fluid – There is no preferred hydration fluid, and the choice may vary with the clinical circumstances [1]. If transfusions are also needed, they should be given slowly and in low volume.

Potassium and calcium should be withheld from the initial hydration fluids, due to the risk of hyperkalemia and hyperphosphatemia (with resultant calcium phosphate precipitation) once tumor breakdown begins.

•We generally favor initial hydration with 5 percent dextrose/one-quarter normal (isotonic) saline, especially if glucocorticoids are being given (eg, for remission induction therapy for acute lymphoblastic leukemia) because they can cause sodium retention and hypertension.

•Patients with hyponatremia or volume depletion should initially be hydrated using isotonic saline or another isotonic fluid. Some experts prefer a balanced electrolyte solution, such as lactated Ringer's or calcium-free plasmalyte (sodium chloride, sodium gluconate, sodium acetate, potassium chloride, magnesium chloride), to avoid the large amount of chlorine in normal saline.

●Monitoring – Close monitoring of vital signs and urine output is essential. Monitoring in an intensive care unit (ICU) may be needed for selected patients with a high risk for TLS.

Urine output should be maintained within a range of 80 to 100 mL/m² per hour (2 mL/kg per hour for both children and adults, 4 to 6 mL/kg per hour if ≤10 kg).

The patient should be monitored for symptoms of volume overload, such as peripheral edema, weight, and respiratory status.

●Diuretics – Diuretics can be used, if needed, to maintain adequate urine output, but they are generally not required for patients with relatively normal renal and cardiac function.

Diuretics are contraindicated in patients with hypovolemia or obstructive uropathy.

Loop diuretics (eg, furosemide) are generally preferred because they induce both diuresis and increase potassium excretion.

●Alkalinization – We do not routinely alkalinize the urine for TLS prophylaxis unless there is severe metabolic acidosis because there is no evidence that alkalinization improves clinical outcomes with TLS.

In the past, urine was routinely alkalinized to pH >6.5 to 7 using either acetazolamide and/or sodium bicarbonate to increase uric acid solubility and diminish uric acid precipitation in kidney tubules. However, alkalinization can potentially promote calcium phosphate deposition in the kidneys, heart, or other organs in the face of hyperphosphatemia, and alkalosis can increase calcium binding to albumin, thereby increasing the risk of cardiac arrhythmias and tetany.

There is a particular concern with urinary alkalinization in patients receiving rasburicase. Although alkaline urine promotes the excretion of uric acid, it does not substantially increase the solubility of xanthine and hypoxanthine, which increase with the use of rasburicase. (See 'Rasburicase' above.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tumor lysis syndrome".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Tumor lysis syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Description – Tumor lysis syndrome (TLS) is an oncologic emergency caused by massive tumor cell lysis and the release of potassium, phosphate, and uric acid into the systemic circulation. Deposition of uric acid and/or calcium phosphate in renal tubules can cause acute kidney injury.

●Overview (see 'Overview' above)

•Clinical presentation – Symptoms (eg, vomiting, lethargy, flank/pelvic pain, heart dysrhythmias, seizures, tetany) reflect the metabolic consequences of hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, and kidney dysfunction.

TLS most often occurs when treating highly proliferative cancers (especially hematologic malignancies) with large tumor burdens and/or great sensitivity to cancer therapy, but it can occur spontaneously.

•Diagnosis and grading

-TLS is defined by increased levels of serum uric acid, potassium, and phosphorus and/or decreased calcium (table 1).

-The severity of TLS is graded by the level of serum creatinine, heart arrhythmias, and/or seizures (table 2).

•Risk factors – Risk varies with the type of malignancy, disease burden, cancer treatment, and comorbid conditions.

●Prophylaxis – Preventive measures are guided by the risk for TLS (table 3), comorbid conditions, pre-existent electrolyte abnormalities, medications, and cancer treatments.

•High risk – We suggest intravenous (IV) hydration plus rasburicase, rather than hydration plus allopurinol (Grade 2B). (See 'High risk' above.)

-Rasburicase – We administer a single infusion of rasburicase (recombinant urate oxidase), with additional treatments if needed, rather than successive daily treatments. (See 'Rasburicase' above.)

Rasburicase should not be given with known or suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency, or with anaphylaxis, hypersensitivity, hemolysis, or methemoglobinemia after prior rasburicase treatment. (See 'Rasburicase' above.)

If G6PD results are not available, emergency use is discussed. (See 'Administration' above.)

Rasburicase can spuriously decrease uric acid values unless specimens are promptly chilled and processed. (See 'Possible spurious uric acid levels' above.)

-IV hydration – Urine output should be maintained at ≥80 to 100 mL/m² with adequate IV hydration. Loop diuretics are typically not necessary and are contraindicated in patients with hypovolemia or obstructive nephropathy. (See 'Intravenous hydration' above.)

•Intermediate risk – We suggest IV hydration plus allopurinol, rather than hydration plus rasburicase (Grade 2C). (See 'Intermediate risk' above.)

-Allopurinol – Allopurinol decreases new uric acid formation but does not reduce pre-existing serum uric acid. Allopurinol should not be used with uric acid ≥8 mg/dL (476 micromol/L). Administration, toxicity, and drug-drug interactions are described above. (See 'Allopurinol' above.)

Allopurinol should not be used with azathioprine or mercaptopurine and may not be suitable for patients with an increased risk for adverse effects associated with human leukocyte antigen (HLA)-B*58:01, which is more common with Han Chinese, Thai, or Korean ancestry, as discussed above. (See 'Cautions and toxicity' above.)

Febuxostat can be used as a hypouricemic agent when neither allopurinol nor rasburicase is suitable.

-IV hydration – Hydration and maintenance of adequate urine output are discussed above. (See 'Intravenous hydration' above.)

●Monitoring – Baseline evaluation and ongoing monitoring are guided by TLS risk factors and comorbidities. (See 'Monitoring' above.)

●Management of TLS – Hyperkalemia, hyperuricemia, hypocalcemia, and kidney dysfunction require immediate management; consultation with a kidney specialist is advisable. (See 'Management of TLS' above.)

•Electrolyte abnormalities – Manage potassium, phosphate, and calcium. (See 'Electrolyte abnormalities' above.)

-Hyperkalemia (eg, oral potassium binders, glucose plus insulin). (See "Treatment and prevention of hyperkalemia in adults".)

-Hyperphosphatemia (eg, oral phosphate binders). (See "Overview of the causes and treatment of hyperphosphatemia".)

-Avoid calcium repletion, unless symptomatic with hypocalcemia. (See "Clinical manifestations of hypocalcemia".)

•Kidney replacement therapy – Management of acute kidney injury. (See 'Kidney replacement therapy' above.)

Indications for kidney replacement therapy are discussed separately. (See "Overview of the management of acute kidney injury (AKI) in adults".)