Tumor lysis syndrome: Prevention and treatment

INTRODUCTION — Tumor lysis syndrome (TLS) is an oncologic emergency that is caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation. Catabolism of the nucleic acids to uric acid leads to hyperuricemia; the marked increase in uric acid excretion can result in the precipitation of uric acid in the renal tubules and renal vasoconstriction, impaired autoregulation, decreased renal flow, oxidation, and inflammation, resulting in acute kidney injury. Hyperphosphatemia with calcium phosphate deposition in the renal tubules can also cause acute kidney injury. High concentrations of both uric acid and phosphate potentiate the risk of acute kidney injury because uric acid precipitates more readily in the presence of calcium phosphate and vice versa. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Pathogenesis'.)

TLS is defined both by laboratory criteria (table 1) and by clinical features (table 2). (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Definition and classification'.)

TLS most often occurs after the initiation of cytotoxic therapy in patients with clinically aggressive and highly aggressive lymphomas (particularly the Burkitt subtype) and T-cell acute lymphoblastic leukemia (ALL). However, it can occur spontaneously and with other tumor types that have a high proliferative rate, large tumor burden, or high sensitivity to cytotoxic therapy. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Etiology and risk factors'.)

The emergence of effective targeted anticancer drugs, used alone or in combination with conventional cytotoxic agents, has led to an increase in the frequency and severity of TLS in hematologic cancers that previously were rarely associated with this complication [1], including (see "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Hematologic malignancies'):

●Venetoclax (ABT-199), a B-cell lymphoma 2 (BCL2) inhibitor used for chronic lymphocytic leukemia, small lymphocytic leukemia, and acute myeloid leukemia in adults over 75 years old. Because it can cause rapid reduction in chronic lymphocytic leukemia, guidance on risk assessment and prophylaxis for TLS is included in the United States prescribing information for venetoclax. Most recently, it has been suggested that the addition of a creatinine clearance variable would improve risk stratification [2].

●Obinutuzumab (anti-CD20 monoclonal antibody), which is approved for use in relapsed or refractory diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and follicular lymphoma.

●Dinaciclib (cyclin-dependent kinase inhibitor) for advanced ALL or myeloid leukemia.

●Alvocidib (flavopiridol, cyclin-dependent kinase inhibitor), which is under study in intermediate-risk and high-risk acute myeloid leukemia.

This topic review will cover prevention and treatment of TLS. The definition, classification, pathogenesis, risk factors, etiology, and clinical presentation are covered in detail elsewhere, as are issues related to treatment of the particular malignancies that are associated with TLS. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Treatment of Burkitt leukemia/lymphoma in adults" and "Treatment and prognosis of adult T cell leukemia-lymphoma" and "Acute myeloid leukemia: Overview of complications", section on 'Tumor lysis syndrome' and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Complications of ALL/LBL and treatment'.)

CLINICAL IMPACT OF TUMOR LYSIS SYNDROME — The potential severity of complications from TLS necessitates preventive measures in patients who are at high or intermediate risk for this complication (table 3) and prompts immediate treatment in the event that TLS does occur [3]. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Risk stratification'.)

The clinical impact of TLS during treatment was addressed in a retrospective series of 772 consecutive patients undergoing induction chemotherapy for acute myeloid leukemia (AML) [4]. TLS occurred in 130 patients (17 percent), of whom 38 (5 percent) had clinical TLS and 92 (12 percent), laboratory TLS. Clinical (but not laboratory) TLS was associated with a significantly higher risk of death during induction therapy (79 percent [30 of 38 patients] versus 23 percent in those without evidence of clinical TLS). (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Cairo-Bishop definition'.)

The major causes of death in patients with clinical TLS were cardiac arrhythmias and acute kidney injury, and clinical TLS was considered a major cause of death in 19 of the 772 patients (2 percent). In addition to an increase in mortality, the development of TLS is also associated with higher rates of treatment-related complications and costs, as illustrated by the following observations:

●In an analysis of data from the Health Care Utilization project on 600,000 patients treated for a hematologic malignancy, patients who developed acute renal failure requiring dialysis had a significantly longer hospital stay (21 versus 7 days) and fivefold higher total cost per discharge than did those who did not develop renal failure [5].

●Similar findings were noted in a multicenter European analysis of 788 patients undergoing induction treatment for newly diagnosed or recurrent acute lymphoblastic leukemia (ALL), AML, or non-Hodgkin lymphoma (NHL) [6]. The costs incurred by patients who had hyperuricemia and TLS were significantly higher than those of patients who had hyperuricemia but without TLS.

●A separate European analysis demonstrated the cost-effectiveness of preventing hyperuricemia and TLS with prophylactic rasburicase [7]. The incremental cost of prevention was divided by the average number of life-years saved to produce the incremental cost-effectiveness ratio (ICER), which represents the estimated cost per life-year saved. For pediatric patients, who have high life expectancies, the ICER per life-year saved ranged from 425 to 3054 Euros, depending on the country. For adults, the ICER ranged from 23,794 to 41,383 Euros with NHL or ALL to close to 100,000 Euros with AML, largely due to the limited life expectancy of these patients.

●In a retrospective cohort study of administrative data using the Cerner Health Facts database, which captured patient data from more than 400 United States hospitals, clinical and economic outcomes were compared between 26 rasburicase-treated patients and 104 propensity score matched allopurinol-treated controls receiving treatment for cancer between 2005 and 2009 [8]. Rasburicase treatment was associated with a significant 5.3 mg/dL greater reduction in uric acid within two days of treatment initiation (p<0.0001), a shorter length of stay in the intensive care unit (by 2.5 days, p<0.0001), a shorter total length of hospital stay (by five days, p = 0.02), and lower total health care costs per patient per hospitalization (by $20,038, p<0.02) as compared with allopurinol treatment.

These data provide support for routine prophylaxis of TLS in patients at intermediate or high risk for this complication. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Risk stratification'.)

PREVENTION

Overview — For patients who do not have established TLS (table 1), there are several methods for prophylaxis of TLS. (See 'Treatment of established tumor lysis syndrome' below.)

The main prophylactic strategies are intravenous (IV) hydration and the use of hypouricemic agents, such as allopurinol and rasburicase. The specific type of prophylaxis is generally selected based on the estimated risk of TLS, which depends on the disease, the disease burden, and the specific treatment to be administered. A risk stratification strategy, along with treatment guidelines, is outlined in the table (table 3).

Intravenous hydration — Aggressive IV hydration is the cornerstone of preventing TLS and is recommended prior to therapy in all patients at intermediate or high risk for TLS (table 3) [3]. The goal of IV hydration is to improve renal perfusion and glomerular filtration, and induce a high urine output to minimize the likelihood of uric acid or calcium phosphate precipitation in the tubules. 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). In this setting, close monitoring of vital signs and urine output is mandatory, transfusion (if needed) should be given slowly and in low volume, and diuretics can be given to maintain urine output (see below). Monitoring in an intensive care unit (ICU) may be required. Prior to initiation of IV hydration, reversible forms of acute kidney injury (eg, urinary tract obstruction) should be corrected.

A 2008 International Expert Panel on TLS recommended that both children and adults at risk for TLS initially receive 2 to 3 L/m² per day of IV fluid (or 200 mL/kg per day in children weighing ≤10 kg) [3]. Urine output should be monitored closely and 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). Diuretics can be used to maintain the urine output, if necessary, but should not be required in patients with relatively normal renal and cardiac function. Use of diuretics is contraindicated in patients with hypovolemia or obstructive uropathy. The best diuretic for patients with TLS is unknown; loop diuretics such as furosemide appear preferable because they not only induce diuresis, but may also increase potassium secretion.

The choice of hydration fluid depends on the clinical circumstances. The expert panel suggests the initial use of 5 percent dextrose one-quarter normal (isotonic) saline, probably because acute lymphoblastic leukemia (ALL) patients receive steroid during remission induction, which can cause sodium retention and hypertension [3]. In patients with hyponatremia or volume depletion, isotonic saline should be the initial hydration fluid. Due to the risk of hyperkalemia and hyperphosphatemia with calcium phosphate precipitation once tumor breakdown begins, potassium and calcium should be withheld from the hydration fluids, at least initially.

There are no guidelines that address the optimal duration of hydration, which should depend on the tumor burden, the type of chemotherapy used (some regimens induce TLS several days later), the drug sensitivity of the tumor, the patient's ability to drink, and renal function. IV hydration should be continued at least until tumor burden (as indicated by blast cell count as well as liver and spleen size in patients with leukemia, and serum lactate dehydrogenase [LDH] level or tumor size in those with solid tumors) is largely resolved, there is no evidence of significant tumor lysis (as indicated by serum uric acid and phosphorus level), and patient can drink adequately with good urine output.

Urinary alkalinization — The role of urinary alkalinization with either acetazolamide and/or sodium bicarbonate is unclear and controversial. In the past, alkalinization to a urine pH of 6.5 to 7 or even higher was recommended to increase uric acid solubility, thereby diminishing the likelihood of uric acid precipitation in the tubules.

However, this approach has fallen out of favor for the following reasons:

●There are no data demonstrating the efficacy of this approach. In addition, the only available experimental study suggested that hydration with saline alone is as effective as alkalinization in minimizing uric acid precipitation [9].

●Alkalinization of the urine has the potential disadvantage of promoting calcium phosphate deposition in the kidney, heart, and other organs in patients who develop marked hyperphosphatemia once tumor breakdown begins.

Based on these observations, the expert panel concluded that use of sodium bicarbonate was only indicated in patients with metabolic acidosis [3]. The panel could not reach a consensus regarding alkalinization in patients who will receive treatment with allopurinol but suggested that high serum phosphate levels preclude the use of sodium bicarbonate in such patients. If alkalinization is used, it should be initiated when the serum uric acid level is high and discontinued when hyperphosphatemia develops. Alkalinization of the urine is not required in patients receiving rasburicase. (See 'Rasburicase' below.)

Hypouricemic agents

Allopurinol — For the initial management of adult and pediatric patients at intermediate risk for TLS (table 3), we suggest allopurinol rather than rasburicase, as long as pretreatment uric acid levels are not elevated (ie, <8 mg/dL [476 micromol/L]), although administration of a single dose of rasburicase is a reasonable alternative in this setting.

Allopurinol is a hypoxanthine analog that competitively inhibits xanthine oxidase, blocking the metabolism of hypoxanthine and xanthine to uric acid (figure 1). Allopurinol effectively decreases the formation of new uric acid and reduces the incidence of obstructive uropathy in patients with malignant disease at risk for TLS [10,11]. It is inexpensive and orally administered, and thus preferred for patients with a low risk of TLS. However, there are several limitations to its use:

●Because it acts by decreasing uric acid formation, allopurinol does not reduce the preexisting serum uric acid. Thus, for patients with preexisting hyperuricemia (serum uric acid ≥8 mg/dL [476 micromol/L]), rasburicase is the preferred hypouricemic agent. (See 'Rasburicase' below.)

●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'.)

●Since allopurinol may increase the serum concentration of other purines and promote formation of active thioguanine nucleotides, mercaptopurine or azathioprine should be reduced to one-third to one-fourth of the usual dose if used concomitantly with allopurinol [12,13].

●Allopurinol has the potential to interact with a number of other drugs, including cyclophosphamide, bendamustine, high-dose methotrexate, ampicillin, amoxicillin, carbamazepine, loop diuretics, and thiazide diuretics.

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

Dose and administration — The usual allopurinol dose in adults is 100 mg/m² every eight hours (maximum 800 mg per day). In children, the dose is 50 to 100 mg/m² every eight hours (maximum 300 mg/m² per day) or 10 mg/kg per day in divided doses every eight hours [3]. The dose must be reduced by 50 percent in the setting of acute kidney injury due to potential for accumulation of allopurinol and metabolites. According to the manufacturer's labeling, 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 in adults. The concomitant administration of allopurinol and azathioprine or mercaptopurine requires a dose reduction to one-third to one-fourth of the usual dose of the thiopurine because concomitant administration could increase plasma concentrations of these thiopurines, resulting in severe toxicity.

For patients who are unable to take oral medications, IV allopurinol can be administered at a dose of 200 to 400 mg/m² per day, in one to three divided doses (maximum dose 600 mg per day) [14,15]. Treatment is generally initiated 24 to 48 hours before the start of induction chemotherapy. It is continued for up to three to seven days afterward until there is normalization of serum uric acid and other laboratory evidence of tumor lysis (eg, elevated serum LDH levels).

There is a strong genetic association between inheritance of the HLA-B*58:01 allele and severe cutaneous adverse events with allopurinol, particularly in certain Asian populations (Han Chinese, Thai, Korean). Screening is advised by several expert groups for high-risk patients, with avoidance of the drug in those with the inherited high-risk allele [16]. However, the widespread application of screening in other populations is less clear because not all patients with allopurinol-induced severe cutaneous adverse events carry the allele. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Allopurinol'.)

Given the time it takes to carry out HLA testing, Asian patients who are in need of urgent chemotherapy for a tumor at high or moderate risk of TLS should probably receive rasburicase instead of allopurinol. (See 'Rasburicase' below.)

Rasburicase — For the initial management of most pediatric and adult patients at high risk for TLS (table 3), especially those with impaired renal or cardiac function, we recommend rasburicase rather than allopurinol.

An alternative approach to allopurinol for lowering serum uric acid levels is to promote the degradation of uric acid by the administration of urate oxidase (uricase), which catalyzes oxidation of uric acid to the much more water-soluble compound allantoin (figure 1). Urate oxidase is present in most mammals but not humans.

The identification and cloning of the gene encoding urate oxidase in Aspergillus flavus enabled the development of recombinant urate oxidase, rasburicase (Elitek, Fasturtec outside the United States). Rasburicase is expressed in a modified strain of Saccharomyces cerevisiae to minimize the risk of contaminant-related allergic reactions.

Rasburicase is well tolerated, rapidly breaks down serum uric acid, and is effective in preventing and treating hyperuricemia and TLS [10,17-24]. This rapid reduction in serum uric acid is in contrast to the effect of allopurinol, which decreases uric acid formation and therefore does not acutely reduce the serum uric acid concentration.

Efficacy in children — The efficacy and safety of rasburicase for the prevention of TLS in children can be illustrated by the following prospective data:

●An early phase I/II study included 131 patients under the age of 21 who were undergoing induction chemotherapy for hematologic malignancies considered high-risk for TLS (B-ALL or other ALL, advanced stage non-Hodgkin lymphoma [NHL], or acute myeloid leukemia [AML]) [18]. Rasburicase was administered at a dose of 0.15 to 0.2 mg/kg once or twice daily for five to seven days.

Among the 65 patients with hyperuricemia at presentation, the median serum uric acid concentration rapidly decreased from an average of 9.7 to 1 mg/mL (577 to 59 micromol/L). Serum phosphate concentrations decreased to normal within 48 hours, and significant reductions in serum creatinine occurred after 24 hours. No patient required dialysis or developed other clinical consequences of TLS, and there were no adverse events with rasburicase.

●The superiority of rasburicase over allopurinol was shown in a trial of 52 children with high-risk lymphoma or leukemia or any childhood lymphoma or leukemia with a pretreatment serum uric acid concentration ≥8 mg/dL (476 micromol/L); patients were randomly assigned to prophylactic rasburicase (0.2 mg/kg over 30 minutes daily) or allopurinol (100 mg/m² per day in three divided doses), each for five to seven days [10].

Rasburicase therapy was associated with a much greater reduction in serum uric acid four hours after the first dose (86 versus 12 percent reduction in serum levels) and had an earlier onset of action. Serum creatinine levels steadily declined in patients treated with rasburicase, while they increased over the four days of therapy in the allopurinol group. No patient receiving rasburicase required dialysis, compared with one in the allopurinol group. Severe hemolysis developed in one rasburicase-treated patient who had no evidence of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

●An updated Cochrane review evaluating the benefit of urate oxidase for prevention and treatment of TLS in children with cancer included the above randomized trial and five controlled but not randomized studies comparing outcomes in patients treated with allopurinol versus urate oxidase (three of which used uricozyme, a nonrecombinant form of urate oxidase derived from A. flavus, and the other two used rasburicase) [25]. In addition to the randomized trial, which showed a significantly higher frequency of uric acid normalization at four hours and a lower area under the curve (AUC) of uric acid at four days after treatment with rasburicase as compared with allopurinol, the pooled results of five controlled clinical trials also showed significantly lower uric acid levels at days 2 to 4 after urate oxidase treatment (median difference -3.80 mg/dL [95% CI -7.37 to -0.24], -3.13 mg/dL [95% CI -6.12 to -0.14], and -4.60 mg/dL [95% CI -6.39 to -2.81], respectively).

Based on the single randomized trial showing no significant difference in mortality (due to all causes or TLS) or acute kidney injury between the urate oxidase and allopurinol groups [10], and the one controlled clinical trial that failed to demonstrate a significant difference in clinical TLS (risk ratio [RR] 0.77, 95% CI 0.44-1.33), the authors concluded that although urate oxidase might be effective in reducing serum uric acid, it is still unclear whether this translates into a reduction in clinical TLS, acute kidney injury, or mortality. However, it should be noted that the randomized trial was a small study, included very few high-risk patients, and did not have statistical power to detect differences in mortality or risk of acute kidney injury. Moreover, urate oxidase significantly lowered the incidence of acute kidney injury according to the pooled result of five controlled trials (12 of the 429 versus 65 of the 563 patients in the allopurinol group; RR 0.26, 95% CI 0.08-0.89) and significantly lowered mortality due to TLS in a separate analysis of three controlled clinical trials (0 of the 180 versus 11 of the 216 patients in the allopurinol group; RR 0.05, 95% CI 0.00-0.89). We believe that the available data provide clear evidence supporting the use of rasburicase rather than allopurinol for children with high-risk conditions.

Efficacy in adults — Fewer data are available in adults at risk for TLS. Two prospective trials have addressed the benefit of rasburicase in adults:

●The French Groupe d'Etude des Lymphomes de l'Adulte administered rasburicase to 100 patients with aggressive NHL who were considered at high risk for TLS; 11 percent had hyperuricemia at presentation [19]. Rasburicase was begun one day before or on day 1 of the start of combination chemotherapy, at a dose of 0.2 mg/kg IV per day, and was continued for a total of three to seven days.

Control of uric acid was obtained within four hours of the first dose in all patients and was maintained throughout the period of observation. No patient had an increase in serum creatinine, and serum concentrations of potassium, phosphate, and calcium were also well controlled. Overall tolerance to the drug was excellent, although three patients discontinued treatment early because of a grade 3 increase in liver enzymes.

●In the only phase III trial to compare rasburicase with allopurinol, 280 adults with hematologic malignancies at risk for TLS (mainly AML) were randomly assigned to 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) [26]. Compared with allopurinol alone, normalization of serum uric acid (≤7.5 mg/dL) at days 3 to 7 was achieved by a significantly higher percentage of patients receiving rasburicase alone (87 versus 66 percent, p = 0.001); the response rate was also higher for rasburicase plus allopurinol (78 percent) than for allopurinol alone, but the difference was not statistically significant (p = 0.06). Both rasburicase groups were also superior to allopurinol alone in time to control serum uric acid (median time, 4 hours with rasburicase with or without allopurinol versus 27 hours with allopurinol alone).

The incidence of laboratory TLS was significantly lower with rasburicase as compared with allopurinol alone (21 versus 41 percent, p = 0.003) and tended to be lower with the addition of rasburicase to allopurinol (27 percent with allopurinol alone versus 21 percent with the combination, p = 0.054). However, the incidence of clinical TLS (as defined by changes in two or more laboratory parameters [hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia], and at least one of the following events occurring within seven days of treatment [renal failure/injury, need for renal dialysis and/or increase in serum creatinine >1.5 times the upper limit of normal, arrhythmia, seizure]) did not differ; it was 3 percent in each of the rasburicase groups versus 4 percent with allopurinol alone. The percentage of patients who experienced acute kidney injury was 2 percent with rasburicase alone, 2 percent with allopurinol alone, and 5 percent with combined therapy. It should be noted that the study was not designed to demonstrate a reduction in clinical or laboratory TLS and that only 15 percent of the patients had aggressive B-cell malignancies.

No drug-related life-threatening events or deaths occurred in the study. Drug-related events reflecting potential hypersensitivity were reported by five patients, four in the rasburicase arm, and one in the rasburicase plus allopurinol arm; most were grade 1 or 2, but one patient had a grade 3 hypersensitivity reaction that led to treatment discontinuation on day 1. Otherwise, the adverse event profiles were similar.

●Data are also available from a systematic review of rasburicase for prophylaxis or treatment of TLS in adults (which included four controlled trials, only one of which [26] had a non-rasburicase containing arm) and 17 observational studies [27]. The authors concluded that rasburicase was effective in reducing serum uric acid levels in adults with or at risk for TLS, but that evidence was currently lacking to know whether clinical outcomes were improved compared with other therapeutic alternatives.

Notably, the patients were not at particularly high risk of TLS and only different doses or number of doses of rasburicase were compared in the four controlled trials in adults. Hence, these studies had no statistical power and were not designed to show a major improvement in clinical outcome by rasburicase. In our view, the available evidence demonstrates that rasburicase decreases morbidity and laboratory TLS, which can be regarded as an indicator of the risk for clinical TLS, which is in turn, a risk factor for higher hospital mortality [28]. Although the evidence is stronger for use of rasburicase in children with high-risk conditions than in adults, rasburicase has been approved for use in both children and adults by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

Dosing and administration — The EMA and FDA dosing guidelines both recommend a rasburicase dose of 0.2 mg/kg once daily for up to five (FDA) or seven (EMA) days. The expert consensus panel provided alternative dose recommendations based on risk stratification (table 3) [3] (see "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Risk stratification'):

●High-risk patients or a baseline uric acid level ≥8 mg/dL (473 micromol/L) – rasburicase 0.2 mg/kg

●Intermediate-risk patients with baseline uric acid <8 mg/dL – rasburicase 0.15 mg/kg

These are reasonable dosing guidelines. Rasburicase is supplied in vials containing 1.5 or 7.5 mg. We generally round the dose (typically up) to the closest number of full vials, so that the drug is not wasted. In adults, as described below, a flat dose of 3 mg is commonly used.

Doses are generally administered once daily, although if tumor lysis is massive, an increase to twice daily dosing may be needed. The average duration of therapy is two days, but can vary from one to seven days. There are no guidelines from regulatory agencies or expert groups on this point, and the length of treatment has generally been based on clinical judgement, depending on tumor burden, type of cancer and anticancer treatment, and blood uric acid levels following the first dose. Allopurinol treatment can also be started once the serum uric acid is brought down to adequately low or normal levels.

The issue of when to initiate treatment with rasburicase depends on multiple factors, including type of cancer, tumor burden, baseline uric acid level, baseline renal function and hydration status, urgency of anticancer treatment, and anticancer treatment regimen [3]. In some cases, rasburicase can be started on the same day that treatment is initiated. On the other hand, for a patient with Burkitt leukemia or advanced stage Burkitt lymphoma presenting with a high uric acid level, rasburicase may be started early to reduce uric acid to a very low level before treatment is initiated. Low-doses of chemotherapy may be needed during this time to prevent massive tumor lysis.

Responses to rasburicase are dose-related. In a phase I study, a single dose of 0.05 mg/kg was effective in reducing plasma uric acid concentration, while all healthy volunteers treated with doses >0.1 mg/kg had undetectable plasma uric acid concentration within four hours after administration [29].

Single-dose therapy — Single-dose rasburicase is appropriate in patients at intermediate risk (0.15 mg/kg [and rounded up to the nearest vial size]) or high risk (0.2 mg/kg [and rounded up to the nearest vial size]) of TLS. At some institutions, including that of one of the authors, a flat single dose of 3 mg is administered initially to all sized adults, regardless of initial uric acid levels. We monitor every 6 to 12 hours for high-risk patients and those with a high initial uric acid level and give a second single rasburicase dose as needed when and if hyperuricemia recurs.

We would also recommend that all patients receive allopurinol after rasburicase treatment. It is also imperative that serum uric acid levels be measured accurately (with the sample placed on ice while awaiting assay) in patients treated with rasburicase, particularly when a single low dose is used. (See 'Contraindications and restrictions' below and 'Monitoring guidelines' below.)

Small uncontrolled retrospective case series have suggested that lower doses (0.02 mg/kg to 0.2 mg/kg) and/or shorter duration therapy (even in a single dose) can be effective in some patients and minimizes cost [22,30-37]. In some of these studies, adults were treated with a single 3 mg dose [22,34,37].

The efficacy and cost of a single dose of rasburicase compared with daily dosing was addressed in a meta-analysis of 10 studies (eight retrospective and two prospective) [38]. Response rate was defined as the ratio of the number of subjects who responded to treatment over the total subjects in the study group. For single-dose studies, subjects were considered as responders if they did not need another dose of rasburicase within three days to maintain the uric acid level <7.5 mg/dL without significant rebound during this period. For non-single-dose studies, patients who achieved or maintained plasma uric acid level <7.5 mg/dL during days 3 to 7 were considered responders. Overall, the pooled response rate to single-dose therapy (at doses ranging from 0.05 to 0.20 mg/kg) was not significantly different from that of daily administration (0.2 mg/kg/day), 88 versus 90 percent, and single-dose administration generated significant cost savings, approximately $4500 versus $36,000 for drug treatment.

The optimal single rasburicase dose for both adults and children was addressed in a meta-analysis of 15 adult studies (14 retrospective and 1 randomized trial) and 4 observational studies in children [39]. Single doses of 1.5, 3, 4.5, 6, and 7.5 mg, and weight-based single doses of 0.05 and 0.15 mg/kg were compared. The primary outcomes were the response rate at 24 hours after initial rasburicase dose (defined as the ratio of subjects who had a uric acid level <8 mg/dL within 24 hours postdose without receiving additional doses or renal replacement therapy) and the incidence of clinical TLS. For adults, the response rates for the 6 and 7.5 mg and 0.15 mg/kg single doses were 90, 98.6, and 93 percent, respectively, and were higher than for other dosing regimens tested. The single doses of 6 mg and 0.15 mg/kg decreased uric acid levels more than did other regimens; the power of rasburicase to quickly decrease uric acid level was not significantly better with 7.5 as compared with 6 mg. Insufficient information was available to compare the incidence of clinical TLS among the groups. For children, the 1.5 mg and 0.15 mg/kg single-dose regimens were sufficient to manage TLS. However, it should be noted that the sample size was small in each of the pediatric clinical trials (4, 7, 28, and 53 patients, respectively).

Although the impact of baseline uric acid on response was not part of the systematic review, the authors observed that the 3 mg dose also achieved a good response rate (84 percent), although it was lower than in other groups. Notably, this group had a lower baseline uric acid level (8.5 mg/dL) than did the groups receiving higher rasburicase doses. On the other hand, the group receiving the 4.5 mg single dose had the lowest response rate (68 percent), but it also had the highest baseline uric acid level (14.84 mg/dL). The authors concluded that a single dose of 6 mg rasburicase is sufficient to normalize and sustain uric acid level in adults, and that the 3 or 4.5 mg single-dose regimen could be considered in a patient with a uric acid level <12 mg/dL as long as close monitoring for TLS is done.

Contraindications and restrictions — 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 [40]. Patients being considered for rasburicase (especially males) who have the potential for G6PD deficiency by virtue of a history of prior drug-induced hemolytic anemia and/or a racial/ethnic background associated with G6PD deficiency (eg, African-American, Mediterranean, or Southeast Asian descent) should undergo definitive quantitative enzyme assay or genetic testing followed by quantitative enzyme assay if appropriate [41], preferably before administration of rasburicase. If administration of rasburicase is needed in an emergency situation and the results of G6PD testing are not available, rasburicase should be given at a single low dose (eg, 0.02 to 0.05 mg/kg and no more than 3 mg), and hemodialysis should be readily available in the event of significant hemolysis. A second dose should only be given if there was no evidence of hemolysis or methemoglobinemia. 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. Additional details regarding testing for G6PD deficiency are presented separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

●Anaphylaxis – Rasburicase can cause severe hypersensitivity reactions. Anaphylaxis may occur with the initial dose but is more common with repeated courses of rasburicase. In a retrospective review of 97 patients who required repeated courses of rasburicase, none of the patients experienced anaphylaxis during the first course, but six (five with multiple myeloma and one with chronic myeloproliferative disorder) developed anaphylaxis during a subsequent course of treatment [42]. Given the serious nature of anaphylaxis, caution is advised, and treatment for anaphylaxis should be readily available when administering a repeated course of rasburicase several months or longer after the initial course. In general, in the setting of treating relapsed disease, tumor lysis is not a major problem and allopurinol and IV hydration are sufficient unless the patient is allergic to allopurinol.

●Methemoglobinemia – Rasburicase can cause severe methemoglobinemia. If this occurs, the drug should be immediately and permanently discontinued. Additional details of management are presented separately. (See "Methemoglobinemia", section on 'Management (acquired/toxic)'.)

●Spuriously low uric acid measurements – Rasburicase within blood samples will cause enzymatic degradation of uric acid ex vivo if the blood samples are left at room temperature, resulting in spuriously low serum uric acid concentrations, and hence missing the diagnosis of ongoing TLS. Blood samples for determination of uric acid concentrations should be collected in a pre-chilled tube and should be immediately placed on ice, and the assay should be completed within four hours, if possible [43]. (See 'Monitoring guidelines' below.)

●Teratogenicity – There are no studies of rasburicase in pregnant or lactating women. However, studies in animals suggest that it can cause fetal malformations at all dose levels. Thus, rasburicase should only be used in pregnant or lactating women if the perceived benefits outweigh these risks.

Febuxostat — Febuxostat is a new hypouricemic drug that may be used in patients with hyperuricemia who cannot tolerate allopurinol in a setting in which rasburicase is either not available or contraindicated.

Febuxostat is an orally administered, potent, selective inhibitor of xanthine oxidase that was approved in the United States in 2009 and elsewhere for management of chronic hyperuricemia in gout.

It differs from allopurinol in a number of ways:

●It is not a purine base analog; because of the non-purine structure, febuxostat inhibits both reduced and oxidized forms of xanthine oxidase and has minimal effects on other enzymes involved in purine and pyrimidine metabolism [44-46].

●Dose adjustment is not needed in patients with mild to moderate renal impairment [47].

●There are fewer drug-drug interactions with febuxostat than with allopurinol [48].

●It is quite a bit more expensive than allopurinol, at least partly because allopurinol is available as a generic preparation.

A meta-analysis was performed to evaluate the efficacy and safety of febuxostat, as compared with allopurinol, as a preventive measure of TLS [49]. It included six studies that were reported between 2014 and 2017 and involved a total of 659 patients with mainly hematologic malignancy (331 treated with febuxostat and 328 treated with allopurinol). Febuxostat and allopurinol achieved a similar response rate (odds ratio [OR] 1.01, 95% CI 0.55-3.51) and TLS incidence (OR 1.01, 95% CI 0.56-1.81). Serum uric acid levels did not differ between patients treated with febuxostat and those treated with allopurinol at the second day (mean difference -0.21 mg/dL, 95% CI -1.30 to 0.88) and at the seventh day (mean difference -0.43 mg/dL, 95% CI 1.38-0.51) of treatment. Drug-related complications were similarly low between the two groups, with increased liver enzymes being the most common adverse event.

Additional randomized studies of febuxostat and allopurinol are needed for the following reasons:

●First, the findings of the meta-analysis are mainly based on one study [50], which comprised more than one-half of the patients (346 of 659).

●Second, there is only one pediatric study [51], and one other study does not disclose age limits [52]. The doses of febuxostat varied widely among the studies, with the largest dose (120 mg/day) used in the largest randomized trial [50].

●Finally, the total number of patients treated with febuxostat is quite small to determine the safety of this drug in patients treated for cancer, especially in the context of potentially hepatotoxic chemotherapy.

Importantly, if febuxostat is used, the manufacturer advises against taking azathioprine or mercaptopurine concurrently because concomitant administration could increase plasma concentrations of these thiopurines, resulting in severe toxicity.

Monitoring guidelines — Urine output and serial assays of electrolytes and serum uric acid are the key factors to monitor in patients who are at risk for TLS. Urine output and fluid balance should be recorded and assessed frequently.

Although not evidence-based, the 2008 International Expert Panel guidelines made the following recommendations for monitoring in patients at high risk of TLS [3]:

●It is not necessary for all patients to undergo induction therapy in an ICU setting. However, patients at high risk of developing TLS (particularly those with advanced Burkitt leukemia/lymphoma) should be in a position to be readily transferred to an ICU before chemotherapy is started. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Risk stratification'.)

●Children and adults at high risk for developing TLS should be tested for laboratory and clinical TLS parameters (serum concentrations of uric acid, phosphate, potassium, creatinine, calcium, and LDH, as well as fluid input and urine output) four to six hours after the initiation of chemotherapy and every four to eight hours thereafter [3].

For all patients receiving rasburicase (hence deemed at high risk for TLS), serum uric acid should be reevaluated four hours after administration of the first dose and every 6 to 12 hours (depending on the risk and degree of tumor lysis) thereafter until normalization of serum LDH and uric acid levels. As noted above, blood samples for uric acid in patients treated with rasburicase should be collected in a pre-chilled tube and should be immediately placed on ice, and the assay should be completed within four hours, if possible [43]. (See 'Contraindications and restrictions' above.)

Adults at intermediate risk for TLS should be monitored for at least 24 hours after completion of chemotherapy. For multiagent regimens, monitoring should be maintained for 24 hours after administration of the final agent of the first cycle of therapy. If rasburicase is not used initially, serum electrolytes should be measured eight hours after chemotherapy, and the patient might require a one-night hospital stay. If TLS has not occurred within 72 hours of multiagent chemotherapy, the likelihood of TLS is very low.

Others suggest an algorithmic approach to prophylaxis and monitoring based on the estimated risk for or presence of TLS (algorithm 1) [53].

Specific guidelines are available in the US prescribing information for hydration and blood chemistry monitoring for patients receiving venetoclax for chronic lymphocytic leukemia according to the risk for TLS.

TREATMENT OF ESTABLISHED TUMOR LYSIS SYNDROME — Despite appropriate preventive measures, approximately 3 to 5 percent of patients develop laboratory and/or clinical evidence of TLS, despite the prophylactic use of rasburicase. In addition, TLS can occur spontaneously prior to the onset of chemotherapy, 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'.)

Patients who present with or develop TLS during therapy should receive intensive supportive care with continuous urine output and cardiac monitoring and measurement of electrolytes, creatinine, and uric acid every four to six hours [53]. Effective management of these cases involves the combination of treating specific electrolyte abnormalities, the use of rasburicase at 0.2 mg/kg (if it was not given initially) with repeated doses as necessary, attempting to wash out the obstructing uric acid crystals with fluids with or without a loop diuretic, and the appropriate use of renal replacement therapy. Early consultation with an expert in renal medicine is advisable. (See 'Indications for renal replacement therapy' below.)

Electrolyte abnormalities — General guidelines for management of electrolyte abnormalities associated with TLS were provided by the 2008 International Expert Panel [3]. These guidelines are valid for children, but some modification is needed in adults (eg, adults with hyperkalemia who have electrocardiogram [EKG] changes related to hypocalcemia are generally given 1000 mg of calcium gluconate rather than 100 to 200 mg/kg, a typical dosing regimen for children). Modified guidelines for adults and children are outlined in the table (table 4). Briefly:

●Hyperkalemia is the most dangerous component of TLS because it can cause sudden death due to cardiac dysrhythmias. Patients should limit potassium and phosphate intake during the risk period for TLS. In addition, frequent measurement of serum potassium (every four to six hours [53]), continuous cardiac monitoring, and the administration of oral potassium-lowering agents (eg, patiromer or sodium polystyrene sulfonate) are recommended in patients with TLS and acute kidney injury. Glucose plus insulin or beta-agonists can be used as temporizing measures, and calcium gluconate may be used to reduce the risk of cardiac dysrhythmia. If needed, hemodialysis and hemofiltration effectively removes potassium. (See "Treatment and prevention of hyperkalemia in adults" and 'Indications for renal replacement therapy' below.)

●Symptomatic hypocalcemia should be treated with calcium at the lowest doses required to relieve symptoms. To avoid calcium-phosphate precipitation, most symptomatic acutely hypocalcemic patients with hyperphosphatemia due to TLS (particularly if the calcium phosphate product is >60 mg²/dL² [53]) should not be treated with calcium until hyperphosphatemia is corrected. In most situations, clinicians should use other oral phosphate binders, even though there are no good studies demonstrating efficacy [54]. However, patients with severe symptoms of hypocalcemia (eg, tetany or cardiac arrhythmia) should be considered for calcium replacement regardless of the phosphate level. Asymptomatic patients with hypocalcemia do not require treatment.

●Despite treatment with a hypouricemic agent, hyperphosphatemia remains a major problem in TLS and can cause acute kidney injury. Strategies aimed at lowering serum phosphate levels (aggressive hydration and phosphate binder therapy) should be used in conjunction with control of uric acid in patients who have established TLS or who are at high risk of developing TLS. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Hyperphosphatemia'.)

Specific issues pertaining to management of 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".)

Indications for renal replacement therapy — Despite optimal care, severe acute kidney injury develops in some patients, requiring renal replacement therapy. The need for dialysis during induction therapy for high-risk hematologic malignancies has substantially declined since the introduction of rasburicase. In one retrospective series, for example, only 2 of 57 children undergoing induction therapy for Burkitt lymphoma or B-acute lymphoblastic leukemia (ALL) who received prophylactic urate oxidase therapy required dialysis during induction therapy, and none died from acute kidney injury or other metabolic complications [55]. This compares favorably with a 1996 report from the United States Pediatric Oncology Group, in which 21 percent of children with advanced Burkitt lymphoma treated with allopurinol, hydration, and urinary alkalinization required hemodialysis during induction chemotherapy, and 5 percent died following a metabolic/renal complication [56].

In countries where rasburicase is available, hyperuricemia is seldom an indication for dialysis after induction therapy for a hematologic malignancy [18,21]. However, despite the use of rasburicase, approximately 1.5 percent of children and 5 percent of adults require dialysis during induction therapy [21].

Indications for renal replacement therapy are similar to those in patients with other causes of acute kidney injury, although somewhat lower thresholds are used for patients with TLS 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".)

Among the indications for renal replacement therapy in patients with TLS are the following [3,53,57]:

●Severe oliguria or anuria

●Intractable fluid overload

●Persistent hyperkalemia

●Hyperphosphatemia-induced symptomatic hypocalcemia

●A calcium-phosphate product ≥70 mg²/dL²

The prognosis for complete recovery of renal function is excellent if dialysis is initiated early to rapidly reduce serum uric acid and phosphate concentrations. Oliguria due to acute uric acid nephropathy responds quickly to hemodialysis with initiation of a diuresis usually occurring as the serum uric acid concentration falls below 10 mg/dL (595 micromol/L) [58]. Hemodialysis is efficient in removing 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 [58]. Peritoneal dialysis is much less efficient with uric acid clearances below 10 mL/min.

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 [59-62]. The phosphorus clearance with continuous arteriovenous hemodialysis (CAVHD), for example, can reach 40 mL/min at a dialysate flow rate of four liters per hour [60]. 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".)

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

●Definition clinical impact, and risk stratification

•Tumor lysis syndrome (TLS) is an oncologic emergency that is caused by massive tumor cell lysis and the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation. Deposition of uric acid and/or calcium phosphate crystals in the renal tubules can result in acute kidney injury. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Pathogenesis'.)

TLS is observed most frequently in patients with aggressive and highly aggressive lymphomas (particularly the Burkitt subtype) and acute lymphoblastic leukemia following the initiation of cytotoxic therapy, although it may also occur spontaneously and/or in other tumor types with a high proliferative rate, large tumor burden, or high sensitivity to cytotoxic or targeted therapy. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Etiology and risk factors'.)

Tumor-related and patient-related factors can be used to estimate the risk of TLS in individual patients (table 3). (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Risk stratification'.)

•The potential severity of complications from TLS necessitates preventive measures (preferred) in patients who are at high or intermediate risk for this complication, and immediate treatment in the event that TLS does occur. (See 'Clinical impact of tumor lysis syndrome' above.)

●Prophylaxis – Our recommendations for prevention and management are based on a disease-specific estimated risk of TLS (table 3) and follow those of an expert panel on prevention and treatment of TLS. An algorithmic approach to risk stratification and management of TLS is presented in the algorithm (algorithm 1).

•Hydration and urinary alkalinization

-For all patients at high or intermediate risk of TLS, we recommend aggressive fluid hydration (2 to 3 L/m² daily) to achieve a urine output of at least 80 to 100 mL/m² per hour (Grade 1A). In the absence of acute obstructive uropathy and/or hypovolemia, a loop diuretic may be used to maintain the urine output, if necessary. (See 'Intravenous hydration' above.)

-We recommend that intravenous (IV) administration of sodium bicarbonate not be used in the absence of metabolic acidosis (Grade 1B). There is no evidence that urinary alkalinization is of benefit, and there are potential harms, especially when phosphate levels are elevated. (See 'Urinary alkalinization' above.)

•Hypouricemic agents

-Rasburicase and G6PD deficiency – Rasburicase should generally not be given to individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of severe hemolysis. All patients with possible G6PD deficiency should be screened before receiving rasburicase for G6PD activity, especially males; individuals of African, Mediterranean, or Southeast Asian ancestry; and those with a prior history of drug-induced hemolysis.

If emergent administration is needed and G6PD testing results are not available, rasburicase can be given at a single low dose (eg, 0.02 to 0.05 mg/kg and no more than 3 mg), and hemodialysis should be readily available in the event of significant hemolysis. A second dose should only be given if there was no evidence of hemolysis or methemoglobinemia. (See 'Contraindications and restrictions' above and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

-High-risk patients – For the initial management of most pediatric and adult patients at high risk for TLS (table 3), especially those with impaired renal or cardiac function, we recommend rasburicase rather than allopurinol (Grade 1B). (See 'Rasburicase' above.)

For most patients, we recommend a single dose of rasburicase (0.2 mg/kg, rounded up to the nearest vial size) rather than multiple-day therapy (Grade 1B). However, if single-dose therapy is used, uric acid levels must be monitored closely, and with additional doses given when uric acid level remains high. Allopurinol treatment can also be started once the serum uric acid is brought down to adequately low or normal levels. (See 'Dosing and administration' above.)

-Intermediate-risk patients – For the initial management of adult and pediatric patients at intermediate risk for TLS (table 3), we suggest allopurinol rather than rasburicase as long as pretreatment uric acid levels are not elevated (ie, <8 mg/dL [476 micromol/L]) (Grade 2B). However, administration of a single dose of rasburicase (0.15 mg/kg, rounded up to the nearest vial size) is a reasonable alternative. (See 'Allopurinol' above.)

-Low-risk patients – For patients with a low risk of TLS (table 3), we suggest a watch and wait approach with hydration and close monitoring rather than prophylactic allopurinol or rasburicase (Grade 2C).

•Post-treatment monitoring

-Patients at high risk for TLS should receive intensive supportive care with continuous cardiac monitoring, close monitoring of urine output and fluid balance, and frequent serial measurement of electrolytes, creatinine, and uric acid. (See 'Monitoring guidelines' above.)

-For children and adults at intermediate or high risk of developing TLS, measurement of serum levels of uric acid, phosphate, potassium, creatinine, calcium, and lactate dehydrogenase (LDH) should be assessed four to six hours after the initial administration of chemotherapy and every 6 to 12 hours thereafter. Evidence of TLS or a rising level of uric acid should prompt immediate therapeutic intervention. For adult patients at intermediate risk not receiving rasburicase, electrolyte levels should be monitored for at least 24 hours after completion of the final agent of the first cycle of chemotherapy. (See 'Monitoring guidelines' above.)

-Blood samples for uric acid should always be collected in a pre-chilled tube and immediately placed on ice; the assay should be completed within four hours, if possible.

●Treatment of established TLS

•Patients who present with or develop TLS during therapy should receive intensive nursing care with continuous urine output and cardiac monitoring and measurement of electrolytes, creatinine, and uric acid every four to six hours. Effective management involves the combination of treating specific electrolyte abnormalities (table 4) and/or acute kidney injury, the use of hypouricemic agents wash out of the obstructing uric acid crystals with IV fluids and a loop diuretic, and the appropriate use of renal replacement therapy. (See 'Treatment of established tumor lysis syndrome' above.)

If it was not given initially, we recommend rasburicase rather than allopurinol if pretreatment uric acid levels are ≥8 mg/dL (476 micromol/L) (Grade 1B). (See 'Treatment of established tumor lysis syndrome' above.)

If rasburicase is used, we recommend a single dose (0.15 mg/kg, 3 or 6 mg depending on body weight) rather than multiple-day therapy (Grade 1B). However, if single-dose therapy is used, uric acid levels should be monitored closely, and additional doses of rasburicase should be given when hyperuricemia recurs. (See 'Dosing and administration' above.)

Febuxostat may be used in patients with hyperuricemia who cannot tolerate allopurinol in a setting in which rasburicase is not available or is contraindicated. (See 'Febuxostat' above.)

•Indications for renal replacement therapy include (see 'Indications for renal replacement therapy' above):

-Severe oliguria or anuria

-Persistent hyperkalemia

-Hyperphosphatemia-induced symptomatic hypocalcemia

-A calcium-phosphate product ≥70 mg²/dL²