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Tumor lysis syndrome: Prevention and treatment

Authors: Richard A Larson, MD, Ching-Hon Pui, MD


Section Editors: Reed E Drews, MD, Arnold S Freedman, MD, David G Poplack, MD
Deputy Editor: Diane MF Savarese, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Jan 04, 2018.

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: Definition, pathogenesis, clinical manifestations, 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: Definition, pathogenesis, clinical manifestations, 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: Definition, pathogenesis,
clinical manifestations, 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: Definition,
pathogenesis, clinical manifestations, etiology and risk factors", section on 'Hematologic malignancies'):

● Venetoclax (ABT-199), a B-cell lymphoma 2 (BCL2) inhibitor used for chronic lymphocytic leukemia (see
"Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Venetoclax')

● Obinutuzumab (anti-CD20 monoclonal antibody), which is approved for use in relapsed or refractory
diffuse large B-cell lymphoma (see "Treatment of relapsed or refractory diffuse large B cell lymphoma")

● Dinaciclib (cyclin-dependent kinase inhibitor) for advanced acute lymphoblastic or myeloid leukemia

● Alvocidib (flavopiridol, cyclin-dependent kinase inhibitor), which is under study in combination with
cytarabine and mitoxantrone for poor-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: Definition,
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pathogenesis, clinical manifestations, etiology and risk factors" and "Treatment of Burkitt leukemia/lymphoma
in adults" and "Treatment and prognosis of adult T cell leukemia-lymphoma" and "Overview of the treatment
of acute lymphoblastic leukemia in children and adolescents", section on 'Tumor lysis syndrome' and
"Overview of the complications of acute myeloid leukemia", section on 'Tumor lysis syndrome'.)

CLINICAL IMPACT OF TLS — 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 [2]. (See "Tumor lysis syndrome: Definition,
pathogenesis, clinical manifestations, 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) [3]. 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: Definition, pathogenesis, clinical manifestations, etiology and risk factors", section on 'Cairo-
Bishop definition'.)

The major causes of death in patients with clinical TLS were hemorrhage 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 [4].

● 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) [5]. 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 [6]. 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 upon 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 [7]. 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: Definition, pathogenesis, clinical manifestations, etiology and risk
factors", section on 'Risk stratification'.)

PREVENTION

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

IV 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) [2]. 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) [2]. 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 upon 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 [2]. 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 [8].

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● 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 upon these observations, the expert panel concluded that use of sodium bicarbonate was only
indicated in patients with metabolic acidosis [2]. 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
[9,10]. 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 ≥7.5 mg/dL [446 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: Definition, pathogenesis, clinical manifestations, 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 [11,12].

● 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 [2]. 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 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.

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) [13,14]. Treatment is
generally initiated 24 to 48 hours before the start of induction chemotherapy. It is continued for up to three to

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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 [15]. 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, Fasturtek 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 [9,16-23]. 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]) [17]. 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 [9].

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
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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) [24]. 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 upon 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 [9], 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
[18]. 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) [25]. 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).

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The incidence of laboratory TLS was significantly lower with rasburicase as compared with allopurinol
alone (41 versus 21 percent, p = 0.003) and tended to be lower with the addition of rasburicase to
allopurinol (27 versus 21 percent with allopurinol alone, 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.

A systematic review of rasburicase for prophylaxis or treatment of TLS in adults (which included four
controlled trials, only one of which [25] had a non-rasburicase containing arm) and 17 observational studies
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 [26].

However, the patients were not at particularly high risk of TLS and only different dosages 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
[27]. 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 upon risk stratification (table 3) (see "Tumor lysis syndrome:
Definition, pathogenesis, clinical manifestations, etiology and risk factors", section on 'Risk stratification') [2]:

● High-risk patients or a baseline uric acid level >7.5 mg/dL (446 micromol/L) – rasburicase 0.2 mg/kg

● Intermediate-risk patients with baseline uric acid ≤7.5 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.

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

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undetectable plasma uric acid concentration within four hours after administration [28].

Based upon these data, several 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 [21,29-36]. In some of these studies, adults were treated with a single 3
mg dose [21,33,36]. The utility of a single dose of rasburicase was shown in a randomized trial comparing
rasburicase (0.15 mg/kg) given as a single dose versus daily dose for five consecutive days in 80 adult
patients at high to intermediate risk of TLS [22]. Only six (all at high risk) of the 40 patients randomly
assigned to the single-dose arm required a second dose of rasburicase on day 4 because of uric acid levels
>7.5 mg/dL, and no patient in either group developed acute kidney injury. Rasburicase was well tolerated,
with one case of methemoglobinemia and hemolysis in a single patient with G6PD deficiency.

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) [37]. 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. To
analyze the appropriate single dose of rasburicase in adult cancer patients with high risk of TLS, the single-
dose studies were divided into a pooled lower-dose group (3 mg and 0.05 mg/kg, n = 91 patients) and a
pooled standard-dose group (6 mg, 7.5 mg, 0.15 mg/kg, or 0.2 mg/kg, n = 155 patients). The pooled lower
single-dose group failed to control the plasma uric acid (UA) level below 4 mg/dL at 24 hours, whereas the
pooled standard single-dose group maintained the plasma UA level below 4 mg/dL at 24, 48, and 72 hours.
In addition, the response rate of standard-dose group was higher than the lower-dose group (92 versus 84
percent).

Based upon these data, single-dose rasburicase may be used in patients at intermediate risk (0.15 mg/kg
[and rounded up to 3 mg or 6 mg depending on body weight]) or high risk (0.2 mg/kg) of TLS. However, we
would recommend that these patients receive allopurinol after rasburicase treatment. Moreover, uric acid
levels should be monitored closely and additional doses of rasburicase given if and when hyperuricemia
recurs. 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.)

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 [38]. 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 [39], preferably before administration of
rasburicase. If administration of rasburicase is needed in an emergent 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
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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 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 [40]. 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
intravenous 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 "Clinical features, diagnosis, and treatment of methemoglobinemia", section on
'Treatment of acquired methemoglobinemia'.)

● 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, immediately placed on
ice, and the assay completed within four hours, if possible [41]. (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 — In our view, the available data on efficacy and safety are insufficient to suggest the use of
febuxostat as an alternative to allopurinol to prevent TLS in patients at intermediate to high risk for TLS.
Febuxostat may be used judiciously 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 is approved in the
United States 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 [42-44].

● Dose adjustment is not needed in patients with mild to moderate renal impairment [45].

● There are fewer drug-drug interactions with febuxostat than with allopurinol [46].

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

The comparative efficacy of febuxostat versus allopurinol for the prevention of TLS was studied in the double-
blind FLORENCE trial, in which 346 patients with hematologic malignancies at intermediate to high risk of
TLS scheduled to receive the first cycle of cytotoxic chemotherapy were randomly assigned to allopurinol or

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febuxostat, each administered orally for seven to nine days [47]. Investigators could choose a high,
intermediate, or low dose level for the hypouricemic agent, but these only applied if the patient was
randomized to allopurinol (with dose ranges of 200, 300, or 600 mg daily); all patients randomly assigned to
febuxostat received a standard dose (120 mg daily). Although the febuxostat-treated population had a
significantly higher level of LDH, which might reflect a greater malignant disease burden, there was a
significant improvement in one of the co-primary endpoints, mean serum uric acid AUC assessed from
baseline to day 8, with febuxostat (514 versus 708 mg/dL), and mean serum uric acid levels were
significantly lower with febuxostat from the first 24 hours of treatment up to day 8 at each time point.
However, these benefits did not translate into lower levels of serum creatinine (the other primary end point) or
into laboratory or clinical evidence of TLS following chemotherapy. In addition, treatment responder rates
were comparable, and the incidence of drug-related adverse events was also similar in both arms (6.4
percent).

For several reasons, it is difficult to conclude that febuxostat is an appropriate alternative to allopurinol to
prevent TLS in patients at intermediate or high risk:

● It is not known what proportion of patients received the lower dose of allopurinol (ie, 200 mg per day),
while all patients randomized to the febuxostat arm received the fixed high dose (120 mg) [47]. In this
regard, in an earlier study of patients with gout, the urate-lowering efficacy of febuxostat at 40 mg was
comparable to that of allopurinol at 300 mg [48]. A lower dose of febuxostat might be equally effective
and potentially less toxic for prevention of TLS.

● Perhaps more importantly, a greater incidence of liver dysfunction, nausea, joint pain, and rash has been
noted in febuxostat-treated patients than in placebo controls, but not in allopurinol-treated subjects
during clinical trials for gout, and periodic monitoring of liver function is suggested by the manufacturer of
febuxostat. Drug-induced liver dysfunction is a major concern for oncologists treating patients with
lymphoid malignancies because it may exacerbate liver toxicities from certain chemotherapy agents
used in the treatment of lymphoid malignancies (eg, asparaginase, vincristine, and anthracyclines). The
specific types of chemotherapy used in the FLORENCE TRIAL were not indicated.

● Finally, the manufacturer advises against taking azathioprine or mercaptopurine during febuxostat
treatment.

Additional randomized studies are needed to determine the safety of this drug in patients treated for
cancer, especially in the context of potentially hepatotoxic chemotherapy.

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 [2]:

● 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:
Definition, pathogenesis, clinical manifestations, 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 [2].

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

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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, immediately placed on ice, and the assay completed within four hours, if possible (See
'Contraindications and restrictions' above.) [41].

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 monitoring and management based upon the estimated risk for or
presence of TLS (algorithm 1) [49].

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

TREATMENT OF ESTABLISHED TLS — 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: Definition,
pathogenesis, clinical manifestations, etiology and risk factors", section on 'Spontaneous TLS'.)

Patients who present with or develop TLS during therapy should receive intensive supportive care with
continuous cardiac monitoring and measurement of electrolytes, creatinine, and uric acid every four to six
hours [49]. 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 [2]. 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 [49]), 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 per dL2
[49]) 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 [50]. However, patients with severe symptoms of hypocalcemia (eg, tetany or
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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: Definition, pathogenesis, clinical manifestations, 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 [51]. 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 [52].

In countries where rasburicase is available, hyperuricemia is seldom an indication for dialysis after induction
therapy for a hematologic malignancy [17,20]. However, despite the use of rasburicase, approximately 1.5
percent of children and 5 percent of adults require dialysis during induction therapy [20].

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 "Renal 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 renal replacement therapy (RRT)".)

Among the indications for renal replacement therapy in patients with TLS are [2,49,53]:

● 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) [54]. 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 [54]. Peritoneal dialysis is much less efficient with uric acid clearances below 10 mL/min.

Depending upon 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

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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 [55-58]. The phosphorus clearance with CAVHD, for example, can reach 40
mL/min at a dialysate flow rate of four liters per hour [56]. 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 renal 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".)

SUMMARY AND RECOMMENDATIONS

● 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, which results in oliguria or anuria. (See "Tumor lysis syndrome: Definition, pathogenesis, clinical
manifestations, 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 (ALL) 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 therapy. (See "Tumor lysis
syndrome: Definition, pathogenesis, clinical manifestations, 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: Definition, pathogenesis, clinical manifestations, etiology and risk
factors", section on 'Risk stratification'.)

● The best treatment is prevention. Our recommendations for prevention and management are based
upon a disease-specific estimated risk of TLS (table 3) and follow those of an expert panel on prevention
and treatment of TLS [59]. A simplified algorithmic approach to risk stratification and management of
TLS is presented in the figure (algorithm 1) [49].

Prophylaxis

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). If there is no evidence
of acute obstructive uropathy and/or hypovolemia, a loop diuretic may be used to maintain the urine
output, if necessary. (See 'IV hydration' above.)

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

Hypouricemic agents — Hypouricemic agents include allopurinol, rasburicase, and febuxostat.


Rasburicase should generally not be given to individuals with glucose-6-phosphate dehydrogenase (G6PD)
deficiency due to the risk of severe hemolysis, and all patients with possible G6PD deficiency should be
screened for G6PD activity, especially males, individuals of African, Mediterranean, or Southeast Asian
ancestry, and individuals with a prior history of hemolytic reaction to a drug. If administration of rasburicase is

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needed in an emergent situation and the results of G6PD testing 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. 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. (See 'Hypouricemic agents' above and 'Contraindications and restrictions' above and
"Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency".)

● High-risk – 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.)

We recommend a single dose of rasburicase (0.2 mg/kg) rather than multiple-day therapy (Grade 1B).
However, if single-dose therapy is used, uric acid levels must be monitored closely and additional doses
of rasburicase given when the serum uric acid level remains high or hyperuricemia recurs. Allopurinol
treatment can also be started once the serum uric acid is brought down to adequately low or normal
levels. Blood samples for uric acid should be collected in a pre-chilled tube, immediately placed on ice,
and the assay completed within four hours, if possible. (See 'Dosing and administration' above.)

● Intermediate-risk – 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 is a reasonable alternative in this setting [29]. (See 'Allopurinol' above.)

We suggest not using febuxostat as an alternative to allopurinol to prevent TLS in patients at


intermediate to high risk for TLS (Grade 2B). Febuxostat may be used judiciously in patients with
hyperuricemia who cannot tolerate allopurinol in a setting in which rasburicase is not available or
contraindicated. (See 'Febuxostat' above.)

We recommend rasburicase rather than allopurinol if pretreatment uric acid levels are ≥8 mg/dL (476
micromol/L) (Grade 1B). (See 'Management of established TLS' below.)

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 given when hyperuricemia recurs.
Blood samples for uric acid should be collected in a pre-chilled tube, immediately placed on ice, and the
assay completed within four hours, if possible. (See 'Dosing and administration' above.)

● Low-risk – 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).

Posttreatment 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 [2,49]. Evidence of TLS or a rising level of uric acid should prompt immediate therapeutic
intervention. (See 'Treatment of established TLS' above.)

For all patients receiving rasburicase, blood samples for uric acid should be collected in a pre-chilled
tube, immediately placed on ice, and the assay completed within four hours, if possible. (See
'Contraindications and restrictions' above.)
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● For adult patients at intermediate risk not receiving rasburicase, electrolyte levels should be determined
eight hours after chemotherapy and monitored for at least 24 hours after completion of the first cycle of
chemotherapy (24 hours after administration of the final agent for multiagent regimens). (See 'Monitoring
guidelines' above.)

Management of established TLS

● Patients who present with or develop TLS during therapy should receive intensive nursing care with
continuous 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 rasburicase (if it was not given initially), attempting to
wash out the obstructing uric acid crystals with a loop diuretic and intravenous fluids, and the appropriate
use of renal replacement therapy. (See 'Treatment of established TLS' 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

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29. Trifilio S, Gordon L, Singhal S, et al. Reduced-dose rasburicase (recombinant xanthine oxidase) in adult
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51. Patte C, Sakiroglu O, Sommelet D. European experience in the treatment of hyperuricemia. Semin
Hematol 2001; 38:9.
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59. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and prophylaxis of
tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel
consensus. Br J Haematol 2010; 149:578.

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GRAPHICS

Cairo-Bishop definition of laboratory tumor lysis syndrome

Element Value Change from baseline

Uric acid ≥476 micromol/L (8 mg/dL) 25% increase

Potassium ≥6.0 mmol/L (or 6 mEq/L) 25% increase

Phosphorus ≥2.1 mmol/L (6.5 mg/dL) for children or 25% increase


≥1.45 mmol/L (4.5 mg/dL) for adults

Calcium ≤1.75 mmol/L (7 mg/dL) 25% decrease

NOTE: Two or more laboratory changes within three days before or seven days after cytotoxic therapy.

Reproduced with permission from: Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and
adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767. Copyright ©2008 American Society
of Clinical Oncology. All rights reserved.

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Cairo-Bishop clinical tumor lysis syndrome definition* and grading

Grade
Complication
0 1 2 3 4 5

Creatinine ¶Δ ≤1.5 1.5 x ULN >1.5-3.0 x ULN >3.0-6.0 x ULN >6.0 x ULN Death
x
ULN

Cardiac None Intervention Nonurgent medical Symptomatic and Life-threatening Death


arrhythmia ¶ not intervention incompletely (eg, arrhythmia
indicated indicated controlled medically associated with
or controlled with HF, hypotension,
device (eg, syncope, shock)
defibrillator)

Seizure ¶ None - One brief, Seizure in which Seizure of any Death


generalized seizure; consciousness is kind which are
seizure(s) well altered; poorly prolonged,
controlled by controlled seizure repetitive or
anticonvulsants or disorder; with difficult to control
infrequent focal breakthrough (eg, status
motor seizures not generalized seizures epilepticus,
interfering with ADL despite medical intractable
intervention epilepsy)

ULN: upper limit of normal; HF: heart failure; ADL: activities of daily living.
* Clinical tumor lysis syndrome defined as laboratory tumor lysis syndrome plus at least one clinical complication.
¶ Not directly or probably attributable to therapeutic agent.
Δ If no institutional ULN is specified, age/sex ULN creatinine may be defined as follows: >1 to <12 years of age, both
male and female, 61.6 mmol/L; ≥12 to <16 years, both male and female, 88 mmol/L; ≥16 years, female 105.6 mmol/L,
male 114.4 mmol/L.

Reproduced with permission from: Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and
adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767. Copyright © 2008 American Society
of Clinical Oncology. All rights reserved.

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Tumor lysis syndrome (TLS) prophylaxis recommendations based on TLS risk

Intermediate risk disease


Low risk disease (LRD) High risk disease (HRD)
(IRD)
Most solid tumors Rare, highly chemotherapy-sensitive N/A
solid tumors (eg, neuroblastoma,
germ cell tumor, small-cell lung
cancer) with bulky or advanced
stage disease

MM Plasma cell leukemia N/A

CML N/A N/A

Indolent NHL N/A N/A

HL N/A N/A

CLL and WBC <50 x 10 9/L treated CLL treated with fludarabine, CLL treated with venetoclax and
only with alkylating agents rituximab, or lenalidomide, or lymph node ≥10 cm, or lymph node
venetoclax and lymph node ≥5 cm ≥5 cm and absolute lymphocyte
or absolute lymphocyte count ≥25 x count ≥25 x 10 9/L and elevated
10 9/L, and/or those with high WBC baseline uric acid.
≥50 x 10 9/L

AML and WBC <25 x 10 9/L and LDH AML with WBC 25 to 100 x 10 9/L AML and WBC ≥100 x 10 9/L
<2 x ULN
AML and WBC <25 x 10 9/L and LDH
≥2 x ULN

Adult intermediate grade NHL and Adult T cell leukemia/lymphoma, Adult T cell leukemia/lymphoma,
LDH within normal limits diffuse large B-cell, transformed, and diffuse large B-cell, transformed, and
mantle cell lymphomas with LDH > mantle cell lymphomas with bulky
ULN, non-bulky disease and LDH ≥2 x ULN

Adult ALCL Childhood ALCL stage III/IV N/A

N/A Childhood intermediate grade NHL Stage III/IV childhood diffuse large
stage III/IV with LDH <2 x ULN B-cell lymphoma with LDH ≥2 x ULN

N/A ALL and WBC <100 x 10 9/L and LDH Burkitt's leukemia
<2 x ULN
Other ALL and WBC ≥100 x 10 9/L
and/or LDH ≥2 x ULN

N/A Burkitt lymphoma and LDH <2 x ULN Burkitt lymphoma stage III/IV
and/or LDH ≥2 x ULN

N/A Lymphoblastic lymphoma stage I/II Lymphoblastic lymphoma stage


and LDH <2 x ULN III/IV and/or LDH ≥2 x ULN

N/A N/A Intermediate risk disease with renal


dysfunction and/or renal involvement

Intermediate risk disease with uric


acid, potassium, and/or phosphate >
ULN

Prophylaxis recommendations
Monitoring Monitoring Monitoring

Hydration Hydration Hydration

±Allopurinol Allopurinol Rasburicase*

N/A: not applicable; MM: multiple myeloma; CML: chronic myeloid leukemia; NHL: non-Hodgkin lymphoma; HL: Hodgkin
lymphoma; CLL: chronic lymphoid leukemia; WBC: white blood cell count; AML: acute myeloid leukemia; LDH: lactate
dehydrogenase; ULN: upper limit of normal; ALCL: anaplastic large cell lymphoma; ALL: acute lymphoblastic leukemia.
* Contraindicated in patients with a history consistent with glucose-6 phosphate dehydrogenase. In these patients,
rasburicase should be substituted with allopurinol.

Cairo MS, Coiffier B, Reiter A. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS)
in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 2010; 149:578. Copyright
© 2010. Modified with permission of Blackwell Publishing Inc.
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Endogenous production of uric acid

Excessive purine catabolism results in the production of hypoxanthine and


xanthine, which are metabolized to uric acid via the enzymatic action of XO. This
pathway can be blocked by the use of allopurinol, a hypoxanthine analog that
competitively inhibits XO, and febuxostat, a non-purine thiazolecarboxylic acid
derivative that selectively inhibits XO. After about two to three days, allopurinol
and febuxostat result in increased excretion of both hypoxanthine, which is
more soluble than uric acid, and xanthine, which is less soluble than uric acid.
Preformed uric acid is not altered by allopurinol or febuxostat. UO, present in
most mammals but not humans, oxidizes preformed uric acid to allantoin, which
is 5 to 10 times more soluble than uric acid in acid urine. When exogenous UO
(uricase, rasburicase, pegloticase) is administered, serum and urinary uric acid
levels decrease markedly within approximately four hours.

XO: xanthine oxidase; UO: urate oxidase.


* UO is not normally present in humans.

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Algorithmic approach to risk assessment of tumor lysis


syndrome

TLS: tumor lysis syndrome; ULN: Upper limit of normal.

Modified from Howard SC, Jones DP, Pui CH. The Tumor Lysis Syndrome. N Engl J Med 2011;
364:1844.

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Management of electrolyte abnormalities in tumor lysis syndrome

Abnormality Management recommendation

Hyperphosphatemia

Moderate, Restrict phosphate intake (avoid IV and oral phosphate; limit dietary sources)
≥2.1 mmol/L
Phosphate binders:
(6.5 mg/dL)
Calcium acetate * Adult: 2 to 3 tabs (1334 to 2668 mg) with each meal; or
Calcium carbonate* Adult: 1 to 2 grams with each meal; Pediatric: 30 to 40 mg/kg with each meal; or
Sevelamer ¶ Adult: 800 to 1600 mg with each meal; Pediatric: 40 to 54 mg/kg with each meal; or
Lanthanum carbonate Adult: 500 to 1000 mg with each meal Δ; or
Aluminum hydroxide Adult: 300 to 600 mg with each meal; Pediatric: 12.5 to 37.5 mg/kg four times
daily with meals; (avoid use in patients with renal insufficiency)

Severe Dialysis, CAVH, CVVH, CAVHD, or CVVHD

Hypocalcemia, total serum calcium ≤1.75 mmol/L (7 mg/dL) or ionized calcium ≤0.8 mmol/L (3.2
mg/dL)

Asymptomatic No therapy

Symptomatic Calcium gluconate administered slowly with ECG monitoring; patients with acute hypocalcemia
and hyperphosphatemia should not be treated with calcium until the hyperphosphatemia is
corrected (unless they have tetany or a cardiac arrhythmia from hypocalcemia)
Calcium gluconate ◊ Adult: 1 gram (10 mL of 10 percent solution); Pediatric: 50 to 100 mg/kg. Slow
IV infusion (maximum 50 to 100 mg per minute) in large vein. May be repeated after 5 to 10 minutes if
symptoms or ECG changes persist.

Hyperkalemia §

Moderate and Avoid IV and oral potassium


asymptomatic,
ECG and cardiac rhythm monitoring
≥6.0 mmol/L
Sodium polystyrene sulfonate ¥ Adult: 15 to 30 grams orally; Pediatric: 1 gram/kg orally.
Onset 1 to 2 hours. Repeat every 4 to 6 hours up to four times daily as needed based on repeat
serum K+ level.

Severe (>7.0 Same as above, plus:


mmol/L)
To stabilize cardiac membranes:
and/or
symptomatic For patients with ECG changes (widening of the QRS complex or loss of p-waves but not peaked t-waves
alone), give calcium gluconate by slow IV infusion to prevent life-threatening arrhythmias:
Calcium gluconate Adult: 1 gram (10 mL of 10 percent solution); Pediatric: 50 to 100 mg/kg. Slow
IV infusion (maximum 50 to 100 mg per minute) in large vein. May be repeated after 5 to 10
minutes if ECG changes persist.

To temporarily shift potassium into cells:


Give IV insulin and dextrose:
IV insulin and dextrose Adult: regular insulin (10 units) IV plus 100 mL of a 50 percent dextrose
solution (D50) IV; Pediatric: regular insulin (0.1 unit/kg) IV, plus 25 percent dextrose solution (D25)
0.5 gram/kg (2 mL/kg of D25) IV over thirty minutes. May be repeated after thirty to sixty minutes.
Monitor fingerstick glucose closely.
Sodium bicarbonate can be given to induce influx of potassium into cells if patient is acidemic. Sodium
bicarbonate and calcium solutions should not be administered through the same line due to
incompatibility.
Sodium bicarbonate Adult: 45 to 50 mEq; Pediatric: 1 to 2 mEq/kg. Slow IV infusion over five to
ten minutes.
Beta 2 agonist inhalation: Albuterol per nebulisation or metered dose inhaler
Albuterol Adult: 10 to 20 mg in 4 mL saline nebuilzed over 20 minutes or 10 to 20 puffs per
metered dose inhaler over 10 to 20 minutes; Pediatric: 0.1 to 0.3 mg/kg per nebulisation.

Dialysis

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Uremia (renal dysfunction)

Fluid and electrolyte management

Uric acid and phosphate management

Adjust renally excreted drug doses

Dialysis (hemo- or peritoneal)

Hemofiltration (CAVH, CVVH, CAVHD, or CVVHD)

Pediatric dose should not exceed usual adult dose.

IV: intravenous; CAVH: continuous arterial-venous hemofiltration; CVVH: continuous veno-venous hemofiltration; CAVHD:
continuous arterial-venous hemodialysis; CVVHD: continuous veno-venous hemodialysis; ECG: electrocardiogram.
* Calcium-containing binders are generally preferred in presence of hypocalcemia; avoid if hypercalcemic.
¶ Preferred binder in presence of hypercalcemia.
Δ A pediatric dose of lathanum carbonate 7 mg/kg with each meal has been suggested based on limited experience. US
FDA product information states pediatric use is not recommended.
◊ 10% calcium gluconate (90 mg elemental calcium/10 mL) or 10% calcium chloride (270 mg elemental calcium/10 mL)
can be used. Calcium gluconate is usually preferred because it is less likely to cause tissue necrosis if extravasated. For
additional information refer to UpToDate topic on"Treatment of hypocalcemia".
§ For additional information, refer to UpToDate topic on "Treatment and prevention of hyperkalemia in adults".
¥ Patients receiving sodium polystyrene sulfonate should be monitored for the development of hypocalcemia and
hypomagnesemia.

Data from: Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis
syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767.

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Contributor Disclosures
Richard A Larson, MD Grant/Research/Clinical Trial Support: Astellas [leukemia (gilteritinib)]; Erytech
[leukemia (eryaspase)]; Novartis [leukemia (nilotinib, ascininib)]; Daiichi Sankyo [leukemia (quizartinib)];
Celgene [leukemia (enasidenib)]. Consultant/Advisory Boards: Novartis [leukemia (imatinib, nilotinib)]; Ariad
Data Safety Monitoring Board [leukemia (ponatinib)]; CVS/Caremark [leukemia (drug prior authorization
program)]; Celgene Data Safety Monitoring Board [leukemia (azacitidine, durvalumab)]; Amgen [leukemia
(blinatumomab)]; Astellas [leukemia (gilteritinib)]; Jazz [leukemia (CPX-351)]. Ching-Hon Pui,
MD Consultant/Advisory Boards: Adaptive Biotechnologies [Deep sequencing for minimal residual disease
detection]. Reed E Drews, MD Nothing to disclose Arnold S Freedman, MD Consultant/Advisory Boards:
Kahr Therapeutics [SAB]. Other Financial Interest: Novartis [DMB (Ofatumumab)]; Bayer [DMB (Bayer
17833)]. David G Poplack, MD Nothing to disclose Diane MF Savarese, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.

Conflict of interest policy

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