Disclosures: Richard A Larson, MD Clinical Trial Support: Amgen [leukemia (Blinatumomab)]; Astellas [leukemia (ASP2215)]; Ariad [leukemia (Ponatinib)]; Erytech [leukemia (ERYASP)]; Ambit Bioscience [leukemia (quizartinib)]. Consultant/Advisory Boards: Ariad [leukemia (Ponatinib)]; Amgen [leukemia (Blinatumomab)]; Astellas [leukemia (ASP2215)]; Bayer [leukemia (Copanlisib)]; BristolMyers [leukemia (Dasatinib)]; Celgene [leukemia (Azacitidine)]; CVS/Caremark [leukemia (multiple drugs for hematologic malignancies)]; Incyte [leukemia]; Novartis [leukemia (Nilotinib)]; Pfizer [leukemia (Gemtuzumab ozogamicin)]. Ching-Hon Pui, MD Nothing to disclose. Reed E Drews, MD Nothing to disclose. Arnold S Freedman, MD Grant/Research/Clinical Trial Support: Immunogen [cancer (IMGN 529-0301)]. Other Financial Interest: Axio [cancer DSMB (pixantrone)]. David G Poplack, MD Nothing to disclose. Diane MF Savarese, MD Nothing to disclose.
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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'.)
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, 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 tumor lysis syndrome (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 . (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) . 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 renal failure, 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 .
●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) . 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 . 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.
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'.)
IV hydration — Aggressive intravenous (IV) hydration is the cornerstone of preventing tumor lysis syndrome (TLS) and is recommended prior to therapy in all patients at intermediate or high risk for TLS (table 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) . 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 . 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 .
●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 . 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.)
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 [7,8]. 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 [9,10].
●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 . 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) [11,12]. 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 . 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 "Prevention of recurrent 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.)
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 [14-16].
●Dose adjustment is not needed in patients with mild to moderate renal impairment .
●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 febuxostat, each administered orally for seven to nine days . 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 Area under the Curve (AUC) assessed from baseline to day 8, with febuxostat (514 versus 708 mgxh/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 in 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).
●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) . 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 . 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.
Rasburicase — 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 [7,21-28]. 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]) . 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 .
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.
●A Cochrane review evaluating the benefit of urate oxidase for prevention and treatment of TLS in children with cancer included the above randomized trial and three controlled but not randomized studies comparing outcomes in patients treated with allopurinol versus urate oxidase (two of which used uricozyme, a nonrecombinant form of urate oxidase derived from A. flavus, and the other, rasburicase) . The frequency of normalization of uric acid was significantly higher with urate oxidase (relative risk [RR] 19.09, 95% CI 1.28-285.41), as was the area under the curve of uric acid. One single controlled clinical trial reported significantly lower mortality due to TLS (RR 0.05, 95% CI 0.00-0.89) and a lower incidence of acute kidney injury (RR 0.13, 95% CI, 0.05-0.35) with urate oxidase as compared with allopurinol.
Based upon the single randomized trial showing no significant difference in mortality or acute kidney injury between urate oxidase and allopurinol , 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 mortality or acute kidney injury. 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. We believe that the available data represent high-quality 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 . 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 versus 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) . 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 (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  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 .
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 . 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') :
●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 undetectable plasma uric acid concentration within four hours after administration .
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 [26,34-41]. In some of these studies, adults were treated with a single 3 mg dose [26,38,41]. 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 . 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) . 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 is CONTRAINDICATED in patients with G6PD deficiency because hydrogen peroxide, a byproduct of uric acid breakdown, can cause severe hemolysis in this setting . 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 , preferably before administration of rasburicase. If hemolysis occurs, rasburicase should be immediately and permanently discontinued, and an alternative hypouricemic agent should be used. Additional details regarding testing for G6PD deficiency are presented separately. (See "Diagnosis and treatment 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 . 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 . (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.
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 :
●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 .
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, immediately placed on ice, and the assay completed within four hours, if possible (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.
TREATMENT OF ESTABLISHED TLS — Despite appropriate preventive measures, approximately 3 to 5 percent of patients develop laboratory and/or clinical evidence of tumor lysis syndrome (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 . 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 . 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 ), continuous cardiac monitoring, and the administration of oral 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 '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 ) 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 . 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: 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 . 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 .
In countries where rasburicase is available, hyperuricemia is seldom an indication for dialysis after induction therapy for a hematologic malignancy [22,25]. However, despite the use of rasburicase, approximately 1.5 percent of children and 5 percent of adults require dialysis during induction therapy .
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 (acute renal failure) 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 [1,47]:
●Severe oliguria or anuria
●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) . Hemodialysis is efficient in removing uric acid; the clearance is about 70 to 100 mL/min, and serum uric acid levels fall by about 50 percent with each six-hour treatment . 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 frequently necessary to perform hemodialysis at 12 to 24-hour intervals.
Continuous renal replacement therapies such as arteriovenous hemodialysis (CAVHD) with a high dialysate flow rate, 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 [52-55]. The phosphorus clearance with CAVHD, for example, can reach 40 mL/min at a dialysate flow rate of four liters per hour . 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 therapies: Overview".)
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 T-cell 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 . A simplified algorithmic approach to risk stratification and management of TLS is presented in the figure (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). 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.)
●High-risk – For the initial management of 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.)
All patients (especially males) with the potential for glucose-6-phosphate dehydrogenase (G6PD) deficiency by virtue of their racial/ethnic background (African, Mediterranean, Southeast Asian ancestry) or prior history of hemolytic reaction to a drug should be screened for G6PD deficiency prior to administration of rasburicase. If the screening test is positive, definitive testing (ie, measurement of red blood cell nicotinamide adenine dinucleotide phosphate [NADPH] formation) is recommended. We recommend not using rasburicase in patients with G6PD deficiency (Grade 1A). (See 'Contraindications and restrictions' above and "Diagnosis and treatment of glucose-6-phosphate dehydrogenase deficiency".)
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 . (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.)
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.)
●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 [1,47]. 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.)
●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
•Hyperphosphatemia-induced symptomatic hypocalcemia
•A calcium-phosphate product ≥70 mg2/dL2
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