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Kedar Toraskar
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| ©2013 UpToDate ® |
Richard A Larson, MD
Ching-Hon Pui, MD
Reed E Drews, MD
Arnold S Freedman, MD
David G Poplack, MD
Diane MF Savarese, MD
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, and the marked increase in uric acid excretion can result in the precipitation of uric acid in the renal tubules and can also induce renal vasoconstriction, impaired autoregulation, decreased renal blood flow, and inflammation, resulting in acute kidney injury. Hyperphosphatemia with calcium phosphate deposition in the renal tubules can also cause acute kidney injury.
TLS most often occurs after the initiation of cytotoxic therapy in patients with high-grade lymphomas (particularly the Burkitt subtype) and acute lymphoblastic leukemia. However, TLS can occur spontaneously and with other tumor types that have a high proliferative rate, large tumor burden, or high sensitivity to cytotoxic therapy.
The pathogenesis, definition, classification, risk factors, etiology, and clinical presentation of TLS will be reviewed here. Prevention and treatment of TLS are discussed elsewhere, as are issues related to treatment of the particular malignancies that are associated with TLS are discussed separately. (See "Tumor lysis syndrome: Prevention and treatment" 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", section on 'Tumor lysis syndrome' and "Overview of the complications of acute myeloid leukemia", section on 'Tumor lysis syndrome'.)
PATHOGENESIS — In the setting of a malignancy with a high proliferative rate, large tumor burden, and/or a high sensitivity to treatment, initiation of cytotoxic chemotherapy, cytolytic antibody therapy, radiation therapy, or sometimes glucocorticoid therapy alone can result in the rapid lysis of tumor cells. (See 'Etiology and risk factors' below.)
This releases massive quantities of intracellular contents (potassium, phosphate, and nucleic acids that can be metabolized to uric acid) into the systemic circulation. The metabolic consequences include hyperkalemia, hyperphosphatemia, secondary hypocalcemia, hyperuricemia, and acute kidney injury. High levels of both uric acid and phosphate increase the severity of acute kidney injury because uric acid precipitates readily in the presence of calcium phosphate crystals, and calcium phosphate precipitates readily in the presence of uric acid crystals.
Hyperuricemia — Hyperuricemia is a consequence of the catabolism of purine nucleic acids to hypoxanthine and xanthine and then to uric acid via the enzyme xanthine oxidase (figure 1). Uric acid is poorly soluble in water, particularly in the usually acidic environment in the distal tubules and collecting system of the kidney. Overproduction and overexcretion of uric acid in TLS can lead to crystal precipitation and deposition in the renal tubules, and acute uric acid nephropathy with acute kidney injury. (See "Uric acid renal diseases".)
With the development of effective hypouricemic agents (rasburicase and allopurinol), hyperuricemia is no longer the major metabolic complication associated with TLS [1,2] (see "Tumor lysis syndrome: Prevention and treatment", section on 'Hypouricemic agents' and "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of TLS').
As an example, in a report of 102 patients with intermediate to high-grade non-Hodgkin lymphoma who received aggressive combination chemotherapy with allopurinol prophylaxis, laboratory abnormalities developed in 42 percent of the patients, but only 6 percent developed "clinical" TLS [1]. With the use of allopurinol, the serum uric acid concentration rose by more than 25 percent in only 28 patients, and the peak exceeded the upper limit of normal (ULN, 8 mg/dL [476 micromol/L]) in only nine patients and exceeded 15 mg/dL (893 micromol/L) in only three patients, one of whom developed acute kidney injury.
Hyperphosphatemia — The phosphorus concentration in malignant cells is up to four times higher than in normal cells. Thus, rapid tumor breakdown often leads to hyperphosphatemia which can cause secondary hypocalcemia. When the calcium concentration times phosphate concentration (the calcium phosphate product) exceeds 60 mg2/dL2, there is an increased risk of calcium phosphate precipitation in the renal tubules, which can lead to acute kidney injury. In addition, precipitation in the heart may lead to cardiac arrhythmias. (See "Overview of the causes and treatment of hyperphosphatemia".)
Since the widespread use of hypouricemic agents, calcium phosphate deposition (nephrocalcinosis) rather than hyperuricemia has become the major mechanism of acute kidney injury in TLS [1,3,4]. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Hypouricemic agents' and "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of TLS'.)
Xanthinuria — Allopurinol blocks the catabolism of hypoxanthine and xanthine, leading to an increase in the levels of these metabolites (figure 1). Xanthine is much less soluble than uric acid, and urinary alkalinization increases the solubility of xanthine much less than the solubility of uric acid because the pKa is much higher for xanthine (7.4 versus 5.8) [5].
Thus, patients with massive TLS who are receiving allopurinol are at risk for xanthine precipitation in the tubules, resulting in xanthine nephropathy or xanthine stone formation [6-10]. Because the serum xanthine level is not routinely measured, its effect on the risk of acute kidney injury is not certain. In contrast to the effect of allopurinol, xanthine excretion is not increased by rasburicase (recombinant urate oxidase), which is now preferred in most patients at high risk for TLS. Rasburicase promotes the degradation of uric acid to the much more water-soluble compound allantoin. However, in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, hydrogen peroxide, a breakdown product of uric acid, can cause methemoglobinemia and in severe cases, hemolytic anemia. For this reason, rasburicase is contraindicated in patients with G6PD deficiency. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Rasburicase'.)
CLINICAL MANIFESTATIONS — The symptoms associated with TLS largely reflect the associated metabolic abnormalities (hyperkalemia, hyperphosphatemia, and hypocalcemia). They include nausea, vomiting, diarrhea, anorexia, lethargy, hematuria, heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and possible sudden death [11].
Acute uric acid or calcium phosphate deposition does not usually cause symptoms referable to the urinary tract, although flank pain can occur if there is renal pelvic or ureteral stone formation. The urinalysis classically shows many uric acid crystals or amorphous urates in an acid urine (picture 1), but is occasionally relatively normal due to lack of output from the obstructed nephrons.
DEFINITION AND CLASSIFICATION — Although there is a general consensus that TLS represents a set of metabolic complications that arise from treatment of a rapidly proliferating and drug-sensitive neoplasm, there have been relatively few attempts to specifically define the syndrome [12,13]. The 1993 Hande-Garrow classification system distinguished between laboratory versus clinical TLS within four days of initial anticancer treatment, but did not take into account patients who already had abnormal laboratory values prior to treatment or those who developed metabolic abnormalities at a later time point [1].
Cairo-Bishop definition — The Cairo-Bishop definition, proposed in 2004, provided specific laboratory criteria for the diagnosis of TLS both at presentation and within seven days of treatment [13]. It also incorporated a grading system to help delineate the degree of severity of TLS.
- Laboratory TLS (TLS) was defined as any two or more abnormal serum values, as outlined in the table (table 1), present within three days before or seven days after instituting chemotherapy in the setting of adequate hydration (with or without alkalinization) and use of a hypouricemic agent.
- Clinical TLS (CTLS) was defined as laboratory TLS plus one or more of the following that was not directly or probably attributable to a therapeutic agent: increased serum creatinine concentration (≥1.5 times the upper limit of normal [ULN]), cardiac arrhythmia/sudden death, or a seizure.
A grading system for severity of TLS (on a scale from zero to five) in patients with laboratory TLS was based on the degree of elevation in serum creatinine, the presence and type of cardiac arrhythmia, and the presence and severity of seizures (table 2). This scheme for grading severity is far more useful than the most recent modification of the widely used NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03), which only grades TLS as grade 3 (present), grade 4 (life-threatening consequences; urgent intervention indicated) or grade 5 (death) [14].
The Cairo-Bishop classification has been adopted by the Children's Oncology Group for use in treatment protocols for advanced stage lymphoma and by an international panel of experts assembled to establish evidence-based guidelines for prevention and treatment of pediatric and adult TLS [11,15]. (See "Tumor lysis syndrome: Prevention and treatment" and "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of TLS'.) In a review, Howard et al suggested that two or more laboratory abnormalities should be present simultaneously to define laboratory TLS and that any symptomatic hypocalcemia should constitute clinical TLS [16].
ETIOLOGY AND RISK FACTORS — The risk of TLS is greatest in patients treated for hematologic malignancies but is not uniform among these disorders (table 3).
Certain intrinsic tumor-related factors are associated with a higher risk. These include [1,11,13,15-19]:
- High tumor cell proliferation rate
- Chemosensitivity of the malignancy
- Large tumor burden, as manifested by bulky disease >10 cm in diameter and/or a white blood cell count >50,000 per microL, a pretreatment serum lactate dehydrogenase (LDH) more than two times the upper limit of normal, organ infiltration, or bone marrow involvement
There are also clinical features that predispose to the development of TLS [1,11,13,15,16,18]:
- Pretreatment hyperuricemia (serum uric acid >7.5 mg/dL [446 micromol/L]) or hyperphosphatemia
- A preexisting nephropathy or exposure to nephrotoxins
- Oliguria and/or acidic urine
- Dehydration, volume depletion, or inadequate hydration during treatment
The importance of impaired renal function as a risk factor for TLS was illustrated in a series of 102 patients with high-grade NHL [1]. Patients with a baseline serum creatinine >1.5 mg/dL (133 micromol/L) had a markedly higher rate of clinical TLS than did those with a lower serum creatinine (36 versus 2 percent).
Hematologic malignancies — The tumors most frequently associated with tumor lysis syndrome (TLS) are clinically aggressive non-Hodgkin lymphomas (NHLs) and acute lymphoblastic leukemia (ALL), particularly Burkitt lymphoma/leukemia (table 3) [1,17,20-24].
The incidence of TLS in these patients can be illustrated by the following reports:
- In the series cited above of 102 adults with high-grade NHL, most of whom received prophylaxis with allopurinol alone, the overall incidence of TLS was 42 percent and 6 percent developed "clinical" TLS [1]. Clinical TLS was defined in this series as serum potassium >6.0 meq/L, serum creatinine >2.5 mg/dL [221 micromol/L], serum calcium ≤6.0 mg/dL [1.5 mmol/L], the development of a life-threatening arrhythmia, or sudden death.
- The incidence of TLS was assessed in a series of children with advanced stage Burkitt's lymphoma/leukemia who were enrolled in two multicenter trials [17]. All were treated with aggressive intravenous hydration, urinary alkalinization (urine pH 7), and allopurinol but not rasburicase, which was not available at that time. Among the 218 evaluable children with Burkitt ALL or stage III/IV Burkitt lymphoma with a high pretreatment serum LDH (≥500 U/L [8.3 kat/L]), TLS (laboratory and/or clinical) developed in 16.1 percent and anuria in 9.2 percent.
Other hematologic malignancies that are less commonly associated with TLS include other clinically aggressive lymphomas such as anaplastic large cell lymphoma, T-cell or B-ALL, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and plasma cell disorders, including multiple myeloma and isolated plasmacytomas [1,18,25-29].
The incidence of TLS in AML was addressed in a single institution series of 772 adult patients who received induction chemotherapy between 1980 and 2002 [18]. Prophylactic measures included intravenous hydration and allopurinol. Overall, 130 (17 percent) developed TLS (5 percent clinical, 12 percent laboratory according to the Cairo-Bishop definition described above). On multivariate analysis, the following pretreatment laboratory findings were independent risk factors for TLS: serum LDH above laboratory normal values, serum creatinine ≥1.4 mg/dL (124 micromol/L), pretreatment serum uric acid >7.5 mg/dL (446 micromol/L), and white blood cell (WBC) count ≥25,000/microL. These four factors were used to develop a scoring system to predict the development of TLS in AML. (See 'Risk stratification in acute leukemia' below.)
Most cases of TLS in patients with hematologic malignancies follow treatment with combination cytotoxic chemotherapy. However, TLS has also been described in case reports with glucocorticoids alone in patients with NHL and ALL [30,31], with therapeutic monoclonal antibodies (primarily rituximab in patients with high-grade NHL [21-23] but also bortezomib in multiple myeloma [28,29]), with imatinib for chronic myeloid leukemia [32], and with radiation therapy alone for NHL and ALL [24,33].
Solid tumors — TLS has been rarely described after treatment of nonhematologic solid tumors [19,34]. These include breast cancer [35-37], small cell carcinoma (mostly involving the lung) [19,35], neuroblastoma [35], germ cell tumors [19,38], medulloblastoma [19], sarcoma [19,39], ovarian cancer [40,41], squamous cell carcinoma of the vulva [42], metastatic colorectal cancer [43], urothelial cancer [44], gastrointestinal stromal tumors [45], melanoma [19], and hepatocellular carcinoma [19].
Spontaneous TLS — Spontaneous acute kidney injury associated with marked hyperuricemia prior to the initiation of therapy has been described in NHL and acute leukemia [20,25,46,47], and in at least one patient with inflammatory breast cancer [48]. The actual incidence of this syndrome is difficult to ascertain. In a series of 33 patients with aggressive or highly aggressive NHL, three had marked hyperuricemia (plasma uric acid concentration >17 mg/dL [1012 micromol/L]) and acute kidney injury requiring hemodialysis prior to the initiation of chemotherapy [20].
Interestingly, spontaneous TLS is associated with hyperuricemia but frequently without hyperphosphatemia. It has been postulated that rapidly growing neoplasms with high cell turnover rates produce high serum uric acid levels through rapid nucleoprotein turnover but that the tumor is able to reutilize released phosphorus for resynthesis of new tumor cells [25]. In contrast, TLS after chemotherapy is due to cell destruction in the absence of reuptake of phosphorus, and thus, hyperphosphatemia.
RISK STRATIFICATION — In 2008, an international expert panel published evidence-based guidelines for the prevention and management of TLS [11], which were subsequently refined and updated [15]. A risk stratification system for TLS was proposed using the type of malignancy, the burden of disease, treatment, expected response to treatment, and renal function (table 4). The recommended therapy varied according to the risk category. Both the stratification system and the specific treatment recommendations were defined by consensus opinion; neither has been validated in a prospectively defined group of patients.
High-risk — Included in the high-risk group (>5 percent risk of TLS) are [15]:
- All Burkitt leukemia, stage III or IV Burkitt lymphoma or early stage Burkitt lymphoma with serum LDH level two or more times the upper limit of normal (≥2xULN)
- Other ALL with a WBC ≥100,000 per microL and/or serum LDH level ≥2X ULN
- AML with WBC ≥100,000 per microL
- Stage III or IV lymphoblastic lymphoma or early stage lymphoblastic lymphoma with serum LDH level two or more times the upper limit of normal (≥2X ULN)
- Adult T-cell lymphoma/leukemia, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, transformed lymphoma, or mantle cell lymphoma with serum LDH level above the ULN and a bulky tumor mass
- Stage III or IV childhood diffuse large B-cell lymphoma with serum LDH level ≥2X ULN
- Patients with intermediate risk disease (see below) with renal dysfunction and/or renal involvement, or uric acid, potassium, or phosphate levels above the ULN
In keeping with the recommendations of the expert panel [11], we recommend that all patients that fit into these high-risk categories receive aggressive IV hydration and prophylactic rasburicase rather than allopurinol prior to treatment initiation (unless they have G6PD deficiency) (see "Tumor lysis syndrome: Prevention and treatment", section on 'Rasburicase' and "Tumor lysis syndrome: Prevention and treatment", section on 'Contraindications and restrictions').
Other definitions for high-risk have been proposed. As an example, the SFCE (French Society Against Cancers and Leukemias of Children and Adolescents) classifies children as high-risk for TLS if they have one of the following: leukocyte count >50,000 per microL, large tumor burden (major hepatomegaly or splenomegaly, lymph nodes or a mediastinal mass >5 cm), T-cell or B-cell lymphoma, L3 ALL (Burkitt leukemia), AML, any other leukemia with serum LDH >2x the ULN, creatinine >ULN for age and weight, uric acid ≥300 micromol/L if ≤10 years of age, or ≥350 micromol/L if >10 years old, and serum phosphorus level >2 mmol/L [49]. They recommend that all such patients receive rasburicase 0.2 mg/kg per day for five days.
Intermediate-risk — The intermediate-risk group (risk of TLS 1 to 5 percent) includes [15]:
- Adult T-cell lymphoma/leukemia, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, transformed lymphoma, or mantle cell lymphoma with serum LDH level above ULN but without bulky disease
- Stage III or IV childhood anaplastic large cell lymphoma with serum LDH level <2X ULN
- Stage III or IV childhood diffuse large B-cell lymphoma with serum LDH level ≥2X ULN
- Early stage Burkitt lymphoma with serum LDH level <2X ULN
- ALL with WBC <100,000/microL and serum LDH level <2X ULN
- AML with WBC 25,000 to 100,000/microL, or AML with WBC<25,000/microL and LDH ≥ 2X ULN
- Early stage lymphoblastic lymphoma with serum LDH level <2X ULN
- Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with fludarabine, rituximab, or lenalidomide and/or those with a high WBC (≥50,000/microL)
- Rare bulky solid tumors that are highly sensitive to chemotherapy (such as neuroblastoma, germ cell cancer, small cell lung cancer)
However, there is disagreement among experts as to the overall risk of TLS with CLL/SLL. Some clinicians consider that patients with CLL/SLL and a WBC count between 10,000 and 50,000/microL are at relatively low risk for TLS, regardless of treatment, while others consider all patients with CLL/SLL to be at risk for TLS if they have a WBC ≥50,000, or low circulating WBC counts and a packed marrow, particularly if they are older and have borderline renal function. Although initially reported with fludarabine and rituximab, there are now several reports of TLS occurring after lenalidomide or flavopiridol therapy for fludarabine-refractory CLL [50,51].
In keeping with the recommendations of the expert panel, we generally use allopurinol rather than rasburicase for prophylaxis in most of these patients in the absence of pretreatment hyperuricemia. An alternative approach is administration of a single dose of rasburicase [52,53]. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Allopurinol' and "Tumor lysis syndrome: Prevention and treatment", section on 'Dosing and administration'.)
Some clinicians routinely place all CLL/SLL patients on allopurinol prior to initial chemotherapy, and treatment protocols from the Cancer and Leukemia Group B (CALGB) routinely recommend allopurinol 300 mg daily for the first 14 days of chemotherapy, thereafter at the clinician's discretion. However, as noted above, patients with CLL and a WBC 10,000 to 50,000/microL have a relatively low risk of TLS, regardless of treatment, and others approach these patients with hydration and close monitoring rather than routine prophylaxis with any hypouricemic agent. In our view, treatment of these patients should be individualized based upon circulating WBC count, status of the bone marrow, and renal function.
Low-risk — Patients at low risk for TLS (<1 percent risk) include [15]:
- AML with WBC <25,000/microL and serum LDH level <2X ULN
- CLL/SLL with a WBC ≤50,000/microL and not treated with fludarabine/rituximab
- Multiple myeloma and CML
- Other adult NHL that do not meet the criteria for high-risk of intermediate risk, with serum LDH level within normal limits
- Other solid tumors
We generally recommend hydration but do not administer any form of prophylactic hypouricemic therapy or phosphate binders to patients in the low-risk category. This is in agreement with the expert panel recommendation for a "watch and wait" approach with close monitoring rather than routine prophylaxis in these patients [15]. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Prevention'.)
Risk stratification in acute leukemia — Predictive models for the probability of TLS in patients treated for AML or pediatric ALL have been developed [18,54,55]. As previously described, a scoring system to predict TLS was developed and validated in a series of 772 adult patients with AML treated at a single institution over a 22-year period [18]. (See 'Hematologic malignancies' above.)
The patients were randomly divided into two groups; the prognostic model was developed in one group and validated in the other. In multivariate analysis, four pretreatment laboratory findings were independent risk factors for TLS: serum LDH above laboratory normal values, serum creatinine ≥1.4 mg/dL (124 micromol/L), pretreatment serum uric acid >7.5 mg/dL (446 micromol/L), and white blood cell (WBC) count ≥25,000/microL. FAB classification was not an independent predictor of TLS. (See "Classification of acute myeloid leukemia".)
The authors assigned a point value to these factors and developed a scoring system to predict the probability of clinical TLS (table 5):
- Score 0 — 0 percent
- Score 1 — 1.4 percent
- Score 2 — 4.1 percent
- Score 3 — 11.5 percent
- Score 4 — 17.8 percent
- Score 5 — 36.8 percent
- Score 6 — 41.7 percent
The authors suggested that the model might permit risk-adapted management of TLS in AML, specifically the selection of those high-risk patients who should receive prophylactic rasburicase. However, they did not make a specific recommendation as to which score should be used as the cutoff for the use of rasburicase versus allopurinol. In general, these models are complex, and they lack standardized guidelines for supportive care guidelines. We generally prefer the risk stratification system proposed by the expert consensus panel (table 4) [11]. Prevention and treatment of TLS according to estimated risk of TLS are discussed in detail elsewhere. (See "Tumor lysis syndrome: Prevention and treatment".)
SUMMARY
- Tumor lysis syndrome (TLS) is an oncologic emergency that is caused by massive tumor cell lysis and the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation. Deposition of uric acid and/or calcium phosphate crystals in the renal tubules can result in acute kidney injury. (See 'Pathogenesis' above.)
- Laboratory TLS (TLS) is defined as any two or more of the following metabolic abnormalities and presents within three days before or seven days after instituting chemotherapy: hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia (table 1).
- Clinical TLS is defined as laboratory TLS plus one or more of the following that was not directly or probably attributable to a therapeutic agent: increased serum creatinine concentration (≥1.5 times the ULN), cardiac arrhythmia/sudden death, or a seizure. A grading system for TLS based upon the severity of clinical TLS is presented in the table (table 2)
- TLS is observed most frequently in patients with high-grade lymphomas (particularly the Burkitt subtype) and mature B-cell acute lymphoblastic leukemia following the initiation of cytotoxic therapy, although it may also occur spontaneously and/or in other tumor types with a high proliferative rate, large tumor burden, or high sensitivity to cytotoxic therapy. However, with the development of effective targeted therapy, TLS is now being reported in cancers that previously were only rarely associated with this complication, eg, colon cancer and chronic myeloid leukemia. (See 'Etiology and risk factors' above.)
- Risk stratification based upon tumor-related and patient-related factors can permit an assessment of the risk of TLS which may assist in selecting therapy (table 4). A simplified algorithmic approach to risk stratification for TLS is presented in the figure (algorithm 1) [16]. (See 'Risk stratification' above.)
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Kedar Toraskar
UpToDate is an online clinical decision support resource featuring over 10,000 clinical topics designed to give immediate answers to clinical questions at the point of care. Visit us on the web at www.uptodate.com.
| ©2013 UpToDate ® |
Richard A Larson, MD
Ching-Hon Pui, MD
Reed E Drews, MD
Arnold S Freedman, MD
David G Poplack, MD
Diane MF Savarese, MD
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", 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 [1]. (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) [2]. 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 [3].
- 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) [4]. 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 [5]. 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'.)
PREVENTION
IV hydration — Aggressive intravenous (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) [1]. The goal of IV hydration is 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). 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) [1]. 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. 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% dextrose one-quarter normal (isotonic) saline, probably because ALL patients receive steroid during remission induction, which can cause sodium retention and hypertension [1]. 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 tumor lysis syndrome 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 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 7.0 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 [6].
- 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 [1]. 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 — 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]. However, there are several limitations to its use:
- Because it acts by decreasing uric acid formation, allopurinol does not reduce the serum uric acid concentration before treatment is initiated. 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 also reduces the degradation of other purines, dose reductions of 65 to 75 percent are needed in patients being treated with mercaptopurine or azathioprine [9,10].
- Allopurinol has the potential to interact with a number of other drugs, including cyclophosphamide, high-dose methotrexate, ampicillin, and thiazide diuretics.
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 [1]. The dose must be reduced by 50 percent in the setting of acute kidney injury.
Among 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).
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 tumor lysis syndrome (TLS) [7,13-19]. 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 NHL, or AML) [14]. 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 1.0 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 [7].
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 to 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 Aspergillus flavus, and the other, rasburicase) [20]. The frequency of normalization of uric acid was significantly higher with urate oxidase (relative risk [RR] 19.09, 95% CI 1.28 to 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 to 0.89) and a lower incidence of acute kidney injury (RR 0.13, 95% CI, 0.05 to 0.35) with urate oxidase as compared to allopurinol.
Based upon the single randomized trial showing no significant difference in mortality or acute kidney injury between urate oxidase and allopurinol [7], 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 represents 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 [15]. 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) [21]. Compared to 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 to 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 [21] 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 [22].
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 [23]. 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 United States 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') [1]:
- 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.
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.
Responses 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 [24].
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 [18,25-32]. In some of these studies, adults were treated with a single 3 mg dose [18,29,32]. 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 [19]. 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 glucose-6-phosphate dehydrogenase (G6PD) deficiency.
The efficacy and cost of a single dose of rasburicase compared to daily dosing was addressed in a meta-analysis of 10 studies (eight retrospective and two prospective) [33]. 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 UA level below 4 mg/dl at 24 hours, whereas the pooled standard single dose group maintained the plasma urate 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 black box warning about anaphylaxis, hemolysis, hemoglobinuria, methemoglobinemia, and interference with serum uric acid measurements:
- Rasburicase is CONTRAINDICATED in pregnant or lactating women and in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, because hydrogen peroxide, a byproduct of uric acid breakdown, can cause severe hemolysis and methemoglobinemia in patients with the enzyme deficiency [34]. 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 or racial/ethnic background (African-American, Mediterranean, or Southeast Asian descent) should undergo screening with available semiquantitative tests. If the screening test is positive, definitive testing using measurement of red blood cell NADPH formation is recommended.
The diagnosis of G6PD deficiency is discussed in detail separately. (See "Diagnosis and treatment of glucose-6-phosphate dehydrogenase deficiency".) - 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 prechilled tube, immediately placed on ice, and the assay completed within four hours, if possible [35]. (See 'Monitoring guidelines' below.)
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 [1]:
- It is not necessary for all patients to undergo induction therapy in an intensive care unit (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 lactate dehydrogenase [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 [1].
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 prechilled tube, immediately placed on ice, and the assay completed within four hours, if possible (See 'Contraindications and restrictions' above.) [35].
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) [36].
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 [36]. 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 [1]. These guidelines are valid for children, but some modification is needed in adults (eg, adults with hyperkalemia who have 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 [36]), 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 [36]) 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 [37]. 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-ALL who received prophylactic urate oxidase therapy required dialysis during induction therapy, and none died from acute kidney injury or other metabolic complications [38]. This compares favorably to 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 [39].
In countries where rasburicase is available, hyperuricemia is seldom an indication for dialysis after induction therapy for a hematologic malignancy [14,17]. However, despite the use of rasburicase, approximately 1.5 percent of children and 5 percent of adults require dialysis during induction therapy [17].
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 [1,36]:
- Severe oliguria or anuria
- Persistent hyperkalemia
- Hyperphosphatemia-induced symptomatic hypocalcemia
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) [40]. 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 [40]. 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 [41-44]. The phosphorus clearance with CAVHD, for example, can reach 40 mL/min at a dialysate flow rate of four liters per hour [42]. 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 is usually anuric. (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 tumor lysis syndrome [45]. A simplified algorithmic approach to risk stratification and management of TLS is presented in the figure (algorithm 1) [36].
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
- High-risk — For the initial management of pediatric and adult patients at high risk for TLS (table 3), 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 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, allopurinol treatment should also be given, uric acid levels must be monitored closely and additional doses of rasburicase given when and if hyperuricemia recurs. Blood samples for uric acid should be collected in a prechilled 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 [25]. (See 'Allopurinol' 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 prechilled 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, 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 LDH should be assessed four to six hours after the initial administration of chemotherapy, and every 6 to 12 hours thereafter [1,36]. 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 prechilled tube, immediately placed on ice, and the assay completed within four hours, if possible. (See 'Contraindications and restrictions' above.) - 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
REFERENCES
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