Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors

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 and in the cardiac conduction system can result in arrhythmias.

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. (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 "Acute myeloid leukemia: Overview of complications", section on 'Tumor lysis syndrome' and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Complications of ALL/LBL and treatment'.)

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. With the emergence of new effective and targeted anticancer drugs or new combinations of drugs, TLS has also been observed in patients with cancers that were previously rarely associated with this complication. (See '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 kidney diseases".)

With the development of effective hypouricemic agents, allopurinol and especially rasburicase, 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 tumor lysis syndrome'.)

As an example, in a report of 102 patients with intermediate- to high-grade non-Hodgkin lymphoma (NHL) who received aggressive combination chemotherapy with allopurinol prophylaxis, laboratory abnormalities developed in 42 percent of the patients, and 6 percent developed "clinical" TLS [1]. With the prophylactic use of allopurinol, the serum uric acid concentration rose by more than 25 percent in 28 patients, and the peak exceeded the upper limit of normal (8 mg/dL [476 micromol/L]) in nine patients and exceeded 15 mg/dL (893 micromol/L) in three patients, one of whom developed acute kidney injury. In another study of 100 adult patients with aggressive NHL who received rasburicase for prophylaxis during the first course of chemotherapy, all patients had normal uric acid levels throughout chemotherapy, even though 11 percent presented with hyperuricemia at the time of diagnosis [3].

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, leading to tetany or seizures. 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. Renal replacement therapy may be needed if the calcium phosphate product is ≥70 mg²/dL². (See "Overview of the causes and treatment of hyperphosphatemia" and "Tumor lysis syndrome: Prevention and treatment", section on 'Indications for renal replacement therapy'.)

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 [1,4,5]. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Hypouricemic agents' and "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome'.)

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) [6].

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 [7-11]. 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 concentration 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 [12].

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 [13,14]. 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 [14]. It also incorporated a grading system to help delineate the degree of severity of TLS.

●Laboratory TLS was defined as any two or more abnormal serum values (either a value above the upper limit of normal [ULN] or a 25 percent increase in the serum value over baseline), as outlined in the table (table 1), present within three days before or seven days after instituting chemotherapy in the setting of adequate volume expansion (with or without alkalinization) and use of a hypouricemic agent.

●Clinical TLS 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 ULN), cardiac arrhythmia/sudden death, or a seizure.

Grading system — 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 National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03), which only grades TLS as grade 3 (present), grade 4 (life-threatening consequences; urgent intervention indicated), or grade 5 (death) [15].

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 [12,16] (see "Tumor lysis syndrome: Prevention and treatment" and "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome'). 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 [17].

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 [1,12,14,16-20]:

●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 [1,12,14,16,17,19]:

●Pretreatment hyperuricemia (serum uric acid >7.5 mg/dL [446 micromol/L]) or hyperphosphatemia (serum phosphate >4.5 mg/dL [1.44 micromol/L])

●A preexisting nephropathy or exposure to nephrotoxins

●Oliguria and/or acidic urine

●Volume depletion or inadequate volume expansion 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 non-Hodgkin lymphoma (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 TLS are clinically aggressive NHLs and acute lymphoblastic leukemia (ALL), particularly Burkitt lymphoma/leukemia (table 3) [1,18,21-25], and chronic lymphocytic leukemia (CLL).

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 mEq/L, serum creatinine >2.5 mg/dL [221 micromol/L], serum calcium ≤6 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 lymphoma/leukemia who were enrolled in two multicenter trials [18]. All were treated with aggressive intravenous volume expansion, 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 were less commonly associated with TLS (before the current era of precision medicine) include other clinically aggressive lymphomas, such as anaplastic large cell lymphoma, T-cell or B-ALL, acute myeloid leukemia (AML), CLL, and plasma cell disorders, including multiple myeloma and isolated plasmacytomas [1,19,26-30].

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 [19]. Prophylactic measures included intravenous volume expansion 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 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 [31,32], with therapeutic monoclonal antibodies (primarily rituximab in patients with high-grade NHL [22-24] but also bortezomib in multiple myeloma [29,30]), with imatinib for chronic myeloid leukemia [33], with venetoclax for CLL or AML, and with radiation therapy alone for NHL and ALL [25,34,35].

The emergence of effective targeted anticancer drugs, used alone or in combination with conventional cytotoxic agents, has led to an increase in the frequency and severity of TLS in hematologic cancers that previously were rarely associated with this complication [36], including:

●Venetoclax, a BCL-2 inhibitor used for CLL and AML. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax' and "Acute myeloid leukemia: Management of medically unfit adults", section on 'HMA plus venetoclax'.)

●Obinutuzumab (anti-CD20 monoclonal antibody), approved for relapsed or refractory diffuse large B-cell lymphoma. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

●Chimeric antigen receptor T-cell therapy for lymphoid malignancy [37].

In some cases (eg, venetoclax for CLL), a gradual stepwise dose-escalation strategy has been used successfully in an effort to reduce the risk of TLS [38-40]. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax'.)

Solid tumors — TLS has been rarely described after treatment of nonhematologic solid tumors [20,41]. These include breast cancer [42-44], small cell carcinoma (mostly involving the lung) [20,42], neuroblastoma [42], germ cell tumors [20,45], medulloblastoma [20], sarcoma [20,46], ovarian cancer [47,48], squamous cell carcinoma of the vulva [49], metastatic colorectal cancer [50], urothelial cancer [51], gastrointestinal stromal tumors [52], melanoma [20], hepatocellular carcinoma [20,53], renal cell and soft tissue sarcoma treated with pazopanib [54,55], medullary thyroid cancer treated with selpercatinib [56], and prostate cancer [57].

Agents that have been associated with TLS include docetaxel (especially with extensive or bulky disease); pazopanib, a tyrosine kinase inhibitor that is highly bound to albumin, was associated with TLS in a patient with clear cell renal cell carcinoma and low serum albumin level; and selpercatinib, used for medullary thyroid cancer [55,57-59].

Patients at risk for TLS (eg, rapidly growing tumors, high tumor burden, renal impairment, volume depletion, kidney impairment, hyperuricemia) should be closely monitored for TLS before and during treatment, with correction of volume depletion and reduction of high serum uric acid levels prior to initiation of docetaxel.

Spontaneous TLS — Spontaneous acute kidney injury associated with marked hyperuricemia prior to the initiation of therapy has been described in NHL and acute leukemia [21,26,60,61], and in at least one patient with inflammatory breast cancer [62]. 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 [21].

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 [26]. By 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 [12], which were subsequently refined and updated [16]. 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 [16]:

●All Burkitt leukemia, stage III or IV Burkitt lymphoma or early stage Burkitt lymphoma with serum lactate dehydrogenase (LDH) level two or more times the upper limit of normal (≥2 times the upper limit of normal [ULN])

●Other acute lymphoblastic leukemia (ALL) with a white blood cell (WBC) count ≥100,000 per microL and/or serum LDH level ≥2 times the ULN

●Acute myeloid leukemia (AML) with WBC count ≥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 (≥2 times the ULN)

●Chronic lymphocytic leukemia (CLL) treated with venetoclax and lymph node ≥10 cm or lymph nodes ≥5 cm plus absolute lymphocyte count ≥25 x 10⁹/L, and elevated serum uric acid level

●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 ≥2 times the ULN

●Patients with intermediate-risk disease 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 [12], we recommend that all patients that fit into these high-risk categories receive aggressive intravenous (IV) volume expansion and prophylactic rasburicase, rather than allopurinol, prior to treatment initiation (unless they have glucose-6-phosphate dehydrogenase 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 French Society Against Cancers and Leukemias of Children and Adolescents classifies children as at 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 >2 times 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 [63]. 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 [16]:

●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 but without bulky disease

●Stage III or IV childhood anaplastic large cell lymphoma with serum LDH level <2 times the ULN

●Early stage Burkitt lymphoma with serum LDH level <2 times the ULN

●ALL with WBC <100,000/microL and serum LDH level <2 times the ULN

●AML with WBC 25,000 to 100,000/microL or AML with WBC <25,000/microL and LDH ≥ 2 times the ULN

●Early stage lymphoblastic lymphoma with serum LDH level <2 times the ULN

●CLL/small lymphocytic lymphoma (SLL) treated with fludarabine, rituximab, or lenalidomide, or venetoclax with lymph nodes ≥5 cm or an absolute lymphocyte count ≥25 x 10⁹/L, and/or those with a high WBC count (≥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, flavopiridol, or venetoclax therapy for relapsed or fludarabine-refractory CLL [38,64,65]. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

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 [66,67]. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Allopurinol' and "Tumor lysis syndrome: Prevention and treatment", section on 'Dosing and administration'.)

Management should be individualized based upon circulating WBC count, status of the bone marrow, renal function, and treatments. Some clinicians routinely place all patients with CLL/SLL 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, most patients with CLL and a WBC count 10,000 to 50,000/microL have a relatively low risk of TLS, and some experts manage with volume expansion and close monitoring rather than routine prophylaxis with a hypouricemic agent.

A debulking strategy and dose ramp-up approach have been used in the treatment of patients with intermediate- or high-risk CLL receiving venetoclax [68]. In a study of 80 previously untreated patients with high-risk CLL, in whom ibrutinib monotherapy was given for three cycles followed by the addition of venetoclax in the fourth cycle, only three patients developed laboratory evidence of TLS [69]. Notably, among patients with AML, significant reduction of venetoclax dose is recommended when used in combination with other chemotherapy agents and azole antifungal drugs, which are strong CYP3A inhibitors (table 5), since coadministration can lead to seven- to ninefold increase in venetoclax level [70].

Low risk — Patients at low risk for TLS (<1 percent risk) include [16]:

●AML with WBC count <25,000/microL and serum LDH level <2 times the ULN

●CLL/SLL with a WBC count ≤50,000/microL and not treated with fludarabine/rituximab or venetoclax

●Multiple myeloma and chronic myelogenous leukemia (CML)

●Other adult non-Hodgkin lymphomas that do not meet the criteria for high risk or intermediate risk, with serum LDH level within normal limits

●Other solid tumors

We generally recommend volume expansion 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 [16]. (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 [19,71,72]. 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 [19]. (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 WBC count ≥25,000/microL. French-American-British classification was not an independent predictor of TLS. (See "Acute myeloid leukemia: Classification".)

The authors assigned a point value to these factors and developed a scoring system to predict the probability of clinical TLS (table 6):

●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) [12]. Prevention and treatment of TLS according to estimated risk of TLS are discussed in detail elsewhere. (See "Tumor lysis syndrome: Prevention and treatment".)

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

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

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

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

SUMMARY

●Description – Tumor lysis syndrome (TLS) is an oncologic emergency 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.)

●Presentation – Clinical findings reflect the associated metabolic abnormalities (hyperkalemia, hyperphosphatemia, and hypocalcemia) and include nausea, vomiting, diarrhea, anorexia, lethargy, hematuria, heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and possible sudden death. (See 'Clinical manifestations' above.)

●Definition – The Cairo-Bishop definition for TLS is commonly used (see 'Cairo-Bishop definition' above):

•Laboratory TLS – ≥2 key metabolic features (hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia (table 1)) that present within three days before or seven days after instituting chemotherapy.

•Clinical TLS – Laboratory TLS plus ≥1 of the following findings that are not directly or probably attributable to a therapeutic agent: increased serum creatinine concentration (≥1.5 times the upper limit of normal), cardiac arrhythmia/sudden death, or a seizure.

●Grading of TLS – Based on the severity of clinical TLS, as described in this table (table 2). (See 'Grading system' above.)

●Risk factors – TLS is observed most frequently in patients with high-grade lymphomas (eg, Burkitt lymphoma) and acute lymphoblastic leukemia/lymphoblastic lymphoma following 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 'Risk factors' above.)

Development of various targeted agents has led to cases of TLS in cancers that were once rarely associated with this complication (eg, colon cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, lymphoid malignancies).

●Risk stratification – 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) [17]. (See 'Risk stratification' above.)