Approach

Tumor lysis syndrome (TLS) may be asymptomatic in the early stages, and by the time symptoms appear it can be life threatening.

Optimal management of TLS involves identifying all patients at risk of TLS, and preventing the development of TLS.[4][35]

A definitive diagnosis of TLS is based on blood biochemistry and clinical signs and symptoms.[2] A detailed history and exam is important.

History

TLS is the most common oncologic emergency in children and young adults with hematologic malignancies.[28] It most commonly develops in highly proliferative hematologic malignancies, particularly high-grade non-Hodgkin lymphoma (NHL; e.g., Burkitt lymphoma), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML).[1][8] TLS occurs less frequently in multiple myeloma and the indolent hematologic malignancy, chronic lymphocytic leukemia (CLL).[4][5][6][7][12][13]

Reports of TLS in solid (non-hematologic) tumors, such as renal cell cancer, breast cancer, small cell lung cancer, testicular cancer, and neuroblastoma, are uncommon.[15][16][17] However, with advances in cancer treatment and increasing availability of highly effective therapies (e.g., targeted agents), the incidence of TLS is likely to increase across all malignancies, including solid tumors.[5][6][7][8][18][19][20][21][22][26]

Patients can be categorized as low, intermediate, or high risk depending on the type of malignancy, treatment sensitivity (of the tumor), disease stage, white blood cell (WBC) count, tumor burden (bulk), lactate dehydrogenase (LDH) level, and pre-existing renal impairment/renal abnormality.[35]

Low-risk patients include those with:[35]

  • Solid tumors, except rare solid tumors that are chemosensitive (e.g., neuroblastoma, germ cell tumors, small cell lung cancer), or others with bulky or advanced disease

  • Chronic myeloid leukemia: chronic phase

  • Chronic lymphocytic leukemia when treated exclusively with alkylating agents

  • Multiple myeloma

  • Hodgkin lymphoma

  • Acute myeloid leukemia with WBC count <25,000/microliter and LDH <2 times the upper limit of normal (ULN)

  • Indolent/low proliferating non-Hodgkin lymphoma (e.g., small lymphocytic lymphoma, follicular lymphoma, marginal B-cell lymphoma, MALT lymphoma, mantle cell lymphoma [non-blastoid], cutaneous T-cell lymphoma, and anaplastic large cell lymphoma [adults])

Patients with low-risk disease who have renal dysfunction/involvement should be categorized as intermediate risk.[35]

Intermediate-risk patients include those with:[35][41]

  • Rare solid tumors that are chemosensitive (e.g., neuroblastoma, germ cell tumors, small cell lung cancer), or others with bulky or advanced-stage disease

  • Early-stage Burkitt lymphoma with LDH <2 times ULN

  • Early-stage lymphoblastic lymphoma with LDH <2 times ULN

  • Acute lymphoblastic leukemia with WBC count <100,000/microliter and LDH <2 times ULN

  • Acute myeloid leukemia with WBC count ≥25,000/microliter to <100,000/microliter, or WBC count <25,000/microliter and LDH ≥2 times ULN

  • Chronic lymphocytic leukemia with WBC count ≥50,000/microliter and/or treated with fludarabine or targeted agents (e.g., rituximab, lenalidomide, obinutuzumab, venetoclax)

Patients with intermediate-risk disease who have renal dysfunction/involvement, or uric acid, potassium, and/or phosphate levels above the normal range, should be categorized as high risk.[35]

High-risk patients include those with:[35][41]

  • Certain high-grade non-Hodgkin lymphoma (e.g., advanced-stage Burkitt lymphoma or lymphoblastic lymphoma) and bulky high-grade non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma)

  • Acute lymphoblastic leukemia with WBC count ≥100,000/microliter, or WBC count <100,000/microliter and LDH ≥2 times ULN

  • Acute myeloid leukemia with WBC count ≥100,000/microliter

  • Chronic lymphocytic leukemia treated with venetoclax if there is a high tumor burden (lymph node ≥10 cm or lymph node ≥5 cm and absolute lymphocyte count [ALC] ≥25,000/microliter) or a medium tumor burden (lymph node 5 cm to <10 cm; or ALC ≥25,000/microliter) in those with creatinine clearance <80 mL/min

Additional risk factors for TLS include:[1][28]

  • Recent cancer treatment (particularly chemotherapy)

  • Dehydration

  • Volume depletion

  • Use of nephrotoxic agents (e.g., aminoglycoside antibiotics, nonsteroidal anti-inflammatory drugs, and intravenous contrast agents)

  • Advanced age (and reduced glomerular filtration rate)

Symptom onset

TLS is most commonly associated with the initiation of chemotherapy, particularly regimens with highly active, cell cycle phase-specific drugs (e.g., etoposide, cytarabine).[1][2]​​[12][20]​​ There are increasing reports of TLS with targeted agents (e.g., venetoclax, sunitinib, bortezomib) and immunotherapy (e.g., monoclonal antibodies).[5][6][7][8][18][19][20][21][22]

There are reports of TLS occurring with other treatments, such as corticosteroids, hormonal therapy, intrathecal chemotherapy, and radiation therapy, but these are uncommon.[23][24][25][26][27]

Clinical manifestations of TLS typically occur within 12 to 72 hours after initiation of cancer treatment.[2][3] Laboratory signs of TLS may appear as early as 6 hours after treatment initiation.[4][5][7]

Symptoms suggestive of the clinical syndrome include nausea, vomiting, anorexia, diarrhea, muscle weakness, muscle cramps, tetany, flank pain, lethargy, paresthesia, laryngeal spasm, cloudy urine, and joint pain/discomfort.

Spontaneous TLS (i.e., occurring without initiation of cancer treatment) has also been reported, mainly in association with high-grade hematologic malignancies (e.g., B-cell ALL).[20] Spontaneous TLS is uncommon.

Exam

Signs related to the characteristics or the complications of TLS include:

  • Acute kidney injury: hypertension, hypotension, oliguria, anuria, hematuria, peripheral edema

  • Cardiac arrhythmias: syncope, chest pain, dyspnea

  • Severe hypocalcemia: tetany, Chvostek sign, Trousseau sign, seizures, confusion, delirium, hallucinations, laryngeal spasm (rare)

  • Severe hyperphosphatemia: seizures.

Mild hypocalcemia is often asymptomatic.

Clinical exam is likely to reveal signs attributable to the underlying malignancy, such as palpable lymphadenopathy or splenomegaly in the case of lymphoproliferative disorders.

Lymphadenopathy and splenomegaly may indicate a large tumor burden, which is associated with a high risk of TLS.[28]

Laboratory investigations

Biochemistry and complete blood count should be checked prior to initiation of cancer treatment, and for 2 to 3 days after initiation of treatment.

Pre-existing renal impairment (elevated serum creatinine ≥1.5 times the upper limit of normal), dehydration (with elevated blood urea nitrogen), and volume depletion are predisposing risk factors for TLS that may be modifiable and should be identified prior to initiation of cancer treatment.[1][28]

Elevated serum lactate dehydrogenase, leukocytosis, and hyperuricemia prior to initiation of cancer treatment correlate with large tumor burden and are considered independent risk factors for TLS.[2][9][29][30]

Elevated levels of phosphate and potassium prior to initiation of cancer treatment increases the likelihood of developing laboratory and clinical TLS.[30]

Urinary pH should be checked prior to initiation of cancer treatment and always in the presence of hyperuricemia, as urate nephropathy is more likely at acidic pH levels.[14]

Laboratory TLS is defined as an abnormality in two or more of the following, occurring within 3 days before or 7 days after initiation of cancer treatment:[2]

  • Uric acid ≥476 micromol/L (≥8 mg/dL) or 25% increase from baseline

  • Potassium ≥6.0 mmol/L (≥6.0 mEq/L) or 25% increase from baseline

  • Phosphate ≥2.1 mmol/L (≥6.5 mg/dL) in children or ≥1.45 mmol/L (≥4.5 mg/dL) in adults, or 25% increase from baseline

  • Calcium ≤1.75 mmol/L (≤7 mg/dL) or 25% decrease from baseline.

Clinical TLS is defined as laboratory TLS plus one or more of the following:[2]

  • Increased serum creatinine (≥1.5 times upper limit of normal)

  • Cardiac arrhythmia or sudden death

  • Seizure.

If there is evidence of TLS, treatment should be initiated and biochemistry repeated at least twice daily until normalized.

Cardiac monitoring

In the presence of hyperkalemia, hyperphosphatemia, and hypocalcemia, an ECG with or without continuous cardiac monitoring is required as life-threatening arrhythmias may develop. Continuous cardiac monitoring is advised during any pharmacologic treatment of an arrhythmia or when potassium is significantly high (>7 mmol/L [7 mEq/L]).

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