Aetiology

Tumour lysis syndrome (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 radiotherapy, but these are uncommon.[23][24][25][26][27]

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

TLS most commonly develops in highly proliferative haematological malignancies, particularly high-grade non-Hodgkin's lymphoma (e.g., Burkitt's lymphoma and diffuse large B-cell lymphoma), acute lymphoblastic leukaemia, and acute myeloid leukaemia.[1][8] It occurs less frequently in multiple myeloma and the indolent haematological malignancy, chronic lymphocytic leukaemia.[4][5][6][7][12][13]

Reports of TLS in solid (non-haematological) tumours, such as renal cell cancer, breast cancer, small cell lung cancer, testicular cancer, and neuroblastoma, are uncommon.[15][16][17] However, the incidence of TLS is likely to increase across all malignancies, including solid tumours, due to advances in cancer treatment.[5][6][7][8][18][19][20][21][22][26]

The risk of developing TLS is increased if there is a large tumour burden (i.e., a bulky tumour mass consisting of rapidly dividing cancer cells) and if the tumour is sensitive to chemotherapy or other cancer treatments (e.g., targeted agents).[1][2][20][28] Elevated serum lactate dehydrogenase, leukocytosis, and hyperuricaemia prior to initiation of cancer treatment correlate with large tumour burden and are considered independent risk factors for TLS.[2][9][29][30]

Pre-existing renal impairment (elevated serum creatinine ≥1.5 times the upper limit of normal), dehydration (with elevated urea), 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]

There is an increased likelihood of developing TLS with advancing age.[9] However, this is most likely related to a reduction in glomerular filtration rate that develops with advancing age. Increasing age is not, therefore, considered an independent risk factor for TLS.[9]

Pathophysiology

TLS is caused by rapid breakdown of large numbers of cancer cells and subsequent release of large amounts of intracellular content (potassium, phosphate, and nucleic acids) into the bloodstream, usually following the initiation of cancer treatment.

Cancer cells have a high turnover rate and contain large amounts of purine nucleic acids (which are metabolised to uric acid) and phosphate. The release of large amounts of intracellular content into the bloodstream overwhelms normal homeostatic mechanisms resulting in hyperuricaemia, hyperphosphataemia, hyperkalaemia, and/or hypocalcaemia.[31]

Large amounts of cellular byproducts in the bloodstream can impair renal function and cause acute kidney injury.

  • Hyperuricaemia: in combination with acidic urine and reduced urinary flow, may result in precipitation of uric acid crystals, renal tubular obstruction, and a decline in renal function. This is the most common mechanism of acute kidney injury in TLS.

  • Hyperphosphataemia: may lead to the formation of calcium phosphate crystals and precipitation, resulting in nephrocalcinosis and urinary obstruction.

  • Secondary hypocalcaemia: reported as a consequence of hyperphosphataemia; may be symptomatic if severe.

  • Hyperkalaemia: related to massive cell degradation; may be exacerbated by the development of acute kidney injury or lactic acidosis.

The clinical manifestations of TLS are directly related to these pathophysiological abnormalities. Hyperkalaemia, hyperphosphataemia, and hypocalcaemia may result in cardiac arrhythmias and sudden death. Hypocalcaemia can lead to muscle cramps, tetany, and seizures. Acute kidney injury may lead to fluid overload and pulmonary oedema.[2][32][33]

Classification

Cairo and Bishop definition of laboratory TLS and clinical TLS (2004)[2]

This classification groups patients with TLS into two categories:

  • Laboratory TLS: abnormality in two or more of the following, occurring 3 days before or 7 days after initiation of chemotherapy:

    • 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: laboratory TLS plus one or more of the following:

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

    • Cardiac arrhythmia or sudden death

    • Seizure.

Aetiological classification

Cancer treatment

  • TLS associated with initiation of cancer treatment (chemotherapy, targeted agents, immunotherapy [e.g., monoclonal antibodies], corticosteroids, hormonal therapy, or radiotherapy).

Spontaneous

  • TLS occurring prior to initiation of cancer treatment.

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