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Jones GL, Will A, Jackson GH, Webb NJ, Rule S; British Committee for Standards in Haematology. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2015 Jun;169(5):661-71. doi: 10.1111/bjh.13403. Epub 2015 Apr 15. PMID: 25876990.
Definition, Etiology, PathogenesisTop
Tumor lysis syndrome (TLS) is an oncologic emergency with life-threatening metabolic disturbances resulting from a rapid lysis of tumor cells. It may develop following exposure to chemotherapy (tumor chemosensitivity) or occur spontaneously in some malignancies that have high tumor burden or a rapid proliferation rate. The most common malignancies associated with TLS include acute lymphoblastic leukemia (ALL) and high-grade non-Hodgkin lymphoma (NHL), specifically Burkitt lymphoma. Though uncommon, TLS can also occur in multiple myeloma and solid tumors, particularly with the advent of novel systemic therapies. The rapid lysis of tumor cells leads to release of large amounts of potassium, purines (further broken down to uric acid), and phosphate.
Several clinical factors, in addition to tumor properties, can increase the risk of TLS. These include preexisting kidney injury or chronic kidney disease, baseline hyperphosphatemia, volume depletion, and concurrent use of nephrotoxic agents.
The availability of new targeted anticancer drugs (eg, venetoclax, obinutuzumab) has led to an increase in the frequency and severity of TLS in hematologic cancers that previously were rarely associated with TLS, such as chronic lymphocytic leukemia (CLL) or multiple myeloma.
Clinical Features and DiagnosisTop
Clinical manifestations of TLS are associated with consequences of metabolic disturbances. Tumor cell phosphate storage capacity is several-fold higher than that of nonmalignant cells. As TLS occurs, a large amount of released phosphate binds the circulating calcium, leading to precipitation in the myocardium and renal tubules. Calcium phosphate product, along with uric acid crystal deposition, leads to severe renal vasoconstriction and tubular damage, causing acute kidney injury (AKI). Calcium phosphate crystal deposition and hyperkalemia (secondary to tumor cell release) collectively can lead to significant cardiac arrhythmias and sudden death. Lastly, circulating serum calcium binding to the released phosphate reduces serum calcium concentration and can progress to symptomatic hypocalcemia.
The diagnosis of TLS includes both laboratory and clinical criteria. Laboratory TLS can be diagnosed according to the Cairo-Bishop definition in a patient with high tumor burden who within 3 days prior or 7 days after initiation of treatment develops ≥2 of:
1) Hyperphosphatemia (≥1.45 mmol/L [4 mg/dL] in adults, ≥2.1 mmol/L [6.5 mg/dL] in children, or 25% increase from the baseline value).
2) Hyperkalemia (≥6.0 mmol/L [6 mEq/L] or 25% increase from baseline).
3) Hyperuricemia (≥476 mmol/L [8 mg/dL] or 25% increase from baseline).
4) Hypocalcemia (≤1.75 mmol/L [7 mg/dL] or 25% reduction from baseline).
Clinical TLS can be diagnosed when criteria for laboratory TLS are met in the presence of AKI, cardiac arrhythmias/sudden cardiac death, or seizures.
Several risk stratification scores allow patients to be placed in low-, intermediate-, and high-risk categories; details of risk stratification are beyond the scope of this chapter. However, the highest risk is marked by Burkitt lymphoma (stage III-IV); acute myeloid leukemia with a white blood cell (WBC) count >100×109/L; ALL with a WBC >100×109/L and lactate dehydrogenase (LDH) >2 × upper limit of normal; chronic lymphocytic leukemia with high lymph node burden undergoing treatment and elevated LDH; heavy tumor burden or bulky lymphadenopathy in diffuse large B-cell lymphoma; adult T-cell leukemia; transformed lymphoma; or mantle cell lymphoma.
1. Patients from the intermediate-risk and high-risk groups require clinical (diuresis, fluid balance, and, in case of high risk, additional electrocardiography) and laboratory (uric acid, phosphates, potassium, creatinine, calcium, LDH) monitoring. Laboratory tests are performed, depending on the clinical situation, every 6 to 12 hours until the risk of TLS is resolved and 24 hours after the end of the first cycle of chemotherapy.
2. Hydration: IV hydration and volume repletion are the cornerstone of TLS prevention. This allows for renal perfusion and excretion of calcium phosphate and uric acid, preventing precipitation and kidney injury. IV fluids with a target of 2 to 3 L/m2 daily to achieve a target urine output of ≥80 to 100 mL/m2/h are recommended; however, this should be done carefully to avoid volume overload, which could further predispose to cardiac arrhythmia. Loop diuretics can be attempted to increase urine output if adequate volume repletion has been achieved.
3. Uric acid reduction: Oral allopurinol is a purine analogue that inhibits xanthine oxidase, the enzyme responsible for the generation of uric acid, the product of human purine metabolism. At 100 mg/m2 tid (maximum, 800 mg/d), it is used in patients at intermediate risk of TLS. If oral allopurinol is unavailable, IV allopurinol can be attempted (maximum, 600 mg/d; the cost may be a factor). In patients at high risk, rasburicase (0.15-0.2 mg/kg once daily or a fixed one-time 3-mg dose) can be used, if available. Rasburicase is a recombinant urate oxidase enzyme that converts the existing uric acid to allantoin, which is more soluble in urine than uric acid. Rasburicase differs from allopurinol, since it can affect the existing plasma uric acid; allopurinol affects only the future production of uric acid by inhibiting xanthine oxidase. Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as it can precipitate hemolysis. Testing for G6PD is recommended for those at risk (ie, males of African, Mediterranean, or South-Asian ancestry). The duration of therapy can vary from 1 to 7 days (the cost of this treatment may be prohibitive). Do not use allopurinol concomitantly, as it may reduce the effectiveness of rasburicase. Blood samples for uric acid testing in patients treated with rasburicase should be transported to the laboratory on ice to avoid falsely low results (rasburicase degrades uric acid in vitro at room temperature).
On the basis of available evidence, febuxostat is currently not recommended for TLS prevention, unless other drugs are not available or not tolerated.
In patients with suspected or confirmed TLS, the following therapies can be used (if available):
1) Uric acid lowering with rasburicase, if not already done for prevention (and using the same dose), along with IV hydration (and diuretics if necessary to promote diuresis; see Prevention, above). Allopurinol prevents new uric acid formation by inhibiting xanthine oxidase, whereas rasburicase results in rapid metabolism of existing uric acid (within hours). Allopurinol may be used if rasburicase is not available or cannot be used (G6PD deficiency); however, owing to its mechanism of action, it will not affect preexisting uric acid levels. Furthermore, it may lead to accumulation of nonsoluble xanthine, increasing the risk of renal injury.
2) Electrolyte disturbance management: Restrict phosphate and potassium in all patients. Those with hyperkalemia should have cardiac monitoring and serial 4- to 8-hour measurements of levels of uric acid creatinine and electrolytes (including potassium, calcium, and phosphate). Hyperkalemia should be managed with routine hyperkalemia management strategies (see Hyperkalemia), including shifting (insulin with glucose [dextrose] and beta-agonists), bowel excretion (via sodium polystyrene sulfonate), and renal excretion (with diuretics if adequately volume replete). Phosphate binders (calcium carbonate) can be used for the management of hyperphosphatemia and IV calcium replacement for hypocalcemia. Also see Water and Electrolyte Disturbances.
3) A calcium-phosphate (Ca × P) product ≥70 mg2/dL2 (5.6 mmol2/L2), refractory hyperkalemia, refractory fluid overload, and refractory severe symptomatic hypocalcemia can be considered indications for renal replacement therapy (see Chronic Kidney Disease).