Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011 May 12;364(19):1844-54. doi: 10.1056/NEJMra0904569. Review. Erratum in: N Engl J Med. 2018 Sep 13;379(11):1094. PubMed PMID: 21561350; PubMed Central PMCID: PMC3437249.
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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 non-Hodgkin lymphoma (NHL), specifically Burkitt lymphoma. Though uncommon, TLS can also occur in multiple myeloma and solid tumors. The rapid lysis of tumor cells leads to release of large amounts of potassium, purines (further broken down to uric acid), and phosphate.
Several risk factors, in addition to tumor properties, can predispose to TLS. These include preexisting kidney injury or chronic kidney disease, baseline hyperphosphatemia, volume depletion, and presence of other nephrotoxic agents.
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 a normal cell type. As TLS occurs, large amounts of released phosphate bind the circulating calcium and lead to precipitation in the myocardium and renal tubules. Calcium phosphate deposition, along with uric acid crystal deposition, leads to severe renal vasoconstriction and tubular damage, causing acute kidney injury (AKI). Calcium phosphate crystal deposition along with hyperkalemia (secondary to tumor cell release) collectively can lead to significant cardiac arrhythmias. 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 in a patient with high tumor burden who within 3 days prior or 7 days after initiation of treatment developed ≥2 of hyperphosphatemia (≥1.45 mmol/L in adults, ≥2.1 mmol/L in children, or 25% increase from the baseline value), hyperkalemia (≥6.0 mmol/L or 25% increase from baseline), hyperuricemia (≥476 mmol/L or 25% increase from baseline), or hypocalcemia (<1.75 mmol/L or 25% reduction from baseline). Clinical TLS can be diagnosed 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. The highest risk is marked by Burkitt lymphoma (stage III-IV); acute myeloid leukemia with a white blood cell (WBC) count >100,000/microL; ALL with a WBC >100,000/microL and lactate dehydrogenase (LDH) >2 × upper limit or normal; chronic lymphocytic leukemia with high lymph-node burden undergoing treatment; heavy tumor burden or bulky lymphadenopathy in diffuse large B-cell lymphoma; adult T-cell leukemia; transformed lymphoma; or mantle cell lymphoma.
1. 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/m2/24 h 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.
2. Uric acid reduction: Oral allopurinol at 100 mg/m2 tid (maximum, 800 mg/d) is used in patients at intermediate risk for TLS. If oral allopurinol cannot be used, IV allopurinol can be attempted (maximum, 600 mg/d). In patients at high risk, rasburicase (0.15-0.2 mg/kg once daily or a fixed 3-mg dose) can be used if available. The duration of therapy can vary from 1 to 7 days (the cost of this treatment may be prohibitive). On the basis of available evidence, febuxostat is currently not recommended for TLS prevention.
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; see Prevention, above). Allopurinol prevents new uric acid formation, whereas rasburicase results in rapid metabolism of existing uric acid.
2) Electrolyte disturbance management: Restrict phosphate and potassium in all patients. Those with hyperkalemia should have cardiac monitoring and serial 6-8 h bloodwork measured. Hyperkalemia should be managed with routine hyperkalemia management strategies, including shifting (insulin with glucose [dextrose] and beta-agonists), bowel excretion (via sodium polystyrene sulfonate), and renal excretion (with diuretics if adequate volume repletion is maintained). 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.