Kimberly *Z* McClelland, MPH

Medical Intensive Care Unit

Senior Rotation

February 25, 2014

TUMOR LYSIS SYNDROME

KEY POINTS

• Tumor lysis syndrome (TLS) is a metabolic derangement resulting from massive

destruction of malignant cells, leading to electrolyte abnormalities and, consequently,

renal, cardiac, and neurologic dysfunction and possibly death if left untreated

• Symptoms of TLS can occur spontaneously but usually occur within 12 to 72 hours after

initiation of cytoreductive chemotherapy in patients with hematologic malignancies or high

tumor burden

• Treatment consists of intravenous hydration and potassium-, phosphate-, and/or uric acid-

lowering medications or dialysis when indicated

• Complications, such as acute renal failure, electrolyte disturbances, seizures, and

arrhythmias, can compromise further cancer therapy or lead to death

• Early identification and prophylactic management of patients at risk for TLS may prevent

potentially life-threatening sequelae

BACKGROUND - DESCRIPTION

• TLS is caused by the massive and abrupt release of cellular components, including

nucleic acids, potassium, and phosphates, from malignant cells into the blood, which

usually occurs with the initiation of cytotoxic therapy but, rarely, can occur spontaneously

• Hyperuricemia, lactic acidosis, hyperphosphatemia, hyperkalemia, and secondary

hypocalcemia occur as a result of TLS

• Hyperuricemia is defined as a plasma or serum uric acid concentration greater than the

upper limit of normal (usually >7.4 mg/dL in male patients and >5.8 mg/dL in female

patients)

• TLS occurring during induction chemotherapy that is characterized by laboratory

abnormalities traditionally is classified as laboratory TLS, whereas clinical TLS includes

both laboratory abnormalities and clinical features.

• Only a minority of patients with laboratory TLS will develop clinical TLS

BACKGROUND - EPIDEMIOLOGY

• The incidence of TLS differs according to the type of tumor and the definition of TLS

• A population-based study in patients with acute myeloid leukemia undergoing induction

chemotherapy found that 12% of patients had laboratory TLS, and 5% had clinical TLS.

Only clinical TLS was associated with a higher mortality rate

• A retrospective study in patients with intermediate- to high-grade non-Hodgkin lymphoma

found that the incidence of laboratory TLS was 42%, and the incidence of clinical TLS was

approximately 6%

CAUSES & RISK FACTORS - CAUSES

• TLS is caused by the sudden destruction of a large number of malignant cells, resulting in

the massive release of intracellular nucleic acids (metabolized to uric acid), potassium,

and phosphorus into the blood

CAUSES & RISK FACTORS - RISK FACTORS

• Tumor grade, tumor burden, and degree of chemosensitivity: TLS is more likely to occur

in patients with high-grade tumors with a large burden and high chemosensitivity, such as

hematologic malignancies, small-cell cancer, and germ cell tumors, and is associated less

commonly with chemo-insensitive tumors, such as melanoma, and hepatocellular

carcinoma

• Type of therapy: TLS is more likely to occur with chemotherapy and is associated less

commonly with targeted therapies and radiation therapy; however, the condition also may

occur spontaneously before treatment

• Patient-related factors include the following:

• Compromised kidney function due to preexisting renal dysfunction or dehydration,

concurrent use of nephrotoxic drugs, or renal obstruction

• Preexisting hyperuricemia from any cause

• Systemic infection

SCREENING

• Not applicable

PRIMARY PREVENTION

• Prevention of TLS focuses on monitoring fluid intake and output and uric acid, electrolyte

(serum phosphorus, potassium, and calcium), creatinine, and lactate dehydrogenase

(LDH) levels before and during cytotoxic therapy

• The frequency of monitoring depends on the risk of developing clinical TLS

• Laboratory testing should be done daily in low-risk patients, every 8 to 12 hours in

intermediate-risk patients, and every 6 to 8 hours in high-risk patients

POPULATION AT RISK

• Patients with lymphomas (e.g., non-Hodgkin lymphomas, including Burkitt lymphoma,

lymphoblastic lymphoma, and diffuse large-cell lymphoma), leukemias (e.g., acute

lymphoblastic leukemia, acute myelogenous leukemia), or solid tumors with high

proliferative rates (e.g., small-cell lung cancer and germ cell tumors)

• Patients with increased tumor burden as evidenced by bulky disease, baseline elevated

LDH levels, and hyperleukocytosis

• Patients with preexisting renal failure

• Patients with baseline elevated uric acid levels

POPULATION AT RISK

• In 2010, an international TLS expert consensus panel published comprehensive guidelines for assessing therisk of TLS, which incorporated renal function status as well as cancer types. The risk of developing TLSwas divided into three categories:

• Low risk (less than 1% risk of developing TLS), such as in patients with normal kidney function/norenal involvement and Hodgkin lymphoma, indolent lymphomas, or solid tumors

• Intermediate risk (1%-5% risk of developing TLS), such as in patients with abnormal kidney functionand/or renal involvement and low-risk diseases; adults with non-bulky, diffuse, large B-celllymphoma and elevated LDH levels; patients with early-stage aggressive lymphomas and LDHlevels greater than twice the upper normal limit; patients with acute myelogenous leukemia and aleukocyte count of 25,000 to 100,000/µL; and patients with acute lymphoblastic leukemia, an LDHlevel less than twice the upper normal limit, and a leukocyte count <100,000/µL

• High risk (greater than 5% risk of developing TLS), such as in adults with bulky, diffuse, large B-cell lymphoma and elevated LDH levels; patients with advanced-stage aggressive lymphomas (eg,Burkitt lymphoma/leukemia); patients with intermediate-risk disease and abnormal kidney functionand/or renal involvement; and patients with acute leukemias (myeloid and lymphoid) and a leukocytecount >100,000/µL

• Intravenous hydration and anti-hyperuricemic therapy also should be considered

PREVENTIVE MEASURES

• Patients at risk of developing TLS should be monitored closely, especially in the first 72hours of treatment. Serum electrolyte, LDH, and uric acid levels should be measuredfrequently, depending on the risk of developing TLS

• Use of nephrotoxic agents, including contrast dye, should be avoided in patients withunderlying renal dysfunction who are scheduled to undergo induction chemotherapy

• Use of loop diuretics is controversial in light of studies showing that diuretics do notdecrease mortality and morbidity and should only be considered in adults withouthypovolemia or obstructive uropathy in order to maintain urine output >100 mL/hr

• Urine alkalinization with sodium bicarbonate has been found to be ineffective inpreventing uric acid nephropathy and has been associated with increased precipitation ofcalcium phosphate and xanthine in the renal tubules and, therefore, is no longerrecommended, except in special situations, such as in patients with metabolic acidosis

• Alkalinization of the urine is not necessary in patients receiving treatment withrasburicase

PREVENTIVE MEASURES

• Aggressive intravenous hydration (normal saline, 2 to 3 L/m2/d in adults) is the primary

preventive strategy for TLS and is most effective if initiated 48 hours before and continued

for 72 hours after cytotoxic therapy

• The goal is to enhance urine flow (urine output of 80-100 mL/m2/h), promote the excretion

of uric acid and phosphorus, and decrease the risk of uric acid precipitation in the renal

tubules

• Caution must be exercised in elderly patients and in patients with compromised cardiac

function due to the risk of fluid overload

PREVENTIVE MEASURES

• Anti-hyperuricemic therapy should be considered in patients with a 1% or higher risk of

developing TLS

• The choice of agent depends on the degree of risk and lack of contraindications

• Allopurinol, a xanthine oxidase inhibitor, is recommended in patients with a 5% or lower

risk of developing TLS and in patients with a greater than 5% risk in whom rasburicase is

contraindicated. Several studies have shown allopurinol to be effective in improving uric

acid levels in patients with preexisting hyperuricemia and in preventing uric acid elevation

in patients with normal pretreatment uric acid levels

• Rasburicase, a recombinant urate oxidase, is the agent of choice in patients with a

greater than 5% risk of developing TLS, no history of hypersensitivity or hematologic

reactions to rasburicase, and without glucose-6-phosphatase dehydrogenase (G6PD)

deficiency. Several drug trials and a systematic review in pediatric patients have shown

rasburicase to be effective in preventing and reversing TLS-associated hyperuricemia in

both children and adults

PREVENTIVE MEASURES

• The diagnosis of TLS should be considered in any patient with risk factors for TLS in whom chemotherapyhas been initiated

• The symptoms and signs of TLS are usually nonspecific. Laboratory values are critical for diagnosis

• Laboratory TLS was defined as the presence of two or more of the following criteria within 3 days beforeor 7 days after the initiation of chemotherapy:

• Uric acid level =8 mg/dL or a 25% increase from baseline

• Potassium level =6.0 mEq/L or a 25% increase from baseline

• Phosphorus level =6.5 mg/dL or a 25% increase from baseline

• Calcium level =7 mg/dL or a 25% decrease from baseline

• Clinical TLS was defined as the presence of laboratory TLS and one or more of the following criteria:

• Creatinine level =1.5 times the upper limit of normal

• Cardiac arrhythmia or sudden death due to hyperkalemia

• Seizure

CLINICAL PRESENTATION - SYMPTOMS

• Patients may be asymptomatic

• When present, symptoms are nonspecific and usually reflect the associated metabolic

abnormalities (uremia, hyperkalemia, hyperphosphatemia, and hypocalcemia) directly or

indirectly, with abnormal renal, cardiac, and/or neurologic function, such as:

• Palpitations with associated dyspnea, dizziness, and syncope

• Symptoms of heart failure, such as swelling and orthopnea

• Anorexia, nausea, vomiting, and diarrhea

• Oliguria and hematuria

• Lethargy

• Signs

CLINICAL PRESENTATION - SIGNS

• When present, signs are nonspecific and usually reflect the associated metabolic

abnormalities (uremia, hyperkalemia, hyperphosphatemia, and hypocalcemia) directly or

indirectly, with abnormal renal, cardiac, and/or neurologic function, such as:

• Tachycardia or bradycardia, hypotension, and decreased urine output

• Irregular heart rate due to arrhythmias

• Chvostek sign may be elicited in patients with hypocalcemia

• Jugular venous distension and dependent edema if heart failure is present

• Altered mental status and disorientation related to electrolyte disturbances or

postictal state

• Evidence of seizures, such as tongue biting, incontinence, or bodily injury

• Sudden death

DIAGNOSTIC TESTING

• Measurement of the following is indicated:

• Serum uric acid, as elevated levels can represent either preexisting hyperuricemia

and/or one component of TLS

• Serum potassium, as elevated levels are seen characteristically before the maximal

levels of phosphorus and uric acid are reached and can potentiate arrhythmias

• Serum phosphorus, as abnormal levels can lead to secondary hypocalcemia

• Renal function tests may show impaired renal function secondary to deposition of uric

acid and calcium phosphate in renal tubules

• Electrocardiographic findings are reflective of electrolyte abnormalities

DIFFERENTIAL DIAGNOSIS

• Hyperuricemia without other features of TLS can be caused by uric acid overproduction

and/or decreased excretion. Patients may have a previous history of hyperuricemia.

• Quantification of uric acid excretion can aid in establishing the diagnosis

• Overproduction and decreased excretion of uric acid are seen in patients with idiopathic

primary hyperuricemia or gout (acute or chronic)

• Overproduction of uric acid is seen in the setting of certain malignancies, such as

myeloproliferative disorders (e.g., polycythemia vera), leukemias, lymphomas, plasma cell

disorders, and small-cell lung cancer; chemotherapy for malignancy; congenital

syndromes; psoriasis; obesity; and alcohol abuse

• Decreased excretion of uric acid is seen in patients with reduced renal function,

congenital syndromes, hyperparathyroidism, or hypothyroidism and may occur as a result

of treatment with medications such as diuretics, nicotinic acid, salicylates, and

cyclosporine

DIFFERENTIAL DIAGNOSIS

• TLS must be differentiated from other causes of electrolyte disturbances and renal

dysfunction that may occur in patients with cancer and that may require specific

treatment, such as renal failure

• Patients with cancer are at increased risk for renal dysfunction due to volume depletion,

obstructive uropathy, and acute tubular necrosis from nephrotoxic drugs used in treatment

(e.g., antibiotics, contrast dye, and chemotherapeutic agents)

• A thorough history and physical examination, urinalysis and microscopy, and

ultrasonography may aid in differentiation

• Hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia may be associated

with acute renal failure regardless of the underlying etiology

• In patients with TLS, the rapid lysis of malignant cells causes hyperuricemia, lactic

acidosis, hyperphosphatemia, hyperkalemia, and secondary hypocalcemia and may

progress to acute renal failure in a minority of patients

CONSULTATION

• Consultation with a nephrologist should be considered for assistance in diagnosing renal

dysfunction

• A hematologist/oncologist should be consulted for treatment of any underlying malignancy

TREATMENT - SUMMARY

• TLS is a life-threatening condition that necessitates immediate action and close

monitoring

• Clinical TLS can develop despite appropriate preventive measures

• The primary goal of treatment is correction of electrolyte disturbances

• Medications and other agents (e.g., radiocontrast dye) that may exacerbate kidney injury

should be avoided

• Dialysis is recommended in patients with refractory hyperkalemia, acidosis, fluid overload,

uric acid levels >15 mg/dL, or uremic symptoms

TREATMENT - SUMMARY

• In patients with hyperkalemia:

• Intravenous or oral potassium should be avoided, and potassium-lowering

medications, such as sodium polystyrene sulfonate, should be considered

• In patients with symptomatic or severe hyperkalemia:

• Calcium gluconate should be administered to decrease myocardial membrane

excitability

• Emergency treatment to shift potassium intracellularly includes one or more of the

following: regular insulin and dextrose, nebulized albuterol, and sodium bicarbonate

• Therapies to decrease the total body potassium content include sodium polystyrene

sulfonate and hemodialysis or peritoneal dialysis

TREATMENT - SUMMARY

• In patients with hyperphosphatemia:

• Phosphorus intake should be minimized

• Calcium salts should not be administered, unless the patient has severe symptoms

due to hypocalcemia or severe and/or symptomatic hyperkalemia. Otherwise,

calcium salts may cause calcium phosphate precipitation

• Preferred phosphate binders include aluminum hydroxide, sevelamer hydrochloride,

and lanthanum carbonate

• Hemodialysis is indicated if there is no response to medical therapy

TREATMENT - SUMMARY

• In patients with symptomatic hypocalcemia, slow administration of calcium gluconate (50-

100 mg/kg/dose intravenously) should be considered; close monitoring is necessary due

to the potentially increased risk of calcium phosphate deposition

• In adult patients with hyperuricemia, treatment with allopurinol or rasburicase is indicated

CONTRAINDICATIONS TO

ALLOPURINOL OR RASBURICASE

• Both agents should be avoided in patients with hypersensitivity to the drug or any other

component.

• Rasburicase is contraindicated in patients with G6PD deficiency

MEDICATIONS

• Sodium polystyrene sulfonate

• Calcium gluconate

• Insulin

• Albuterol

• Sodium bicarbonate

• Aluminum hydroxide

• Sevelamer hydrochloride

• Lanthanum carbonate

• Allopurinol

• Rasburicase

NON-DRUG TREATMENTS

• Dialysis

SPECIAL CIRCUMSTANCES - COMORBIDITIES

• Patients with preexisting renal failure or hyperuricemia are at increased risk of developing

TLS, and management of fluid and electrolyte status is more challenging

• Patients taking allopurinol or urosuric agents for coexisting gout or chronic hyperuricemia

may have a decreased risk of TLS; if TLS does occur, the rapid increase in serum uric

acid levels may precipitate a gouty attack

• Patient satisfaction/lifestyle priorities

• TLS is associated with increased morbidity and mortality, as it may delay future

administration of chemotherapy and other cancer therapies, may lead to renal failure

requiring dialysis, and is associated with the possibility of fatal arrhythmias

FOLLOW-UP - MONITORING

• Fluid intake and output, cardiac status, uric acid levels, electrolyte (serum phosphorus,

potassium, and calcium) levels, creatinine levels, and LDH levels should be monitored

every 4 to 6 hours in patients with clinical TLS and every 6 to 8 hours in patients with

laboratory TLS

• According to the 2008 American Society of Clinical Oncology guidelines, uric acid levels

should be reevaluated 4 hours after administration of rasburicase and every 6 to 8 hours

thereafter until resolution of TLS

PROGNOSIS

• In patients with acute myelogenous leukemia, the development of clinical TLS was

associated with a 2% mortality rate from induction therapy

• Patients with acute TLS and acute kidney injury have an increased mortality rate (both in

hospital and at 6 months) compared to patients without renal injury

COMPLICATIONS

• Complications associated with TLS:

• Acute renal failure

• Elevated serum phosphate levels can lead to secondary hypocalcemia due to

calcium phosphate crystal formation, resulting in tissue calcification and

nephrocalcinosis

• Hyperkalemia can lead to potentially fatal arrhythmias

• Complications associated with therapy:

• Hydration may lead to volume overload and congestive heart failure in patients with

compromised cardiac function

• Allopurinol may cause severe hypersensitivity reactions

• Rasburicase may cause hemolysis in patients with G6PD deficiency

PATIENT EDUCATION

• Patients should be informed of the following:

• TLS primarily is encountered at the time of initiation of chemotherapy but may occur

before starting any therapy

• The syndrome results from the release of the contents of cancer cells after being

killed by chemotherapy and can be life-threatening, potentially leading to kidney

failure and/or death

• The best approach to prevention is administration of fluids and agents that affect the

formation or metabolism of uric acid

QUESTION

A patient with extremely severe myeloma with a plasmacytoma is admitted for combinationchemotherapy. Two days later, the creatinine rises. What is the most likely cause?

• A. Cisplatin

• B. Hyperuricemia

• C. Bence-Jones proteinuria

• D. Hypercalcemia

• E. Hyperoxaluria

B. Two days after chemotherapy, the creatinine rises in a person with a hematologic malignancy.This is most likely from tumor lysis syndrome leading to hyperuricemia. Cisplatin, as with most drugtoxicities, would not produce a rise in creatinine for 5 to 10 days. Bence-Jones protein andhypercalcemia both cause renal insufficiency, but it would not be rapid and it would not happen as aresult of treatment. Treatment for myeloma would end up decreasing both the calcium and Bence-Jones protein levels because they are produced from the leukemic cells. Cancer cells do notrelease oxalate.

ADDITIONAL QUESTION

What would have prevented this event?

• Allopurinol, hydration, and rasburicase should have been given prior to chemotherapy to

prevent renal failure from tumor lysis syndrome

NOW, WHAT DID YOU LEARN?

What are the main risk factors associated with TLS?

• TLS is more likely to develop in patients with a high tumor burden, a tumor that is sensitive tocytotoxic therapies, or preexisting renal disease. TLS occurs most commonly during inductionchemotherapy in patients with hematologic malignancies

What additional criteria are needed for laboratory TLS to be considered clinical TLS?

• Clinical TLS is defined as laboratory TLS in addition to a creatinine level =1.5 times the upperlimit of normal, cardiac arrhythmia or sudden death, or seizure

What is the approach to prevention of TLS?

• There are two main components: maintenance of urine output through hydration and use ofantihyperuricemic agents. Hydration and treatment with allopurinol should be started 48 hoursbefore and continued for 72 hours after initiation of cytotoxic therapy.

• Treatment with rasburicase can be started earlier, as efficacy is seen within 4 hours, therebyallowing chemotherapy to be initiated earlier

NOW, WHAT DID YOU LEARN?

How is TLS treated?

• Treatment consists of aggressive supportive care, correction of any electrolyte

disturbances, and administration of allopurinol or rasburicase

What are the main contraindications to treatment with allopurinol or rasburicase?

• Both agents should be avoided in patients with hypersensitivity to the drug or any other

component

• Rasburicase is contraindicated in patients with G6PD deficiency

REFERENCES

• 1) Smalley RV, Guaspari A, Haase-Statz S, Anderson SA, Cederberg D, Hohneker JA. Allopurinol:intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol. 2000;18:1758-63

• 2) Cheuk DK, Chiang AK, Chan GC, Ha SY. Urate oxidase for the prevention and treatment oftumor lysis syndrome in children with cancer. Cochrane Database Syst Rev. 2010:CD006945

• 3) Coiffier B, Mounier N, Bologna S, et al. Efficacy and safety of rasburicase (recombinant urateoxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy ofaggressive non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe d'Etude des Lymphomesde l'Adulte Trial on Rasburicase Activity in Adult Lymphoma) study. J Clin Oncol. 2003;21:4402-6

• 4) Cortes J, Moore JO, Maziarz RT, et al. Control of plasma uric acid in adults at risk for tumorLysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinolcompared with allopurinol alone—results of a multicenter phase III study. J Clin Oncol.2010;28:4207-13

• 5) Jeha S, Kantarjian H, Irwin D, et al. Efficacy and safety of rasburicase, a recombinant urateoxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric andadult patients: final results of a multicenter compassionate use trial. Leukemia. 2005;19:34-8

THANK YOU!