Tumor lysis syndrome resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Twinkle Singh, M.B.B.S. [2]; Rim Halaby, M.D. [3]

Overview

Tumor lysis syndrome (TLS) is a group of metabolic abnormalities resulting from rapid lysis of malignant cells and massive release of cell breakdown products into the blood among patients with hematologic malignancies treated with chemotherapy. Metabolic complications include hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia and hyperuricosuria.

Causes

Life Threatening Causes

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. Tumor lysis syndrome is a life-threatening condition and must be treated as such irrespective of the causes.

Common Causes

• Acute lymphoblastic leukemia
• Acute myeloid leukemia
• Burkitt's lymphoma
• Chronic lymphocytic leukemia
• Chronic myeloid leukemia
• Multiple myeloma
• Non-Hodgkin's lymphoma

Management

Prevention

Shown below is an algorithm summarizing the approach to tumor lysis syndrome according to the guidelines by American Society of Clinical oncology and an expert TLS panel consensus.

Risk assessment of patients for TLS

Low Risk Disease (LRD): ❑ Solid tumors ❑ Multiple myeloma ❑ Indolent Non-Hodgkin's lymphoma ❑ Hodgkin's lymphoma ❑ AML with WBC count ≤25,000 cells/μL and LDH < 2× ULN ❑ CLL with WBC count < 50,000 cells/μL, treated only with alkylating agents ❑ CML

Intermediate Risk Disease (IRD): ❑ Bulky or advanced stage solid tumors ❑ Plasma cell leukemia ❑ Stage III/IV Non-Hodgkin's lymphoma with LDH > 2xULN ❑ AML with WBC count ≤25,000 cells/μL and LDH > 2× ULN OR AML with WBC count 25,000-100,000 cells/μL ❑ CLL treated with fludarabine or rituximab or CML with WBC count > 50,000 cells/μL ❑ ALL with WBC < 100,000 cells/μL and LDH > 2xULN ❑ Burkitt's lymphoma stage I/II with LDH < 2x ULN ❑ Lymphoblastic lymphoma stage I/II with LDH < 2x ULN ❑ Diffuse large B cell lymphoma

High Risk Disease (HRD): ❑ AML with WBC count > 100,000 cells/μL ❑ ALL with WBC >100,000 cells/μL AND/OR LDH > 2xULN ❑ Burkitt's lymphoma stage III/IV with LDH ≥ 2x ULN ❑ Lymphoblastic lymphoma stage III/IV with LDH ≥ 2x ULN ❑ IRD with renal dysfunction ❑ IRD with uric acid, potassium or phosphate above ULN

❑ Provide hydration with 2-3 L/m²/day IV of a one quarter NS/5%dextrose ❑ Monitor urine output (80-100 ml/m²/hr) ❑ Record the fluid balance ❑ Monitor electrolytes and creatinine daily

❑ Monitoring for laboratory or clinical TLS criteria for 24-72 hrs ❑ Provide hydration with 2-3 L/m²/day IV of a one quarter NS/5%dextrose ❑ Monitor urine output (80-100 ml/m²/hr) ❑ Record the fluid balance ❑ Monitor electrolytes and creatinine every 8-12 hours ❑ Administer allopurinol* ❑ Add 0.15 mg/kg rasburicase in pediatric patients with uric acid level ≥ 7.5 mg/dl for 1-7 days (average 3 days)

❑ Provide hydration with 2-3 L/m²/day IV of a one quarter NS/5%dextrose ❑ Monitor urine output (80-100 ml/m²/hr) ❑ Record the fluid balance ❑ Monitor electrolytes and creatinine every 4-6 hours ❑ Ensure continuous cardiac monitoring ❑ Request renal consult ❑ Delay tumor therapy (individual clinical judgement) ❑ Administer 0.20 mg/kg rasburicase in pediatric patients with uric acid level > 7.5 mg/dl for 1-7 days (average 3 days)

* Allopurinol administration:

• In pediatric patients:
  • 50-100 mg/m2 every 8 hours, orally, maximum dose of 300 mg/m2/d, OR
  • 10 mg/kg/day divided every 8 hours, orally, maximum dose of 800 mg/d
• In adults:
  
  • 100 mg/m2/dose every 8 hours (10 mg/kg/d divided every 8 hours), orally, maximum dose of 800 mg/d, OR
  • 200-400 mg/m²/d, 1 to 3 IV doses, maximum dose 600 mg/d (when oral allopurinol can not be administered)

General Management

Shown below is an algorithm summarizing the initial management of tumor lysis syndrome.

Characterize the symptoms: ❑ Nausea ❑ Vomiting ❑ Anorexia ❑ Lethargy ❑ Diarrhea ❑ Hematuria ❑ Seizures ❑ Muscle cramps ❑ Syncope ❑ Flank pain ❑ Heart failure ❑ Tetany ❑ Arrhythmia

Order tests: ❑ Uric acid ❑ Potassium ❑ Calcium ❑ Phosphate ❑ LDH ❑ Creatinine ❑ Order an EKG

No TLS

Laboratory TLS

Clinical TLS

❑ Stratify the patient by the risk of developing TLS ❑ Initiate the appropriate preventive measures (see the algorithm above)

❑ Provide hydration with 2-3 L/m²/day IV of a one quarter NS/5%dextrose ❑ Monitor urine output (80-100 ml/m²/hr) ❑ Record the fluid balance ❑ Monitor electrolytes and creatinine every 4-6 hours ❑ Ensure continuous cardiac monitoring ❑ Request a renal consult ❑ Normalize electrolyte abnormalities ❑ Administer rasburicase* 0.2 mg/kg

❑ Admit to the intensive care in ICU ❑ Provide hydration with 2-3 L/m²/day IV of a one quarter NS/5%dextrose ❑ Monitor urine output (80-100 ml/m²/hr) ❑ Record the fluid balance ❑ Monitor electrolytes and creatinine every 4-6 hours ❑ Ensure continuous cardiac monitoring ❑ Request a renal consult ❑ Normalize electrolyte abnormalities ❑ Administer rasburicase* 0.2 mg/kg ❑ Hydration ± loop diuretic

* Rasburicase is not FDA approved for the use in the prophylaxis or treatment of tumor lysis syndrome in adults. It is only approved by the FDA for its use in the pediatric population.

Management of Electrolyte Disturbances

Shown below is an algorithm summarizing the management of the electrolytes disturbances in tumor lysis syndrome.

Management of electrolyte disturbances in TLS

Hyperphosphatemia

Hypocalcemia

Hyperkalemia

Moderate ( ≥2.1 mmol/L) ❑ Avoid phosphate in IV solutions ❑ Provide adequate hydration ❑ Administer phosphate binders: ♦ Aluminium hydroxide: 50-150 mg/kg/day every 6 hrs, orally or by NG tube ♦ Calcium carbonate ♦ Lanthanum carbonate ♦ Sevelamer Severe ❑ Hemodialysis ❑ Peritoneal dialysis ❑ Continuous venovenous hemofiltration

Asymptomatic ❑ No treatment required Symptomatic ❑ Administer calcium gluconate 50-100 mg/kg IV, given slowly with EKG monitoring ❑ Request a renal consult if phosphate level is high

Asymptomatic ( ≥ 6.0 mmol/L) ❑ Avoid IV or oral potassium intake ❑ Administer sodium polystyrene sulfonate 1 g/kg with 50 % sorbitol ❑ Ensure cardiac monitoring Severe ( > 7 mmol/L)/ Symptomatic: ❑ Perform the above mentioned actions ❑ Administer regular insulin 0.1 U/kg IV plus glucose infusion (25 % dextrose 2 ml/kg) ❑ Administer calcium gluconate 100-200 mg/kg/dose slow infusion with ECG monitoring for arrhythmias ❑ Administer sodium bicarbonate 1-2 mEq/kg IV push ❑ Hemodialysis

❑ Monitor the patient

No improvement Renal dysfunction

Improvement

❑ Ensure fluid and electrolyte management ❑ Order dialysis ❑ Adjust the dose of drugs excreted by the kidneys

❑ Continue treatment ❑ Continue laboratory monitoring ❑ Continue cardiac monitoring

Cairo and Bishop Definition for Laboratory Tumor Lysis Syndrome (LTLS)

Laboratory tumor lysis syndrome (LTLS) is considered to be present if 2 or more of the following serum abnormalities are present within 3 days before or 7 days after cytotoxic therapy. Shown below is a table summarizing the Cairo and Bishop definitions for laboratory tumor lysis syndrome.

Element	Value	Change from baseline
Uric acid	≥476 μmol/L or 8 mg/dL	25 % increase
Potassium	≥6 mmol/L or 6mg/L	25 % increase
Phosphorus	≥2.1 mmol/L for children ≥1.45 mmol/L for adults	25 % increase
Calcium	≤1.75 mmol/L	25% decrease

Cairo and Bishop Definition and Grading for Clinical Tumor Lysis Syndrome (CTLS)

Clinical tumor lysis syndrome is said to be present if LTLS is present in addition to 1 or more of the following clinical correlations summarized in the table below.

Abbreviation: ULN: upper limit of normal

Complication	Grade
	0	1	2	3	4	5
Creatinine	≤1.5×ULN	1.5×ULN	>1.5-3.0×ULN	>3-6×ULN	>6×ULN	Death
Cardiac arrhythmia	None	Intervention not indicated	Medical intervention indicated, but not urgently	Controlled with a device or symptomatically and incompletely controlled medically	Life threatening	Death
Seizure	None	-	One well controlled generalized seizure OR infrequent multiple focal motor seizures not affecting activities of daily living	Poorly controlled seizure disorder, seizure with altered consciousness	Prolonged seizure such as status epilepticus or intractable epilepsy	Death

Do's

• Consider additional risk factors that place the patient in a higher risk group:

  • Bulky disease ( > 10 cm)
  • LDH > 2x upper limit of normal
  • Oliguria
  • Dehydration
  • Pre-existing renal failure
  • High proliferation rate of tumor and rapid response to therapy
  • Baseline plasma uric acid > 7.5 mg/dl

• Administer loop diuretics in case the urine output is not appropriate despite aggressive hydration, in the absence of hypovolemia, dehydration and obstructive nephropathy.

• Consider the following during the administration of allopurinol:
  

  • Start treatment 1-2 days before induction therapy and continue till 3-7 after the chemotherapy or until the serum values are normalized.
  • Reduce dose by 50 % in cases of renal insufficiency.
  • Reduce doses of 6-mercaptopurine and azathioprine by 65-75% if administered with allopurinol.
  • Also adjust doses of dicumarol, uricosuric drugs, cytotoxic drugs and thiazide diuretics if they are administered with allopurinol.

• Administered IV rasburicase over 30 min.

  • Note that rasburicase is not approved for adults and geriatric population in United States.

• Immediately initiate hyperkalemia management in case of severe (>7 mg/dl) hyperkalemia, or if the EKG shows widening of QRS complex.

• Ensure that dialysis should be accessible to all high risk disease patients before cytotoxic chemotherapy is started.
• Request a renal consult for all high risk disease patients.

Dont's

• Do not administer calcium, phosphate and potassium with the initial hydration fluids.
• Alkalinization is currently not recommended for prevention or treatment of TLS.
• Do not administer rasburicase in patients with G6PD deficiency, pregnant women, lactating women or in the case of a history of anaphylactic reaction.
• Do not treat with allopurinol after a course of rasburicase.
• Do not administer sodium bicarbonate and calcium through the same IV line.

References

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