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]

Definition

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

Classification

Cairo and Bishop classified and graded TLS as laboratory tumor lysis syndrome (LTLS) and clinical tumor lysis syndrome (CTLS).

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

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.

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 plus 1 or more of the following clinical correlations:

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	Status epilepticus, intractable epilepsy	Death

ULN: Upper limit of normal

Modified LTLS and CTLS criteria by Howard et al

• CTLS is considered to be present in cases of any cardiac dysrhythmia, symptomatic hypocalcemia or acute kidney injury is present along with LTLS.
• LTLS is considered to be present if 2 or more of the following serum abnormalities are present during the same 24 hour period within 3 days or 7 days after cytotoxic therapy.

Element	Value
Uric acid	≥ 476 μmol/L or 8 mg/dL, > ULN for age in children
Potassium	≥ 6 mmol/L or 6mg/L
Phosphorus	≥ 2.1 mmol/L for children, ≥ 1.45 mmol/L for adults
Calcium	Corrected calcium ≤ 1.75 mmol/L or, ionized calcium < 0.3 mmol/L

Prevention of TLS

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

❑ Close monitoring ❑ Ensure hydration with 2-3 L/m²/day IV of a one quarter NS/5%dextrose ❑ Monitor urine out to 80-100 ml/m²/hr

❑ Monitoring for laboratory or clinical TLS criteria for 24-72 hrs ❑ Ensure hydration with 2-3 L/m²/day IV of a one quarter NS/5%dextrose ❑ Monitor urine out to 80-100 ml/m²/hr ❑ 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)

❑ Admit to ICU ❑ Consult nephrology ❑ Monitor for development of laboratory or clinical TLS every 4-6 hours after initiation of chemotherapy ❑ Ensure hydration with 2-3 L/m²/day IV of a one quarter NS/5%dextrose ❑ Monitor urine out to 80-100 ml/m²/hr ❑ Delay tumor therapy (individual clinical judgement) ❑ Ensure cardiac monitoring ❑ 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-300 mg/m2/d) or 10 mg/kg/day divided every 8 hours (maximum dose-800 mg/d)
• In adults: 100 mg/m2/dose every 8 hours (10 mg/kg/d divided every 8 hours) given orally (maximum dose-800 mg/d) or 200-400 mg/m2/day in 1-3 divided doses given IV (maximum, 600 mg/d)

Management of Established TLS

Patient diagnosed with a hematologic malignancy or a solid tumor (rarely)

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

Order TLS screen ❑ Uric acid ❑ Potassium ❑ Calcium ❑ Phosphate ❑ LDH ❑ Creatinine ❑ Cardiac monitoring (EKG)

Patient positive for TLS screen ? (See criteria for LTLS and CTLS above)

No

Yes

Risk stratify as above and manage accordingly

❑ Intensive care in ICU ❑ Continuous cardiac monitoring ❑ Renal consult ❑ Above mentioned laboratory tests every 4-6 hours ❑ Normalize electrolyte abnormalities ❑ Rasburicase 0.2 mg/kg ❑ Hydration ± loop diuretic

Hyperphosphatemia

Hypocalcemia

Hyperkalemia

Hyperuricemia

Moderate ( ≥2.1 mmol/L) ❑ Avoid IV phosphate ❑ Adequate hydration ❑ Phosphate binders ♦ Aluminium hydroxide: 50-150 mg/kg/day every 6 hrs ♦ Calcium carbonate: 30-40 mg/kg with each meal ♦ Lanthanum carbonate: 500-1000 mg with each meal ♦ Sevelamer Severe ❑ Hemodialysis ❑ Peritoneal dialysis ❑ Continuous venovenous hemofiltration

Asymptomatic ❑ No treatment required Symptomatic ❑ Calcium gluconate 50-100 mg/kg IV, given slowly with EKG monitoring ❑ If phosphate levels are high ♦ Renal consult

Asymptomatic ( ≥ 6.0 mmol/L) ❑ Avoid IV or oral potassium intake ❑ Sodium polystyrene sulfonate 1 g/kg with 50 % sorbitol ❑ Cardiac monitoring Severe ( > 7 mmol/L)/ Symptomatic: ❑ Above mentioned actions plus: ❑ Rapid acting insulin 0.1 U/kg IV plus glucose infusion (25 % dextrose 2 ml/kg) ❑ Calcium gluconate 100-200 mg/kg/dose slow infusion with ECG monitoring for arrhythmias. ❑ Sodium bicarbonate 1-2 mEq/kg IV push ❑ Albuterol inhalation ❑ Hemodialysis

Established hyperuricemia ❑ Hydration ♦ 2-3 L/m²/day IV of a one quarter NS/5%dextrose ♦ Urine out maintained up to 80-100 ml/m²/hr ❑ Allopurinol administration

Patient responds?

No

Yes

Renal dysfunction (Uremia)

❑ Continue treatment ❑ Continue laboratory monitoring ❑ Continue cardiac monitoring

❑ Fluid and electrolyte management ❑ Uric acid and phosphate management ❑ Hemodialysis ❑ Peritoneal dialysis ❑ Hemofiltration ♦ Continuous venovenous hemofiltration ♦ Continuous arterial-venous hemodialysis ♦ Continuous arterial-venous hemodialysis ♦ Continuous veno-venous hemodialysis

Do's and Dont's

Risk stratification

• Additional risk factors that place a 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

Prevention and Management of TLS

• Calcium, phosphate and potassium should not be administered with initial hydration fluids.
• Loop diuretics are recommended in case urine output is not maintained adequately, but contraindicated in hypovolemia, dehydration and obstructive nephropathy.
• Alkalinization is currently not recommended for prevention or treatment of TLS.
• Allopurinol administration :
  

  • 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.

• Rasburicase administration:
  

  • Contraindicated in G6PD deficiency or history of anaphylactic reaction.
  • Administered IV over 30 min.
  • Indicated in patients with pre-existing hyperuricemia instead of allopurinol.
  • Indicated if hyperuricemia persists in intermediate risk disease despite use of allopurinol.
  • Not approved for adults and geriatric population in United States.
  • Allopurinol treatment after rasburicase is not required.

• Hyperkalemia management

  • Immediate management is recommended in case of severe (>7 mg/dl) hyperkalemia, or if EKG shows widening of QRS complex.
  • Sodium bicarbonate and calcium should not be administered through the same IV line.
  • Cardiac monitoring should be done continuously.

Monitoring Guidelines

• In pediatrics high risk patients, TLS screen should be done every 4-6 hrs after induction chemotherapy.
• TLS screen include following serum lab values:

  • Uric acid
  • Calcium
  • Phosphate
  • Potassium
  • LDH
  • Fluid input and output

• Uric acid should be monitored in all patients every 6-8 hrs after chemotherapy until normalization of LDH value.
• All adult intermediate risk disease patients should be monitored up to 24 hours after chemotherapy.
• Likelihood of developing TLS is minimal if it does not occur after 2 days of chemotherapy.
• Dialysis should be accessible to all high risk disease patients before cytotoxic chemotherapy is started.
• Renal consult should be placed for all high risk disease patients.

References

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