Tumor Lysis Syndrome Overview

1. Tumor Lysis Syndrome-
Management
Dr.Sreeraj Vasudevan
AIIMS 2014-2016

2. Outline
• Pathophysiology
• Diagnostic Criteria
• Risk Factors/Risk Group
• Prophylaxis
• Established TLS Management

3. Tumor lysis syndrome (TLS) is an oncologic emergency that is caused by massive tumor cell lysis
with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic
circulation.

4. Definition of Tumour Lysis Syndrome
Cairo and Bishop definition for TLS
Laboratory TLS Clinical TLS
>2 of the following metabolic abnormalities occurring from 3
days prior to 7 days after initiation of treatment.
1. Uric acid -8 mg/dL or 25% increase from baseline
2. Potassium-6mEq/L or 25% increase from baseline
3. Phosphorus - >6.5mg/dL (children) or >4.5mg/dL (adults)
or 25% increase from baseline
4. Calcium - <7mg/dL) or 25% decrease from baseline
Laboratory TLS with any of the
following.
1. S. creatinine > 1.5x ULN
(age adjusted)
2. Seizures
3. Cardiac arrhythmia
4. Death
Howard et al criteria :
•Any symptomatic hypocalcaemia also to be considered as a lab criteria.
•Increase in the serum creatinine level of 0.3 mg/dl or the presence of oliguria, defined as an
average urine output of <0.5 ml/kg/hr. for 6 hr

5. Clinical features and Risk Factors
• Non-specific symptoms
• 12-72 hours after chemo or prior to chemo [Spontaneous]
• Lethargy, Nausea,Seizures
• Extreme hypoclcemia: Cramps, Tetany, Seizures, Arrhythmia, Death
• Hyperkalemia: Neuromuscular, Arrhythmia

6. Risk factors for the development of TLS
Characteristics Risk factors
Tumour type Acute Lymphoblastic leukemia
Burkitt’s lymphoma
High grade Non Hodgkin Lymphomas
Lymphoblastic lymphomas
Solid tumours with high proliferation -
Neuroblastoma
Tumour load Bulky disease (>10cm)
High WBC count
Elevated LDH.
Renal function Preexisting kidney injury
Urinary outflow obstruction
Nephrotoxic medications
Baseline uric acid levels Baseline hyperuricemia (>7.5 mg/d)
Chemosensitivity Effective and targeted chemo
immunotherapy.

7. LOW RISK  Most solid tumors
 MM
 CML
 Indolent NHL
 HL
 CLL and WBC <50 x 109/L treated only with alkylating agents
 AML and WBC <25 x 109/L and LDH <2 x ULN
 Adult intermediate grade NHL and LDH within normal limits
 Adult ALCL
INTERMEDIATE RISK  Rare, highly chemotherapy-sensitive solid tumors
 Plasma cell leukemia
 CLL treated with fludarabine, rituximab, or lenalidomide,
or venetoclax and lymph node ≥5 cm or absolute
lymphocyte count ≥25 x 109/L, and/or those with high
WBC ≥50 x 109/L
 AML with WBC 25 to 100 x 109/L OR LDH ≥2 x ULN
 Adult T cell leukemia/lymphoma, diffuse large B-cell,
transformed, and mantle cell lymphomas with LDH >
ULN, non-bulky
 Childhood ALCL stage III/IV
 ALL and WBC <100 x 109/L and LDH <2 x ULN
 Burkitt lymphoma and LDH <2 x ULN
 Childhood intermediate grade NHL stage III/IV with LDH
<2 x ULN
HIGH RISK CLL treated with venetoclax and lymph node ≥10 cm, or lymph node ≥5
cm and absolute lymphocyte count ≥25 x 109/L and elevated baseline uric acid.
AML and WBC ≥100 x 109/L
Adult T cell leukemia/lymphoma, diffuse large B-cell, transformed, and mantle cell
lymphomas with bulky disease and LDH ≥2 x ULN
Stage III/IV childhood diffuse large B-cell lymphoma with LDH ≥2 x ULN
Burkitt's leukemia
Other ALL and WBC ≥100 x 109/L and/or LDH ≥2 x ULN
Burkitt lymphoma stage III/IV and/or LDH ≥2 x ULN
Lymphoblastic lymphoma stage III/IV and/or LDH ≥2 x ULN
Intermediate risk disease with renal dysfunction and/or renal involvement
Intermediate risk disease with uric acid, potassium, and/or phosphate > ULN
Cairo MS, Coiffier B, Reiter A. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases:
an expert TLS panel consensus. Br J Haematol 2010; 149:578

8. Cairo-Bishop grading system for tumour lysis syndrome.
Grade 0 Grade I Grade II Grade III Grade IV Grade V
Lab TLS - + + + + +
Creatinine 1.5xULN 1.5xULN >1.5-3xULN >3-6 x ULN >6xULN Death
Cardiac
arrhythmia
None Intervention not
required
No urgent
medical
intervention
indicated
Symptomatic and
incompletely
controlled by
medically or by
device
(defibrillator)
Life threatening
(Arrhythmia
associated with
CHF,
hypotension,
shock)
Death
Seizure None None Single
episode/episodes
of GTCS well
controlled with
AEDs, or multiple
focal motor
seizures not
interfering with
ADL
Seizures with
altered
consciousness,
poorly controlled
seizures or
breakthrough
seizures despite
medical
interventions.
Prolonged and
repetitive
seizures that are
difficult to
control.
(Status
epilepticus or
refractory
seizures)
Death
ULN – Upper limit of normal, CHF- Congestive heart failure, AEDs – Anti-epileptic drugs, ADL – activities of daily living.

9. Management of TLS
Delay in identifying TLS can be potentially dangerous and life
threatening
• Identification of at risk patients
• Management of risk factors
• Close monitoring
• Timely intervention

10. TLS Prevention
• Hydration
• Hypourecemic drugs
• Urine Alkalinisation
• Lab monitoring

11. TLS Prevention: Hydration
• Wide bore IV access
• IV hydration — Aggressive IV hydration is the cornerstone of preventing TLS
• Recommended prior to therapy in patients at intermediate or high risk for TLS
• The goal of IV hydration :
• A 2008 International Expert Panel on TLS recommended that both children
and adults at risk for TLS initially receive 2 to 3 L/m2 per day of IV fluid
• or 200 mL/kg per day in children weighing ≤10 kg
• Urine output : to maintain within a range of 80 to 100 mL/m2 per hour
• Diuretics can be used to maintain the urine output, if necessary
• Choice of Diuretic: Frusemide
• Choice of Fluid: ?
• Optimal Duration: ?
Coiffier, B., et al., Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin
Oncol, 2008. 26(16): p. 2767-78.

12. TLS Prevention:Urinary alkalinization
• Benefit unclear / controversial
• Sodium Bicarbonate only if metabolic acidosis
• If alkalinization is used, it should be initiated when the serum uric acid
level is high and discontinued when hyperphosphatemia develops
• Not required in patients receiving rasburicase
For Against
No proven efficacy documented
Urine pH > 6.5 improve Uric acid
solubility
0.9% NS hydration itself is as effective in
preventing uric acid precipitation
Alkalinization promote deposition of
calcium phosphate crystals in tissues
including heart

13. TLS Prevention : Hypouricemic agents

14. TLS Prevention : Hypouricemic agents
Allopurinol
• Recommendation: For the initial management of adult and pediatric
patients at intermediate risk for TLS [Pre treatment Uric Acid
<8mg/dL]
• Allopurinol effectively decreases the formation of new uric acid

15. TLS Prevention : Hypouricemic agents
Allopurinol
• Limitations :
• Preexisting serum uric acid is NOT reduced
• XANTHINURIA, deposition of xanthine crystals in the renal tubules, and acute
kidney injury
• Drug interaction
• Hypersensitivity reactions
• Dose and administration :
• Adults -100 mg/m2 every eight hours (maximum 800 mg per day)
• Children-50 to 100 mg/m2 every eight hours (maximum 300 mg/m2 per day)
or 10 mg/kg per day in divided doses every eight hours
• The dose must be reduced by 50 percent in the setting of acute kidney injury

16. TLS Prevention : Hypouricemic agents
Rasburicase
• Recommendations: For the initial management of most pediatric and
adult patients at high risk for TLS ,especially with impaired renal or
cardiac function

17. TLS Prevention : Hypouricemic agents
Rasburicase
• Rapid breakdown & Sustained Response
Stanton C. Goldman et al. Blood 2001;97:2998-3003

18. TLS Prevention : Hypouricemic agents
Rasburicase
• Dosing and administration — The EMA and FDA dosing guidelines both
recommend a rasburicase dose of 0.2 mg/kg once daily for up to five (FDA)
or seven (EMA) days
• Expert Consensus Panel
• High-risk patients or a baseline uric acid level >7.5 mg/dL (446 micromol/L) –
rasburicase 0.2 mg/kg
• Intermediate-risk patients with baseline uric acid ≤7.5 mg/dL – rasburicase 0.15 mg/kg
• Length of treatment has generally been based on clinical judgement
• Allopurinol can a be started once the serum uric acid is brought down to
adequately low levels
• Responses to rasburicase are dose-related

19. TLS Prevention : Hypouricemic agents
Rasburicase
Lower Dose / Shorter duration Rasburicase:
• Based upon these data, single-dose rasburicase may be used in patients at intermediate risk
(0.15 mg/kg [ rounded up to 3 mg or 6 mg depending on body weight]) or high risk (0.2 mg/kg) of TLS
• These patients receive allopurinol after rasburicase treatment
• Uric acid levels should be monitored closely and additional doses of rasburicase given if and when
hyperuricemia recurs
Efficacy and cost of single-dose rasburicase in prevention and treatment of adult tumour lysis syndrome: a meta-analysis.,Feng X etalJ Clin Pharm
Ther. 2013;38(4):301

20. TLS Prevention : Hypouricemic agents
Rasburicase
• Contraindications and restrictions
• Hemolysis in patients with G6PD deficiency
• Anaphylaxis
• Methemoglobinemia
• Spuriously low uric acid measurements
• Rasburicase within blood samples causes enzymatic degradation of uric acid ex vivo if
the blood samples are left at room temperature, resulting in spuriously low serum uric
acid concentrations, and hence missing the diagnosis of ongoing TLS.
• Blood samples for determination of uric acid concentrations should be collected in a pre-
chilled tube, immediately placed on ice, and the assay completed within four hours, if
possible

21. • Febuxostat
• Available data on efficacy and safety are insufficient to suggest the use
of febuxostat as an alternative to allopurinol to prevent TLS in patients at
intermediate to high risk for TLS.
• Febuxostat may be used judiciously in patients with hyperuricemia who
cannot tolerate allopurinol in a setting in which rasburicase is either not
available or contraindicated

22. TLS Prevention:Monitoring Guidelines
• Urine output and serial assays of electrolytes and serum uric acid
• 2008 International Expert Panel guidelines recommendations for
monitoring in high risk of TLS
• laboratory and clinical TLS parameters four to six hours after the initiation of
chemotherapy and every four to eight hours thereafter
• For all patients receiving rasburicase (hence deemed at high risk for TLS),
serum uric acid should be reevaluated four hours after administration of the
first dose, and every 6 to 12 hours
• Adults at intermediate risk for TLS should be monitored for at least 24 hours
after completion of chemotherapy
• If TLS has not occurred within 72 hours of multiagent chemotherapy, the
likelihood of TLS is very low

23. TREATMENT OF ESTABLISHED TLS
• Despite appropriate preventive measures, approximately 3 to 5 percent of
patients develop laboratory and/or clinical evidence of TLS, despite the
prophylactic use of rasburicase
• Intensive supportive care with continuous cardiac monitoring and
measurement of electrolytes, creatinine, and uric acid every four to six
hours
• Combination of
• Treating specific electrolyte abnormalities
• Use of rasburicase at 0.2 mg/kg (if it was not given initially) with repeated doses as
necessary
• Attempting to wash out the obstructing uric acid crystals with fluids with or without
a loop diuretic
• Appropriate use of renal replacement therapy

24. Hyperphoshatemia Recommendations:
Moderate, ≥6.5 mg/dL Restrict phosphate intake (avoid IV and oral phosphate;
limit dietary sources)
Phosphate binders:
• Calcium acetate
:
Adult: 2 to 3 tabs (1334 to 2668
mg) with each meal; or
• Calcium carbonate:Adult: 1 to 2 grams with each
meal; Pediatric: 30 to 40 mg/kg with each meal;
or
• Sevelamer:Adult: 800 to 1600 mg with each
meal; Pediatric: 40 to 54 mg/kg with each meal;
or
• Lanthanum carbonate :Adult: 500 to 1000 mg
with each meal or
• Aluminum hydroxide :Adult: 300 to 600 mg with
each meal; Pediatric: 12.5 to 37.5 mg/kg four
times daily with meals; (avoid use in patients with
renal insufficiency)
Severe
Dialysis, CAVH, CVVH, CAVHD, or CVVHD
Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol
2008; 26:2767.

25. Hypocalcemia, total serum calcium ≤7 mg/dLor ionized calcium ≤3.2 mg/dL
Asymptomatic No Therapy
Symptomatic Calcium gluconate administered slowly with ECG
monitoring
Patients with acute hypocalcemia and
hyperphosphatemia should not be treated with
calcium until the hyperphosphatemia is corrected
(unless they have tetany or a cardiac arrhythmia from
hypocalcemia)
Calcium gluconate:
Adult: 1 gram (10 mL of 10 percent solution)
Pediatric: 50 to 100 mg/kg
Slow IV infusion (maximum 50 to 100 mg per
minute) in large vein
May be repeated after 5 to 10 minutes if
symptoms or ECG changes persist.
Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol
2008; 26:2767.

26. Hyperkalemia
Moderate and asymptomatic, ≥6.0 mEq/L Avoid IV and oral potassium
ECG and cardiac rhythm monitoring
Sodium polystyrene sulfonate
Adult: 15 to 30 grams orally
Pediatric: 1 gram/kg orally.
Onset 1 to 2 hours.
Repeat every 4 to 6 hours up to four times daily
as needed based on repeat serum K+ level
Severe (>7.0 mEq/L) and/or symptomatic For patients with ECG changes (widening of the QRS
complex or loss of p-waves but not peaked t-waves
alone), give calcium gluconate by slow IV infusion to
prevent life-threatening arrhythmias
To temporarily shift potassium into cells:
IV Glucose with Insulin
If acidosis: Soda Bicarbonate
Salbutamol Nebulisation
Dialysis
Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;
26:2767.

27. Indications for renal replacement therapy
• Reduced need with Rasburicase
• Indication for RRT
• Severe oliguria or anuria
• Intractable fluid overload
• Persistent hyperkalemia
• Hyperphosphatemia-induced symptomatic hypocalcemia
• A calcium-phosphate product ≥70 mg2/dL2
• The prognosis for complete recovery of renal function is excellent if dialysis
is initiated early to rapidly reduce serum uric acid and phosphate
concentrations
• Continuous renal replacement therapies may be better tolerated for
Hyperphosphatemia

28. Summary
• TLS is an oncological emergency with High treatment cost, morbidity
and mortality if not prevented.
• Hydration is corner stone in management
• Intermediate risk patient with Uric Acid < 8 should receive Allopurinol
• High risk patient or Established TLS should receive Rasburicase ,Single
dose may be effective.
• Continuous cardiac monitoring with frequent Electrolyte
measurement is needed
• Management of dyselectrolytemia with judicious renal replacement
therapy is needed in established TLS

29. Bibliography
1. Hande, K.R. and G.C. Garrow, Acute tumor lysis syndrome in patients with high-
grade non-Hodgkin's lymphoma. Am J Med, 1993. 94(2): p. 133-9.
2. Cairo, M.S. and M. Bishop, Tumour lysis syndrome: new therapeutic strategies and
classification. Br J Haematol, 2004. 127(1): p. 3-11.
3. Howard, S.C., D.P. Jones, and C.H. Pui, The tumor lysis syndrome. N Engl J Med,
2011. 364(19): p. 1844-54.
4. Coiffier, B., et al., Guidelines for the management of pediatric and adult tumor lysis
syndrome: an evidence-based review. J Clin Oncol, 2008. 26(16): p. 2767-78.
5. Tosi, P., et al., Consensus conference on the management of tumor lysis syndrome.
Haematologica, 2008. 93(12): p. 1877-85.
6. Will, A. and E. Tholouli, The clinical management of tumour lysis syndrome in
haematological malignancies. Br J Haematol, 2011. 154(1): p. 3-13.

30. • Thank You