Prevention and management of tumour lysis syndrome

ID: 108 v.4 Endorsed

Definition, classification, clinical manifestations

Tumour lysis syndrome (TLS) is a life-threatening oncological emergency. It can occur spontaneously or after chemotherapy or
radiotherapy. It is caused by the death, or lysis, of large numbers of cancer cells.
Cell lysis results in the release of intracellular ions, nucleic acids, proteins and their metabolites into the systemic circulation.
The resulting metabolic abnormalities such as hyperuricaemia, hyperkalaemia, hyperphosphataemia, secondary hypocalcaemia
and uraemia, can in turn lead to renal failure, cardiac arrhythmias, seizures, neurological complications and potentially, sudden
death.
TLS is more common on the first cycle of treatment. Early recognition of at risk patients, initiation of prophylaxis prior to
chemotherapy and prompt management of TLS, if it occurs, is essential.

TLS can be classified as either:1

Laboratory TLS (LTLS) - laboratory evidence of the metabolic changes associated with TLS, without symptoms, OR
Clinical TLS (CTLS) - LTLS plus one or more specific abnormal laboratory parameters or the development of a life-threatening
symptom such as cardiac arrhythmia.

Cairo and Bishop definition of laboratory tumour lysis syndrome (LTLS)1, 2

The presence of 2 or more of the metabolic abnormalities below at presentation, OR
Change of 25% from baseline within 3 days prior to or 7 days after commencement of therapy.

Uric acid Greater than or equal to 0.476 mmol/L or 25% increase from baseline

Potassium Greater than or equal to 6.0 mmol/L or 25% increase from baseline

Phosphate Greater than or equal to 1.45 mmol/L or 25% increase from baseline

Corrected calcium Less than or equal to 1.75 mmol/L or 25% decrease from baseline

Cairo and Bishop definition of clinical tumour lysis syndrome (CTLS)1, 2

The presence of LTLS PLUS
One or more of the following clinical complications (not directly or probably attributable to a therapeutic agent):
renal insufficiency defined by increase in serum creatinine greater than or equal to 1.5 x ULN (institution, age and gender
defined),
cardiac arrhythmia/sudden death, and/or
seizure.

Cairo and Bishop tumour lysis syndrome grading1, 2

Cairo and Bishop developed a grading system to assist in assessing the severity of TLS based on degree of elevation of serum
creatinine, presence and type of cardiac arrhythmia and presence and severity of seizures.

Grade 0* 1 2 3 4 5

LTLS - Present Present Present Present Present

Serum Less than or 1.5 Greater than Greater than 3 Greater than 6 Death
creatinine (x equal to 1.5 1.5 to 3 to 6
ULN)**

Cardiac None Intervention not Non-urgent Symptomatically Life threatening Death

arrhythmia indicated medical and
intervention incompletely
indicated controlled
medically or

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 Grade 0* 1 2 3 4 5
controlled with
device (e.g.,
defibrillator)

Seizure None None One brief, Seizure with Prolonged Death

generalised altered repetitive
seizure; consciousness; seizures,
seizure(s) well breakthrough difficult to
controlled with seizures despite control (e.g.
anticonvulsants medication status
or infrequent epilepticus)
focal motor
seizures not
interfering with
ADL

*No laboratory tumour lysis syndrome (LTLS).

**Elevated creatinine is defined as 1.5 times greater than ULN (institution, age and gender defined).
Note: Elevated creatinine, arrhythmia and seizures not directly attributable to a therapeutic agent.

Adapted from © Cairo et al 20041

Clinical manifestations
Although symptoms may occur before the commencement of cytotoxic therapy, they are observed more commonly within 12 to 72
hours after the initiation of cytotoxic treatment.2 Symptoms include:
nausea and vomiting
diarrhoea
anorexia
lethargy
oedema
fluid overload
congestive heart failure
haematuria
cardiac dysrhythmia
seizures
muscle cramps
tetany
syncope.

Risk assessment

Risk factors for developing tumour lysis syndrome include:

high tumour cell proliferation rate
bulky disease (greater than 10 cm)
increased WCC (greater than 25 x 109/L)
increased LDH (greater than 2 x ULN)
chemosensitive malignancies
high intensity or highly potent therapy
novel or targeted therapy, used alone or in conjunction with conventional cytotoxic agents, even in patients with low-grade
disease.3, 4

Malignancies associated with a higher risk of TLS include:

Burkitt lymphoma/leukaemia
acute lymphoblastic leukaemia
lymphoblastic lymphoma
diffuse large-cell lymphoma
solid tumours with high proliferative rate and rapid response to therapy.

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Additional conditions that may predispose patients to developing TLS:
renal insufficiency or renal failure
dehydration
decreased urinary flow
pre-existing uraemia or hyperuricaemia
pre-existing hyperphosphataemia.

Risk stratification
Evidence and expert consensus based guidelines5 stratify the risk of developing TLS as High (greater than 5%), Intermediate (1 to
5%) or Low (less than 1%) and provide algorithms that can be used to assess the risk based on tumour type and other markers.

Patient stratification by tumour lysis risk

High risk Intermediate risk Low risk

Burkitt Early-stage, non-bulky NHL and T-cell lymphomas with LDH Indolent NHL, myeloma, CML
lymphoma/leukaemia > ULN to < 2 x ULN (chronic phase)

ALL with WBC > 100 ALL with WBC < 100 x109/L and LDH < 2 x ULN ALL with WBC < 50 x109/L
x109/L or LDH > 2 x ULN

AML with WBC > 100 AML with WBC 25 to 100 x109/L or LDH > 2 x ULN AML with WBC < 25 x109/L and
x109/L LDH < 2 x ULN

Advanced/bulky aggressive CLL treated with fludarabine, rituximab or lenalidomide CLL treated only with alkylating
Non-Hodgkin and T-cell and/or those with a high WBC > 50 x109/L agents (i.e. no fludarabine or
lymphomas with LDH > ULN rituximab)

CLL and other lymphoma Other haematologic malignancies and solid tumours* with All other haematologic
patients being treated with rapid proliferation and an expected rapid response to malignancies and solid tumours
venetoclax therapy or treated with high intensity/potency therapy not classified as intermediate or
high risk

*e.g. neuroblastomas, germ-cell tumours and small-cell lung cancer

Note: The presence of other TLS risk factors such as renal dysfunction or elevated uric acid, phosphate or potassium levels can increase the level of risk associated with
any given tumour; e.g. Patients stratified to the low risk category, with renal dysfunction and/or renal involvement, are moved to the intermediate risk category.

Adapted from © Coiffier et al 20082 and © Cairo et al 2010.5

Prophylaxis
Early risk assessment and institution of appropriate prophylaxis to prevent TLS is essential. Adequate hydration and maintenance
of urine output is the mainstay of prevention and pre-emptive administration of hypouricaemic agents should be considered.
Consideration should be given to delaying treatment in high risk patients until prophylactic measures can be commenced. If a delay
is not appropriate, then ensure patient is managed in an ICU or haematology/oncology unit with staff with the appropriate expertise
and skills as deemed by the local institution.
If prophylactic measures fail and clinical TLS develops, institutional guidelines for the management of hyperkalaemia,
hyperphosphataemia and hypocalcaemia, as well as other clinical manifestations, need to be initiated immediately.

The following tumour lysis prophylaxis algorithm, dealing with hyperuricaemia, is adapted from Coiffier et al incorporating their
tumour lysis risk stratification. It is intended as a guide only. The decision as to which prophylaxis to use should always be based
on individual patient risk factors, the treatment they are receiving, and local institutional policies.

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 Image © J Clin Oncol 2008 2

Hydration
Increased hydration and enhanced urinary flow promotes urinary excretion of uric acid and phosphate. A 2008 International Expert
Panel on TLS2 recommended vigorous hydration in patients at intermediate or high risk of TLS and those presenting with LTLS or
CTLS prior to treatment.2
Unless contraindicated aim to hydrate with 3 L/m2/day of IV fluid.
Continue for several days to maintain a urine output of at least 100 mL/m2/hour and a urine specific gravity of less than or equal
to 1.010 g/mL.2, 5
Weigh twice daily and maintain strict fluid balance chart.
Diuretics may be used to maintain urine output if necessary, but should not be required in patients with relatively normal renal
and cardiac function and are contraindicated in patients who are hypovolaemic or have obstructive uropathy.
Potassium, calcium and phosphate should not initially be added to hydration fluids to avoid exacerbation of the hyperkalaemia,
hyperphosphataemia and calcium phosphate precipitation that may occur once tumour break down begins.

Urinary alkalinisation6
Urinary alkalinisation with sodium bicarbonate is NOT currently recommended as there is a lack of clear evidence demonstrating
benefit. The only available experimental study suggested that hydration with saline alone is as effective as alkalinisation in
minimising uric acid precipitation.7
Urinary alkalinisation should be avoided in patients with tumour lysis syndrome, especially when rasburicase is available, as
alkalinisation has the potential disadvantage of promoting calcium phosphate deposition, in patients who develop marked

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 hyperphosphataemia once tumour breakdown begins.
If alkalinisation is used, it should be initiated when the serum uric acid level is high and discontinued when hyperphosphataemia
develops.
IV sodium bicarbonate should only be administered to patients with metabolic acidosis.

Hypouricaemic agents

Allopurinol
Allopurinol competitively inhibits xanthine oxidase, blocking the conversion of hypoxanthine and xanthine to uric acid. Allopurinol
effectively reduces formation of new uric acid, however it does not reduce existing levels of uric acid. Therefore, in patients with
pre-existing hyperuricaemia (serum uric acid > 0.45 mmol/L) rasburicase is the preferred hypouricaemic agent5. There is a risk of
acute obstructive renal failure, due to xanthine crystal deposition in the renal tubules, with allopurinol. Allopurinol also can cause
skin rashes and increased liver function tests. There are also a number of clinically significant drug interactions with allopurinol
including cyclophosphamide, high dose methotrexate, mercaptopurine and azathioprine (mercaptopurine and azathioprine require a
60 to 75% dose reduction if used concurrently with allopurinol).

Dosage and administration:

100 mg/m2 orally every 8 hours (maximum 800 mg/day)2, 5

300 mg/day used in practice by majority of haematologists, however increasing allopurinol dose or switching to
rasburicase may be necessary in the presence of deteriorating biochemical or clinical markers.3
Initiate 24 to 48 hours prior to cytotoxic therapy if possible, and continue until three to seven days after completion, or until uric
acid level and other laboratory evidence of tumour lysis (e.g. elevated serum LDH levels) have normalised.
Reduce dose by 50% or more in the presence of renal failure.
Prophylactic hydration with careful monitoring is generally safe to use in patients with an allergy to allopurinol.3
Adjust dose of co-administered interacting drug(s) or allopurinol.

Rasburicase
A recombinant form of urate oxidase, rasburicase converts uric acid to allantoin which is readily excreted in the urine. It is well
tolerated, rapidly lowers serum uric acid, and is effective in prevention and treatment of hyperuricemia in TLS.8 Normalisation of
uric acid level occurs in about four hours. There is no rationale for the use of allopurinol and rasburicase together.

Rasburicase should be considered in patients:

at intermediate or high risk of developing TLS; especially those with renal impairment and/or unable to tolerate high fluid input,
with pre-existing LTLS and/or CTLS (prior to cytotoxic therapy),
unable to tolerate or allergic to allopurinol, or
who do not adequately respond to standard TLS preventive measures of hydration and allopurinol.

Dosage:

0.20 mg/kg once daily IV for 5 to 7 days9 or fixed 3 mg or 6 mg single IV dose (intermediate or high risk patients respectively).10,
11

Initiate 24 to 48 hours prior to cytotoxic therapy.

Administration:9

Dilute in 50 mL sodium chloride 0.9% and infuse IV over 30 minutes (do not use any IV glucose solution for dilution due to
potential incompatibility).
Infuse via a different line/lumen than that used for chemotherapy; if a separate line is not available, flush well with saline
between rasburicase and chemotherapy.
If weight based dosing is used, it is recommended to round the dose to the nearest 1.5 mg (available vial size) to avoid
wastage (rasburicase costs ~$400 per mg).

References
1 Cairo, M.S. and M. Bishop. 2004. "Tumour lysis syndrome: new therapeutic strategies and classification." Br J Haematol
127(1):3-11

2 Coiffier, B., A. Altman, C.H. Pui, et al. 2008. "Guidelines for the management of pediatric and adult tumor lysis syndrome: an

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 evidence-based review." J Clin Oncol 26(16):2767-78.

3 Jones, G.L., A. Will, G.H. Jackson, et al. 2015. "Guidelines for the management of tumour lysis syndrome in adults and
children with haematological malignancies on behalf of the British Committee for Standards in Haematology." Br J
Haematol. 169(5):661-71

4 Howard, S.C., S. Trifilio, T.K. Gregory, et al. 2016. "Tumor lysis syndrome in the era of novel and targeted agents in patients
with hematologic malignancies: a systematic review." Ann Hematol. 95(4):563-73

5 Cairo, M. S., B. Coiffier, A. Reiter, et al. 2010. "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 149(1):578-
586.

6 Howard, S.C., D.P. Jones and C.H. Pui. 2011. "The Tumor Lysis Syndrome." N Engl J Med 364(19): 1844-1854

7 Conger, J.D. and S.A. Falk. 1997. "Intrarenal dynamics in the pathogenesis and prevention of acute urate nephropathy." J Clin
Invest 59(5):786-93.

8 Hummel, M., S. Reiter, K. Adam, et al. 2008. "Effective treatment and prophylaxis of hyperuricemia and impaired renal
function in tumor lysis syndrome with low doses of rasburicase." Eur J Haematol 80(4):331-336.

9 Sanofi-Aventis Australia Pty Ltd. Product Information Fasturtek (rasburicase rys). Date of TGA Approval 19 Mar 2003, Date
of most recent amendment 12 Aug 2010

10 Trifilio, S., L. Gordon, S. Singhal, et al. 2006. "Reduced-dose rasburicase (recombinant xanthine oxidase) in adult cancer
patients with hyperuricemia."Bone Marrow Transplant 37(11):997-1001.

11 Trifilio, S.M., J. Pi, J. Zook, et al. 2011. "Effectiveness of a single 3-mg rasburicase dose for the management of
hyperuricemia in patients with hematological malignancies." Bone Marrow Transplant 46(6) 800-805.

History

Version 4
Date Summary of changes

22/05/2009 All approved tumour lysis syndrome documents on CI-SCaT reviewed, collated and transferred to eviQ.

1/11/2013 Reviewed, updated.

20/05/2016 Reviewed, minor changes made.

31/05/2017 Transferred to new eviQ website. Version changed to V.3.

25/05/2018 Document reviewed and updated the:

Risk factors for developing TLS to include novel/targeted therapies
Dosage and administration of allopurinol to include:
dosage commonly used in practice in presence of deteriorating biochemical markers, or changing to
rasburicase
prophylactic hydration in patients with an allergy to allopurinol.
Version number changed to v.4.

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 This document reflects what is currently regarded as safe practice. While every effort has been made to ensure the accuracy of
the content at the time of publication, the Cancer Institute NSW does not accept any liability, with respect to loss, damage, injury
or expense arising from any such errors or omission in the contents of this work. Any reference throughout the document to
specific pharmaceuticals and/or medical products as examples does not imply endorsement of any of these products. Use is
subject to eviQ’s disclaimer available at www.eviQ.org.au

First approved: 20 July 2006

Last reviewed: 25 May 2018
Review due: 25 May 2023

The currency of this information is guaranteed only up until the date of printing, for any updates please check:
https://www.eviq.org.au/p/108
06 Dec 2020

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