This document provides information about tumor lysis syndrome (TLS). TLS is an oncologic emergency caused by the rapid breakdown of tumor cells after initiation of chemotherapy. This releases intracellular contents like potassium, phosphate, and nucleic acids into circulation, which can overwhelm the kidneys and cause acute kidney injury. TLS risk is highest for certain cancers like acute lymphoblastic leukemia, non-Hodgkin's lymphoma, and acute myeloid leukemia. Prevention focuses on aggressive hydration and use of allopurinol or rasburicase to lower uric acid levels. Electrolyte abnormalities like hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia are managed to prevent complications like kidney damage. Early

1. TumorTumor LysisLysis Syndrome (TLS)Syndrome (TLS)
ByByByBy
Dr/MohamedDr/Mohamed MoustafaMoustafa

2. Introduction
Tumor lysis syndrome (TLS) is an oncologic emergency that
is Caused by rapid & massive tumor cell lysis and release of
large amount of intracellular contentsintracellular contents (potassium,
phosphate and nucleic acids) into the systemic circulationphosphate and nucleic acids) into the systemic circulation
that overwhelms the kidney’s ability to excrete those
products →→→ AKI
Can occur after the initiation of cytotoxic therapy for high-
grade lymphomas (e.g., Burkitt’s) and acute lymphoplastic
leukemia.
Can also be precipitated by radiation therapy, cytotoxic
antibody therapy or sometimes glucocorticoid therapy alone
can result in the rapid lysis of tumor cells .

3. Cont.Cont.
Risk of AKI and life-threatening electrolyte
disturbances is caused by the breakdown of
nucleic acids →→→ uric acid, which can
precipitate in the renal tubules.precipitate in the renal tubules.
Hyperphostatemia with precipitation &deposition
of calcium phosphate crystals in the renal tubules
can also cause AKI.

4. MalagnanciesMalagnancies Associated with high riskAssociated with high risk
of developingof developing TLSTLS
ALL 63%
Non-Hodgkin’s Lymphoma 18%Non-Hodgkin’s Lymphoma 18%
AML 11%
Solid Tumors 5% - Neuroblastoma;
Medulloblastoma; germ cell tumors;
sarcoma

6. Risk FactorsRisk Factors
AA-- Certain intrinsic tumorCertain intrinsic tumor--related factorsrelated factors
are associated with a higher riskare associated with a higher risk
High tumor cell proliferation rate.
ChemosensitivityChemosensitivity of the malignancy.
Large tumor burdenLarge tumor burden, as manifested by bulkybulkyLarge tumor burdenLarge tumor burden, as manifested by bulkybulky
disease >disease >1010 cmcm in diameter and/or a WBC countWBC count
>>5050,,000000 perper microLmicroL..
pretreatment sr. (LDH)(LDH) ˃˃ 22 times the (ULN).times the (ULN).
organ infiltration, or bone marrow involvement.

7. BB-- clinical features that predispose toclinical features that predispose to
the development of TLSthe development of TLS
Pretreatment hyperuricemiahyperuricemia (serum uric
acid >7.5 mg/dL [446 micromol/L]) or
hyperphosphatemiahyperphosphatemia.hyperphosphatemiahyperphosphatemia.
A preexisting nephropathynephropathy or exposure to
nephrotoxinsnephrotoxins..
OliguriaOliguria and/or acidic urineacidic urine.
DehydrationDehydration, volume depletionvolume depletion, or
inadequate hydrationinadequate hydration during treatment.

8. Definition And ClassificationDefinition And Classification
Although there is a general consensus
that TLS represents a set of metabolic
complications that arise from treatment of
a rapidly proliferating and drug-sensitive
complications
a rapidly proliferating and drug-sensitive
neoplasm.
There have been relatively few attempts
to specifically define the syndrome.

9. CairoCairo--Bishop definitionBishop definition
proposed in 2004, provided specific
laboratory criterialaboratory criteria for the diagnosis of TLS
both at presentation and within 7 days ofboth at presentation and within 7 days of
treatment.
It also incorporated a grading systemgrading system to
help delineate the degree of severity of TLS.

10. Cairo Bishop Grading SystemCairo Bishop Grading System
Laboratory TLSLaboratory TLS was defined as any two
or more abnormal serum values, as outlined
in the following table .in the following table .
present within 3 days before or 7 days
after instituting chemotherapy in the setting
of adequate hydration (with or without
alkalinization) and use of a hypouricemic
agent.

12. Clinical TLSClinical TLS
Clinical TLS constitutes Laboratory TLSLaboratory TLS
plus at least oneleast one of the following clinical
complication :complication :
A- serum Creatinine > 1.5 x (ULN).
B- cardiac arrythmia / sudden death.
C- seizure.

13. Clinical TLS & grading systemClinical TLS & grading system
GradeGrade 00†† Grade IGrade I Grade IIGrade II Grade IIIGrade III Grade IVGrade IV Grade VGrade V
LTLSLTLS NoNo YesYes YesYes YesYes YesYes YesYes
CreatinineCreatinine‡‡ ≤≤11..55 ×× ULNULN 11..55 ×× ULNULN
>>11..55––33..00 ××
ULNULN
>>33..00––66..00 ××
ULNULN
>>66 ×× ULNULN DeathDeath
NonurgentNonurgent
SymptomaticSymptomatic
andand
incompletelyincompletely
LifeLife--
threateningthreatening
(eg,(eg,
CardiacCardiac
arrhythmiaarrhythmia‡‡ NoneNone
InterventionIntervention
not needednot needed
NonurgentNonurgent
interventionintervention
neededneeded
incompletelyincompletely
controlledcontrolled
medically ormedically or
controlledcontrolled
with a devicewith a device
(eg,(eg,
arrhythmiaarrhythmia
associatedassociated
with CHF,with CHF,
hypotension,hypotension,
or shock)or shock)
DeathDeath
SeizuresSeizures‡‡ NoneNone NoneNone
One brief,One brief,
generalizedgeneralized
seizure,seizure,
seizuresseizures
controlledcontrolled
withwith
anticonvulsananticonvulsan
t drugs, ort drugs, or
infrequentinfrequent
motormotor
seizuresseizures
Seizures withSeizures with
impairedimpaired
consciousnesconsciousnes
s, poorlys, poorly
controlledcontrolled
seizures,seizures,
generalizedgeneralized
seizuresseizures
despitedespite
medicalmedical
interventionsinterventions
StatusStatus
epilepticusepilepticus
DeathDeath

14. Risk StratificationRisk StratificationRisk StratificationRisk Stratification

16. Clinical Manifestations of TLSClinical Manifestations of TLS
Nausea/Vomiting, diarrhea, anoxeria
lethargy, syncope.
Metabolic Abnormalities Includes
HyperuricemiaHyperuricemia → “uric acid nephropathy” =HyperuricemiaHyperuricemia → “uric acid nephropathy” =
oliguria, renal failure , hematuria.
HyperphosphatemiaHyperphosphatemia → hypocalcemia, renal
failure.
HypocalcemiaHypocalcemia → muscle cramps, tetany,
mental status changes , seizures.
HyperkalemiaHyperkalemia → weakness, dysrhythmias.

17. PreventionPrevention -- MonitoringMonitoring
AA--high risk for developing TLS(high risk for developing TLS(children&adultchildren&adult))
Tested for lab.&clinical TLS parameters(sr. UAUA , Ph.Ph.
, KK , Cr.Cr., CaCa And LDHLDH) Plus Fluid input &urine
output →→ 4-6 hr. after chem.thpy initiation andoutput →→ 4-6 hr. after chem.thpy initiation and
every 4-8 hr. thereafter.
All pts. Receving rasburicaserasburicase→→ sr. UA should be
reevaluated 4 hrs. after the first dose, and every 6
to 12 hrs. (depending on the risk and degree of
tumor lysis) thereafter until normalization of serum
LDHLDH and UAUA levels.

18. PreventionPrevention –– Monitoring (Cont.)Monitoring (Cont.)
BB-- intermediate risk for TLS(Adult)intermediate risk for TLS(Adult)
monitoring should be maintained for 24 hrs. after
administration of the final agent of the first cycle of
therapy.therapy.
If rasburicase is not used initially, serum electrolytes should
be measured 8 hrs. after chemotherapy, and the patient
might require a one night hospital stay. If TLS has not
occurred within 72 hrs. of multiagent chemotherapy, the
likelihood of TLS is very lowvery low.

20. HydrationHydration
both children and adults at risk for TLS initiallyinitially
receive 22 toto 33 L/mL/m22/ day/ day of IV fluid (or 200 mL/kg
/day in children weighing ≤10 kg) .
Urine output GoalUrine output Goal 8080 toto 100100 mLmL/m/m22 /hr/hr.Urine output GoalUrine output Goal 8080 toto 100100 mLmL/m/m /hr/hr.
(2 mL/kg per hr. for both children and adults,
4 to 6 mL/kg per hr. if ≤10 kg).
DiureticsDiuretics can be used to maintain the urine
output, if necessary, but should not be required in
patients with relatively normal renal and cardiac
function.
loop diuretics such as furosemidefurosemide appear
preferable because they not only induce diuresis,
but may also increase potassium secretion.

21. Hydration (Cont.)Hydration (Cont.)
The choice of hydration fluid depends upon the clinical
circumstances.
The expert panel suggests the initial use of 55% dextrose one% dextrose one--
quarter normal (isotonic) salinequarter normal (isotonic) saline, probably because ALL patients
receive steroid during remission induction, which can causereceive steroid during remission induction, which can cause
sodium retentionsodium retention and hypertensionhypertension .
In patients with hyponatremia or volume depletion, isotonic salineisotonic saline
should be the initial hydration fluid.
Due to the risk of hyperkalemia and hyperphosphatemia with
calcium phosphate precipitation once tumor breakdown begins,
potassiumpotassium and calciumcalcium should be withheldwithheld from the hydration
fluids, at least initially.
Monitor for fluid overload in patients with underlying cardiaccardiac
dysfunction or renalrenal insufficiency.

22. UrinaryUrinary AlkalinizationAlkalinization
The role of urinary alkalinization with either
acetazolamide and/or sodium bicarbonate is unclear
and controversial.
. In the past, alkalinization to a urine pH of 6.5 to 7.0
or even higher was recommended to increase uric acidor even higher was recommended to increase uric acid
solubility, thereby diminishing the likelihood of uric acid
precipitation in the tubules.
However,
This approach has fallen outfallen out of favor for the following
reasons:
1- Experimental study suggested that hydration with
saline alonesaline alone is as effective as alkalinization in
minimizing uric acid precipitation.

23. UrinaryUrinary AlkalinizationAlkalinization (Cont.)(Cont.)
2- Alkalinization of the urine has the potential
disadvantagedisadvantage of promoting calcium phosphate
deposition in the kidney, heart, and other organs in
patients who develop marked hyperphosphatemiahyperphosphatemia oncepatients who develop marked hyperphosphatemiahyperphosphatemia once
tumor breakdown begins.
the expert panel concluded that use of sodiumsodium
bicarbonatebicarbonate was only indicated in patients with
metabolic acidosismetabolic acidosis.
If alkalinization is used, it should be initiated when the
serum uric aciduric acid level is highhigh and discontinued when
hyperphosphatemiahyperphosphatemia develops.

24. HyperuricemiaHyperuricemia

26. HyperuricemiaHyperuricemia

27. PreventionPrevention -- HypouricemicHypouricemic AgentsAgents
AllopurinolAllopurinol –(which reduces urate formation
by blocking xanthine oxidase activity),
; takes 22--33 daysdays to be effective.; takes 22--33 daysdays to be effective.
UrateUrate OxidaseOxidase/RasburicaseRasburicase – breaks down
uric acid to allantoin which is more soluble
in urine; acts within several hours.
UO has significantly reduced the need for
rescue dialysis therapy for TLS.

28. PreventionPrevention -- AllopurinolAllopurinol
Decrease production of uric
acid
allopurinol inhibits xanthine
oxidase.
Adult:Adult: 100mg/m2 /day q8 hr.
(max. 800 mg/day)
Xanthine/Hypoxanthine
xanthine oxidase
(max. 800 mg/day)
In childrenIn children : 50-100 mg/m2/day
q8hr.
(max. 300 mg/m2/day ) or
10 mg/ kg /day q8hr.PO/IV
Dose reduction 5050 %% in AKI.
Treatment is generally initiatedinitiated
2424 to 4848 hrs. beforebefore the start of
induction chemotherapy → up toup to
33 to 77 days afterward until
normalization of sr.uric acid and
other lab.evidence of TLS (eg,
elevated Sr. LDH levels).
Uric acid
Allopurinol

29. PreventionPrevention -- UrateUrate OxidaseOxidase
Present in other
mammalian species
Catalyzes conversion of
uric acid to allantoin.
Allantoin more soluble,
easily excreted by kidneys.
Urine alkalinization
Recombinant urate oxidase
(rasburicase) more effective than
allopurinol in prevention and
treatment of hyperuricemia.
Contraindicated
with GG66PD deficiencyPD deficiency, anaphylaxisanaphylaxis,
hemolysishemolysis, hemoglobinuriahemoglobinuria,
MethemoglobinemiaMethemoglobinemia, asthmaasthmaUrine alkalinization
unnecessary if used.
Rasburicase therapy was
associated with a much
greater reduction in serum
uric acid four hrs.four hrs. after the
first dose.
MethemoglobinemiaMethemoglobinemia, asthmaasthma
Serum phosphate concentrations
decreased to normal within 4848 hrshrs,
and significant reductions in serum
creatinine occurred after 2424 hrshrs.
No patient receiving rasburicase
required dialysis,
dose of 00..22 mg/kgmg/kg once daily for
up to five to seven days.

30. Management of electrolyte abnormalitiesManagement of electrolyte abnormalitiesManagement of electrolyte abnormalitiesManagement of electrolyte abnormalities
in TLSin TLS

32. HyperphosphatemiaHyperphosphatemia
Malignant cells contain higher concentration of
phosphorus ( Four times more than normal cells).
Hyperphosphatemia causes secondary hypocalcemia .
when (the calcium phosphate product) exceeds 60when (the calcium phosphate product) exceeds 60
mg2/dL2, there is an increased risk of calcium
phosphate precipitation in the renal tubules, which can
lead to AKI. In addition, precipitation in the heart may
lead to cardiac arrhythmias.
Since the widespread use of hypouricemic agents,
calcium phosphate deposition (nephrocalcinosis) rather
than hyperuricemia has become the major mechanism
of AKI in TLS.

33. Treatment of Established TLSTreatment of Established TLS
HyperphosphatemiaHyperphosphatemia

34. HyperkalemiaHyperkalemia
Moderate and AsymptomaticModerate and Asymptomatic (K>6.0 mmol/L):
remove all K from IVF; ECG monitoring.
May give Sodium Polystyrene sulfonate (1 gram/kg) every 4-6 hours
until normalized.
Severe and/or symptomaticSevere and/or symptomatic (K>7.0 mmol/L); loss of p waves, widened
QRS, peaked T waves):QRS, peaked T waves):
Ca Gluconate (50-100 mg/kg) slow IVP
( insulin iv + dextrose)
• Adult: 10 units regular insulin +100ml (D50)
• Pediatric: IV regular Insulin (0.1 unit/kg) and D25 (0.5 gram/kg = 2 ml/kg)
over 30 minutes. Monitor blood glucose level.
NaHCO3 If acidotic
• Adult : 45-50 meq/kg
• Pediatric: 1-2 meq/kg over 5-10 minutes
Albuterol
• Adult: 10 to 20 mg in 4 ml saline nebulized over 20 mint.
• Pediatric : 0.1 – 0.3 mg/kg nebulized.
Dialysis

35. HypocalcemiaHypocalcemia
AsymptomaticAsymptomatic : No treatment needed if
SymptomaticSymptomatic :
Administer Calcium Gluconate with ECG monitoring
• Adult : 1 gm• Adult : 1 gm
• Pediatric : (50-100 mg/kg) slow iv infusion
however,
Hypocalcemia shouldnot be treated with calcium until
hyperphoshatemia is corrected unless there is (tetany or
arrythmia from hypocalcemia).

36. Dialysis for TumorDialysis for Tumor LysisLysis SyndromeSyndrome
Indications
Oliguria
Hyperkalemia
Azotemia
Hyperphosphatemia
Refractory Hyperuricemia
• Hemodialysis or continuous veno-venous
hemofiltration with dialysis most effective

37. ReferencesReferences
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