Tumour lysis syndrome (TLS)
• Metabolic Derangements
• Rapid Tumour breakdown
• Associated with the initiation of cytotoxic therapy of malignancy
• Affects both Children and Adults
3. • It is an oncologic emergency , which is characterized by a tetrad of abnormalities
• Abrupt release of intracellular ions, nucleic acids, proteins, and their metabolites results
from the rapid destruction of malignant cells and the release of their intracellular
contents into the extracellular space after the initiation of therapy
• The overall incidence of TLS is not well established
• Primarily - Acute lymphocytic leukaemia and high-grade non-Hodgkin's lymphomas, in
particular Burkitt's lymphoma.
• Also recognized in a variety of other malignancies, both hematologic and solid.
• Hematologic malignancies -- AML, CLL, CML, and low-grade and intermediate-grade
• Solid tumours -- Breast cancer, Ovarian and Testicular cancer, neuroblastoma, and small
cell carcinoma of the lungs.
8. Risk Factors
In malignancy with
• High proliferative rate,
• Large tumor burden, -bulky disease >10 cm in diameter and/or
-WBC >50,000 per microL,
- pretreatment serum LDH >2 times UNL,
• Initiation of cytotoxic chemotherapy,
• Cytolytic antibody therapy,
• Radiation therapy,
• Glucocorticoid therapy alone can result in the rapid lysis of tumor cells.
9. • The elevation of the serum LDH level before the initiation of therapy has also
been associated with the recognition of patients at risk for TLS.
• Other predisposing conditions
– Pre treatment hyperuricemia (serum uric acid >7.5 mg/dL or hyperphosphatemia
– Pre existing nephropathy or exposure to nephrotoxins
– Oliguria and/or acidic urine
– Dehydration, volume depletion, or inadequate hydration during treatment
10. Does TLS occur only with i/v chemo?
• TLS is not limited to systemic administration of agents;
• It has been observed with intrathecal administration of chemotherapy and with
Does TLS occur only with chemo?
• Not limited to the administration of chemotherapy alone.
• TLS has been associated with the administration of radiation therapy, corticosteroids,
hormonal agents, biologic response modifiers, monoclonal antibodies, and more recently,
the low-molecular-weight inhibitor, imatinib mesylate, better known as Gleevec
• Spontaneously, before the initiation of any intervention.
• Hyperuricemia and its associated complications are most frequently recognized
manifestations of TLS
• Cause of Hyperuricemia -results from rapid release and catabolism of intracellular
• Purine nucleic acids are catabolized to hypoxanthine, then xanthine, and finally to uric
acid by xanthine oxidase.
• In humans, who lack urate oxidase, uric acid is the final endpoint of purine catabolism
• Uric acid clearance - renal, and in normal circumstances approximately
• Excretion – 500/day.
• pKa of 5.4 to 5.7 and is poorly soluble in water.
• At normal concentrations and at physiologic blood pH, more than 99% of uric
acid is in the ionized form
• The concentration of uric acid has been noted to be elevated in patients with acute
leukemias and lymphomas before the initiation of therapy.
• The high concentrations of uric acid increase the risk for urate crystal precipitation
in the renal collecting ducts and distal tubules, which are sites of urinary
16. Clinical manifestations of hyperuricaemia
• General clinical manifestations of hyperuricemia include nausea, vomiting,
diarrhea, and anorexia.
• Uric acid crystal precipitation within renal tubules results in a decline in
glomerular filtration and the subsequent development of acute renal failure.
• The risk of acute renal failure caused by uric acid precipitation may be increased
• -dehydration, which is often present at the time of diagnosis;
• -ureteral obstruction by tumor;
• -a history of renal insufficiency;
• - possible need for nephrotoxic antibiotics, such as aminoglycosides, in patients
with active infections.
17. • If the hyperuricemia results in acute obstructive uropathy, other clinical
manifestations may include hematuria, flank pain, hypertension, azotemia, acidosis,
edema, oliguria, anuria, lethargy, and somnolence
• Hyperphosphatemia results from the rapid release of intracellular phosphates from
malignant cells, which may contain as much as four times the amount of organic
and inorganic phosphates as normal cells
• Initially , the kidneys are able to respond to the increased concentration of
phosphorus from tumor lysis by increased urinary excretion and decreased tubular
absorption of phosphorus.
• Eventually, however, the tubular transport mechanism becomes saturated and is
unable to maintain normal serum phosphorus concentrations.
19. • The development of hyperphosphatemia may be further exacerbated by acute renal
insufficiency associated with uric acid precipitation, resulting in obstructive uropathy
or other complications of tumor therapy.
• Hyperphosphatemia can lead to the development of acute renal failure after
precipitation with calcium in renal tubules during TLS.
20. Clinical manifestations of Hyperphosphatemia
• Nausea, vomiting, diarrhoea, lethargy, and seizures.
• More importantly, it may result in tissue precipitation of calcium-phosphate
crystals, resulting in
2. Metastatic calcification,
3. Intrarenal calcification,
6. Acute obstructive uropathy.
• The serum concentration of calcium rapidly decreases as precipitation with phosphate
• Hypocalcemia is one of the most serious clinical manifestations of TLS and has been
associated with the development of
1. Paresthesia and tetany with positive Chvostek and Trousseau signs
3. Carpal and pedal spasms
6. Cardiac arrest
22. • Deposition of calcium phosphate in various tissues may be responsible for the following
signs and symptoms:
•Gangrenous changes of the skin
• Hyperkalemia results from the kidneys’ inability to clear the massive load of
intracellular potassium released by lysed tumor cells.
Clinical manifestations of Hyperkalemia
2. Ventricular tachycardia or fibrillation,
4. Sudden death.
Neuromuscular signs and symptoms
1. Muscle weakness,
• Increases in blood urea nitrogen and creatinine levels occur as a result of renal impairment
• Acute clinical manifestations - nausea, vomiting, and lethargy
• Oliguria or anuria leading to fluid retention; edema, hypertension, congestive heart failure,
metabolic disturbances, and exacerbations of hyperphosphatemia and/or hyperkalemia
• flank or back pain; hematuria; and severe acidosis.
Complications of uremia
• Uremic pericarditis Seizures, and/or coma
• Platelet function defect Acute obstructive uropathy
• Cellular immunodeficiency Confusion/ somnolence
• Maintain hydration (>100 ml/hr)
• R/O cardiac disease and Renal insufficieny
• Rasburicase - 0.2 mg/kg i/v
• Screen for Hyperkalemia and treat if preexisting hyperkalemia is present
• Treat hypocalcemia – if symptomatic
• Regular Monitoring of renal function and electrolyte
• The LDH concentration serves as an excellent marker for tumor proliferation and
response to therapy.
26. Initial Management of Patients at Risk for Tumor Lysis
1.Identification of the patient at risk
2. Admit to intensive care or hematology/oncology unit
3. Alert dialysis team of existence of patient and potential emergent need of assisted
4. Establish adequate venous access.
5. Perform baseline electrocardiogram and continuous cardiac monitoring.
28. Hypouricemic agents
• It is necessary to administer a hypouricemic agent, either allopurinol or
rasburicase, before the initiation of therapy.
• Allopurinol is a potent inhibitor of xanthine oxidase and blocks the conversion of
hypoxanthine and xanthine to uric acid.
• Hypoxanthine is more soluble than uric acid is at physiologic pH, xanthine is less soluble
than uric acid. This may result in the formation of xanthine crystals in the kidney and
lead to obstructive uropathy.
• Allopurinol prevents new uric acid formation, it does not reduce the amount of uric acid
• Thus allopurinol requires administration for 2 to 3 days before the serum uric acid
concentration begins to fall and therefore needs to be initiated 2 to 3 days before the
initiation of cytotoxic therapy.
30. • It is usually given orally at 600 mg daily for prophylaxis and 600-900 mg daily
(up to a maximum of 500 mg/m2 daily) for treatment of tumor lysis syndrome.
Patients unable to take oral medications can be given IV allopurinol.
31. Cautions for Allopurinol
• Allopurinol is known to interfere with the degradation of 6- mercaptopurine, 6-
thioguanine, and azathioprine through inhibition of the P450 pathway; thus, the dose of
allopurinol should be reduced 50% to 75% in patients receiving these chemotherapeutic
• Should be used with caution in patients with underlying renal insufficiency, because it can
cause a syndrome consisting of rash, hepatitis, eosinophilia, and worsening renal function
• Previously, urine alkalinization was recommended to increase uric acid solubility and
promote uric acid excretion in patients treated with allopurinol.
• However, it is not currently recommended because of the risk of decreasing ionized
calcium concentrations, decreasing phosphate excretion, and increasing serum phosphate
• Concept- promote the catabolism of uric acid to allantoin by uric acid oxidase.
• Allantoin is 5 to 10 times more soluble in the urine than uric acid.
• Urate oxidase is an endogenous enzyme commonly found in many mammalian
species but not in humans .
• Urate oxidase, extracted from Aspergillus flavus, has been demonstrated to rapidly
and significantly reduce uric acid levels in patients at high risk for TLS.
• Recently, the gene encoding urate oxidase was identified and expressed in yeast to
yield large quantities of the pure recombinant form of urate oxidase Rasburicase.
33. • Rasburicase is administered by intramuscular injection or IV infusion at dosages ranging
from 50-100 U/kg daily.
• It is contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency and
• In G6PD deficiency, excess hydrogen peroxide accumulates as rasburicase breaks down
uric acid and accelerates catabolism of its precursors xanthine and hypoxanthine; this
accumulation places patients at risk for hemolytic anemia and methemoglobinemias.
• Some authorities recommend screening for G6PD deficiency prior to administration of
34. Allopurinol vs Rasburicase
• In a multicenter trial, 52 pediatric patients with hematologic malignancy at high
risk for TLS were randomly assigned to receive allopurinol or rasburicase.
• Uric acid levels
• Pui and colleagues administered rasburicase IV at doses up to 0.2 mg/kg in 131
pediatric patients with newly diagnosed leukemia or lymphoma.
Dec by 85% Dec by 12%
Initial uric acid 4 hours 24 hours
9.7 mg/dl 1mg/dl 0.5 mg/dl
35. • Serum phosphorus and creatinine concentrations also decreased significantly within 1 to 3
• There were very few adverse reactions after administration, and all of these were mild,
making this an excellent therapeutic option.
• Coiffier and associates investigated the safety and efficacy of rasburicase in 100 adult
patients with non-Hodgkin's lymphoma over a 1-year period.
• Of these patients, 66% had elevated LDH levels and 11% were hyperuricemic with
concentrations higher than 7.56 mg/dL.
• Rasburicase was given to all subjects and uric acid levels then measured at 4 hours. All of
the patients responded to rasburicase with normalization of uric acid, and none exhibited
increased creatinine levels or required dialysis
• Febuxostat is a novel xanthine oxidase inhibitor that does not appear to have the
hypersensitivity profile of allopurinol.
• Does not require dosing modification for renal impairment.
• Initial studies suggested that febuxostat is effective and safe for preventing tumor
38. • Hyperkalemia
1. I/V calcium gluconate
2. Insulin neutralizing drip
3. Beta agonist ( nebulization with salbutamol )
4. Sodium polystyrene sulfonate, a potassium binding resin, at a dose of 15 to 60 g/day
given orally or rectally.
• Aluminum hydroxide, given orally or through a nasogastric tube at a dose of 15 mL
(50–150 mg/kg/24 hr) every 4 to 6 hours, should be used to treat
• Serum LDH level serves as an excellent marker for a decrease in tumor lysis ( 48-
• Treat if symptomatic
• Intravenous calcium gluconate (50–100 mg/kg per dose) may be administered to
correct the clinical symptoms; however, this may increase the risk of calcium and
phosphorus deposition and acute obstructive uropathy.
• Uremic pericarditis
• Hypotensive – C/I Haemodialysis
• First – Pericardial drain
• F/B HD when BP normalizes
• ARF , significant uremia, or severe electrolyte abnormalities - initiated as soon as
• Children - Continuous hemofiltration
• The failure to promptly initiate hemodialysis for acute renal failure may turn a potentially
reversible clinical situation into an irreversible one
• Among the indications for renal replacement therapy in patients with TLS are :
– Severe oliguria or anuria
– Intractable fluid overload
– Persistent hyperkalemia
– Hyperphosphatemia-induced symptomatic hypocalcemia
– A calcium-phosphate product ≥70 mg2 /dL