Metabolic derangements that occur with tumor Breakdown
- Spontaneous (Less common associated usually with normal Phosphorus levels) > may occur with high tumor burden (i.e. hyperleukocytosis)
- Post Cytotoxic therapy
Tumor cytotoxicity releases intracellular contents,vincluding nucleic acids, proteins, and electrolytes into the systemic circulation and may lead to development of hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia.
The risk of developing TLS depends on type of leukemia/lymphoma:
- Extremely high risk > Burkitt Lympoma/Leukemia
- High Risk > T cell Leukemia/lymphoma, ALL with WBC >100K, AML with WBC >50K
- Intermediate Risk > Stage III/IV Non-Burkitt NHL, ALL with WBC 50-100K, AML with WBC 10-50K
- Low Risk > Others not mentioned Above.
Consultative Hematology Q : What non hematological malignancies can produce tumor lysis syndrome?
Answer: Small cell carcinoma and Germ cell Tumors fall into intermediate/moderate risk category of TLS.
Hande & Garrow (1) first initiated definition of the clinical and pathologic characteristics of patients at risk for developing TLS. Cairo and Bishop (2) modified these criteria to formulate a commonly used classification system for TLS which is tabulated below.
In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present during the same 24-hour period within 3 days before the start of therapy or up to 7 days afterward.
Clinical tumor lysis syndrome requires the presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or death.
 Hyperuricemia = Uric acid >8.0 mg/dl in adults or above the upper limit of the normal range for age in children.
 Hyperphosphatemia = Phosphorus >4.5 mg/dl in adults or >6.5 mg/dl in children.
- Criteria for Classification of Laboratory Tumor Lysis Syndrome = Potassium >6.0 meq/l
- Criteria for Classification of Clinical Tumor Lysis Syndrome = Cardiac dysrhythmia or sudden death probably or definitely caused by hyperkalemia
- Criteria for Classification of Laboratory Tumor Lysis Syndrome = Corrected calcium <7.0 mg/dl or ionized calcium <1.12
- Criteria for Classification of Clinical Tumor Lysis Syndrome = Cardiac dysrhythmia, sudden death, seizure, neuromuscular irritability, hypotension, or heart failure probably or definitely caused by hypocalcemia
 Acute kidney injury
- Criteria for Classification of Laboratory Tumor Lysis Syndrome = Not applicable
- Criteria for Classification of Clinical Tumor Lysis Syndrome = Increase in the serum creatinine level of 0.3 mg/dl or a single value >1.5 times the upper limit or the presence of oliguria, defined as an average urine output of <0.5 ml/kg/hr for 6 hr.
TLS is a direct consequence of cell lysis and release of intracellular products. When clearance of these products, by excretion (renal or hepatic excretion or phagocytosis by the reticuloendothelial system), is impaired and their serum burden increases, the clinical sequelae of TLS may occur.
 Hyperuricemia: The nucleic acids adenine & guanine are metabolized to xanthine, which is further metabolized by xanthine oxidase to the water-insoluble uric acid.
Humans lack a functional gene for urate oxidase (uricase), which further metabolizes uric acid to the freely soluble and excretable allantoin and hence uric acid production if increases its handling limit by kidney is overwhelmed.
Mechanism of renal injury: Uric acid has potential for uric acid to crystallize within the tubular lumen. An acidic urine pH favors this process. Uric acid crystals can cause direct tubular injury.
 Hyperkalemia: Massive tumor cell lysis releases potassium into the extracellular environment, leading to severe hyperkalemia when uptake capacity by muscle and liver is exceeded.
 Hyperphosphatemia and hypocalcemia: Cell lysis releases significant amounts of phosphate (Note that malignant hematologic cells contain much more intracellular phosphate in comparison to normal mature lymphoid cells). Spontaneous tumor lysis is less commonly associated with hyperphosphatemia. Hyperphosphatemia exerts its predominant toxicity by binding to calcium cations leading to secondary hypocalcemia. Additionally, calcium–phosphate precipitates may deposit in tissues, as seen in nephrocalcinosis, including the kidneys.
AKI in TLS may be due to one or both of these effects:-
- Acute urate nephropathy
- Hyperphosphatemic nephrocalcinosis affecting the renal tubulointerstitium.
 Hydration and diuresis are regarded as mainstays of treatment : Hydrate the patient with with 3000 mL/m2 per day uness a patient presents with signs of acute renal dysfnction and oliguria and Diuresis with frosemide 20-40 mg/dose IV.
Goal of such aggressive hydration is to maintain urine output >100 mL/m2 per hour if there is no evidence of acute obstructive uropathy and/or hypovolemia
 Correction of hyperkalemia : Urgent measures are indicated if cardiac toxicity, muscular paralysis or if severe hyperkalemia is present (serum potassium> 6.5-7 mq/L).
- [a] Glucose and insulin: IV administration of 25% D 100ml + 5-10 U Regular insulin will lead 0.5- to 1 .5-mEq/L decrease in plasma potassium concentrations, begining within 15 minutes, peaking at 60 minutes, and lasting for 4-6 hours.
- [b] Nebulizer therapy: Nebuled albuterol 10-20 mg in 4 mL 0.9% sodium coride injection over 10-15 minutes.
- Note: When it is potentially dangerous to wait for 30-60 minutes for a response to insulin and glucose or nebulisation or if prominent ECG changes are there then
- [c] Calcium Infusion is indicated.
• Calcium gluconate 10% administer intravenously at a rate not greater than 0.7-1 .8 mEq/min
• May be repeated after 5 minutes if ECG does not improve
• The protective effect of calcium begins within minutes, but is relatively short-lived (< 60 mnutes)[d] Potassium-binding cation exchange resins: Sodium polystyrene sulfonate 15-50 g; administer orally or rectally mixed in 50-70% sorbitol solution. May be repeated ever 6 hours untit serum potassium is within normal limits
Refractory Hyperkalemia needs Dialysis.
 Correction of hyperphosphatemia (and hypocalcemia)
- Hyperphosphatemia develops within 24–8 hours following the initiation of chemotherapy
- Hyperphosphatemia may result in precipitation of calcium phosphate in tissues resulting in hypocalcemia, intrarenal calcifcations, nephrocalcinosis, and acute obstructive uropathy
Oral phosphate binders: Aluminum hydroxide 15-30 mL; administer oraly every 6 hours. Another option is using Sevelamer upto 800 mg TDS.
 Correction of hyperuricemia
[a] Xanthine oxidase inhibitor: Allopurinol lOO mg/m2; administer orally every 8 hours (maximum 800 mg/day). Allopuinol Dose Adjustments in Patients with Renal Impairment (10-20 ml/min maximum daily dose = 200 mg/day)
- Note: Because both allopurinol inhibits uric acid synthesis, but have no eﬀect on
preexisting uric acid, serum levels usually do not fall until afer 48-72 hours of treatment.
- Note: Alopurinol inhibits metabolism of azathioprine and 6-MP so their doses must be decreased by 65-75% if they are used concomitantly with allopurinol.
[b] Recombinant urate oxidase: Because urate oxidase degrades uric acid rather than preventing its synthesis, rapid reduction in uric acid occurs as compared to allopurinol
Recomended dose: 0.2 mg/kg for up to 5 days. However, except in rare patients with very high serum levels of uric acid, much less is usually suffcient as example using fixed dose of 1.5 mg/dose.
The half-life of rasburicase is 18-21 hours so 24 h dosing is reasonable. Rasburicase does not require dosage adjustment for decreased creatinine clearance. Antibodies against rasburicase occur in approximately 6-18% of patients repeated course of rasburicase, or use exceeding 5 days may lead to severe allergic reactions.
Note: Rasburicae is contraindicated in G6PD defciency or methemoglobinemia.
Rasburicase enzymatically degrades uric acid in blood samples left at room temperature. To monitor serum/plasma uric acid concentrations after rasburicase treatment samples are to be collected and kept chilled with ice during transfer and processed within 4h.
Urinary alkaltion is not recomended because:
- It favors precipitation of cacium/phosphate complexes in renal tubules, a concern in patients with concomitant hyperphosphatemia
- A metabolic alkalemia may result fom bicarbonate adistration, which can worsen neurologic features of hypocalcemia.
(1) Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med 94: 133–139, 1993
(2) Cairo MS, Bishop M. Tumor lysis syndrome: New therapeutic strategies and classification. Br J Haematol 127: 3–11, 2004