TUMOR LYSIS SYNDROME

TUMOR LYSIS SYNDROME (TLS) 

What is Tumor Lysis Syndrome?

Tumor lysis syndrome (TLS) is a potentially life-threatening oncologic emergency caused by rapid destruction of malignant cells, either:

• Spontaneously, or
• After anticancer therapy(TLS generally occurs 12-72 hours after chemotherapy initiation)

The massive release of intracellular contents produces the characteristic biochemical abnormalities:

↑ K⁺ + ↑ phosphate + ↑ uric acid + ↓ calcium → AKI ± arrhythmia, seizures, shock, death

The most important complications are:

• Hyperkalemia → fatal arrhythmias
• Hyperuricemia → acute kidney injury
• Hyperphosphatemia → hypocalcemia → tetany/seizures/arrhythmias
• AKI → worsening electrolyte abnormalities

TLS is particularly important in hematologic malignancies with a high tumor burden, especially rapidly proliferating tumors.

Pathophysiology

When large numbers of tumor cells lyse:Intracellular contents released

How does uric acid cause AKI?

Uric acid is relatively poorly soluble, especially in acidic urine.

It can precipitate in renal tubules/interstitium:

Hyperuricemia → uric acid crystallization → tubular obstruction + inflammation → ↓ GFR → AKI

However, TLS-associated AKI is multifactorial.

Contributors include:

• Uric acid nephropathy
• Calcium-phosphate precipitation
• Volume depletion
• Sepsis
• Nephrotoxic drugs
• Hemodynamic instability

Important exam point

Uric acid nephropathy is not the only mechanism of AKI in TLS.

Which cancers are high risk?(high risk is defined as >5%)

TLS is particularly associated with rapidly proliferating, highly chemosensitive malignancies.

• There is a Complete table of malignancies with risk stratification(low, intermidiate, High)
• TLS can also occur with:CLL,Multiple myeloma,Solid tumors,Small-cell lung cancer,Germ-cell tumors,Neuroblastoma.
• But spontaneous or treatment-associated TLS is much more characteristic of hematologic malignancies.

Risk stratification

Tumor-related risk factors

High-risk tumor characteristics

• High tumor burden
• Bulky disease
• High WBC
• High LDH
• High proliferation rate
• High chemosensitivity
• High circulating tumor-cell burden

Particularly concerning

LDH >2× ULN + bulky/rapidly proliferating disease

Patient-related risk factors

Risk increases with:

• Pre-existing renal dysfunction
• Dehydration
• Baseline hyperuricemia
• Baseline hyperphosphatemia
• Baseline hyperkalemia
• Reduced urine output
• Hypotension
• Nephrotoxic medications

Thus:Same cancer ≠ same TLS risk

Treatments that can cause TLS

TLS is not limited to conventional chemotherapy.

It may occur following:

Cytotoxic chemotherapy

• Anthracyclines
• Cyclophosphamide
• Platinum agents
• Cytarabine
• Steroids in lymphoid malignancies

Targeted therapy

• Tyrosine kinase inhibitors
• BCL-2 inhibitors
• Monoclonal antibodies

Particularly important

Venetoclax

Because it can cause extremely rapid tumor cell killing in CLL/AML.

Other triggers

• CAR-T therapy
• Radiotherapy
• Immunotherapy
• Hormonal therapy

And occasionally:Spontaneous TLS before any treatment.

Spontaneous TLS

TLS can occur before chemotherapy.This is called:

Spontaneous tumor lysis syndrome.It is particularly reported with aggressive hematologic malignancies and occasionally solid tumors.

Important distinction

Spontaneous TLS may produce:Hyperuricemia + AKI

without the full classical picture of marked hyperphosphatemia.

Because viable kidneys may excrete phosphate efficiently, whereas uric acid production can become overwhelming.

Clinical manifestations

Symptoms are primarily caused by electrolyte abnormalities and AKI.

Hyperkalemia

• Most immediately dangerous.
• Can cause:Weakness,Paresthesia,Palpitations,ECG changes,Ventricular arrhythmias,Cardiac arrest

Hyperphosphatemia

• Usually asymptomatic directly, but causes:↑ phosphate → ↓ calcium
• leading to:Perioral tingling,Paresthesia,Muscle cramps,Tetany,Carpopedal spasm,Seizures,QT prolongation,Arrhythmia.

Hyperuricemia

• Can cause:Oliguria,Hematuria,Flank discomfort,AKI
• But many patients are asymptomatic until renal dysfunction becomes significant.

AKI

May manifest as:Rising creatinine,Oliguria,Anuria,Fluid overload,Metabolic acidosis,Uremia.

Cairo-Bishop definition

TLS is divided into:

1. Laboratory TLS (LTLS)
2. Clinical TLS (CTLS)

Laboratory TLS

Cairo-Bishop laboratory TLS requires ≥2 metabolic abnormalities occurring within the appropriate time window around cancer therapy.

Classically:3 days before to 7 days after treatment with abnormalities in:

And/or a ≥25% change from baseline.

Important

The ≥25% change criterion is part of the classic Cairo-Bishop framework, but in practice the absolute thresholds and clinical context are often more useful.

Clinical TLS

Clinical TLS = Laboratory TLS + ≥1 significant clinical complication

Classically:

• Creatinine ≥1.5 × ULN
• Cardiac arrhythmia
• Seizure
• Death

Howard modification

The classic Cairo-Bishop criteria have limitations.

One important problem is that defining TLS based on percentage changes can classify relatively trivial changes as TLS.

The Howard criteria emphasize:

• ≥2 clinically important metabolic abnormalities
• Occurring simultaneously or within a short period
• Without relying heavily on the ≥25% change criterion

Differential Diagnosis

• Pseudohyperkalemia(very high WBC or platelet count)
• Rhabdomyolysis
• Hemolysis
• Renal failure

Laboratory monitoring

• K⁺,Phosphate,Calcium,Na⁺,HCO₃⁻,Mg²⁺
• Uric acid,Creatinine,BUN
• LDH
• Fluid balance,Urine output

• Low risk: monitor daily.
• Intermediate risk: monitor q12hr.
• High risk: monitor q6hr.
• Established diagnosis of TLS: monitor q4hr.

Management

Prevention is the most important treatment

Main preventive strategies:

1. Hydration
2. Uric-acid reduction
3. Electrolyte monitoring
4. ECG Monitoring
5. Avoid nephrotoxins
6. Early nephrology involvement in high-risk patients

Prevention according to risk

Exact prophylaxis depends on malignancy, tumor burden, renal function, baseline labs, and institutional protocol.

IV hydration

• Hydration increases:Renal perfusion,Urine flow,Excretion of uric acid,Excretion of electrolytes.
• FLUID—Balance salt Solution
• Typical strategy:—Intermediate and high-risk patients with the administration of 2-3 L/m2/day (~175 ml/hr) beginning the day prior to therapy and until the end of the day following treatment completion. 

Urine output

• A commonly used target in adults:≥1–2 mL/kg/h or >80-100 ml/m2/hour.
• The exact target depends on the patient and clinical setting.
• Monitor:Input − output and daily weight.

Diuretics

Loop diuretics(Not thiazides as they Increases Uric acid) may be considered when:

• Adequate volume status exists
• Urine output remains inadequate
• There is a need to prevent fluid overload

Uric-acid–lowering therapy

There are two major drugs: Allopurinol and Rasburicase

They work differently.

Allopurinol vs rasburicase

If TLS is established:Rasburicase is preferred over allopurinol when rapid uric-acid reduction is needed, provided there is no G6PD deficiency.Because:Allopurinol prevents formation while:Rasburicase removes existing uric acid rapidly.

Important laboratory issue with rasburicase

• After rasburicase administration:Uric acid continues to be degraded in the blood sample ex vivo.
• Therefore a falsely low uric acid may be reported.
• Blood for uric acid measurement should be:Collected in a pre-chilled tube and Kept on ice then Processed promptly

Why calcium is tricky in TLS

TLS patients have:Hyperphosphatemia + hypocalcemia

It may be tempting to automatically give calcium.But calcium can bind phosphate:

Ca²⁺ + PO₄³⁻ → calcium-phosphate precipitation

This can worsen:Renal injury,Tissue calcification.

Therefore:Treat symptomatic hypocalcemia only , not merely an asymptomatic low calcium value.

Hyperphosphatemia Management:

1. Stop phosphate intake

Avoid:

• Phosphate-containing fluids
• Phosphate supplements
• Excess dietary phosphate

2. Hydration

If appropriate.

3. Phosphate binders

May be used to reduce GI phosphate absorption.

Examples:

• Sevelamer
• Calcium-based binders in selected circumstances

But calcium-containing binders may be undesirable when calcium-phosphate precipitation is a major concern.

4. Dialysis

For severe/refractory hyperphosphatemia, particularly with AKI.