1.0 Objectives

To describe a policy for the prevention and management of tumour lysis syndrome (TLS)

2.0 Purpose

To facilitate the prevention and management of TLS in patients undergoing systemic anticancer therapy (SACT)

3.0 Scope

3.1

This policy refers to patients undergoing treatment at the Edinburgh Haematology Centre or Edinburgh Cancer Centre, Western General Hospital, Edinburgh.

3.2

It is applicable to the following staff groups:

• Medical
• Nursing
• Pharmacy.

4.0 Outcome

To ensure accurate and timely diagnosis and treatment of patients developing TLS.

• TLS is a life threatening complication of malignancies and systemic anticancer therapy.
• It is characterised by hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia and oliguric renal failure.
• It may occur prior to, or more commonly soon after, systemic anticancer therapy.
• Patients may have metabolic abnormalities alone (laboratory TLS) or both laboratory and clinical problems (clinical TLS).
• The Cairo-Bishop definition of TLS is shown below:

The Cairo-Bishop definition of TLS.

The two main agents used in the prevention and treatment of TLS are:-

1. Allopurinol

• A xanthine oxidase inhibitor - it prevents the conversion of hypoxanthine and xanthine to uric acid.
• Significant adverse effects include skin rash (including rarely: SJS and TENs) and hypersensitivity reactions.
• It may take several days to normalise the level of uric acid.
• Dose is based on renal function (reduce if eGFR<20ml.min)
• If patient has allopurinol allergy/skin reaction consider febuxostat as alternative.

2. Resburicase

• A recombinant urate oxidase - it rapidly converts uric acid into allantoin (an inactive and soluble metabolite), which is easily excreted by the kidney.
• Significant adverse effects include skin rash, bronchospasm and severe hypersensitivity reactions – monitor patient closely during infusion. Fever, headache and GI disorders (vomiting, nausea and diarrhoea) are very common.

Where rasburicase is being used, the addition of allopurinol is unnecessary and has the potential to reduce the effectiveness of rasburicase.

It is contraindicated in G6PD deficiency: patients of African, Mediterranean and Asian descent (with prevalence being higher in males than females) are more commonly affected. Ensure at risk patients are screened for this condition and rasburicase withheld if they are G6PD deficient. Discuss alternative options for TLS prevent and management with the consultant.

7.1 To be given:

• During the first cycle of SACT if patients are considered high risk.
• Prior to salvage or reinduction therapy if patients are considered high risk.
• Prior to cellular therapy (IECT)
• There is no rationale for using prophylaxis during consolidation therapy or prior to hematopoietic stem cell transplantation (HSCT).

7.2 High risk patients

• Give IV fluids 1000ml sodium chloride 0.18%w/v/glucose4%w/v at a maximum of 100ml/hour.
• Monitor urine output / fluid intake on a fluid balance chart.
• Ensure weights chart annotated with ‘Weigh patient twice daily’
  • Treat fluid overload/weight gain with furosemide as appropriate
• Give rasburicase 3mg IV as per NHS Lothian IV guide (only accessible when connected to intranet) up to 4 hours prior to SACT administration as TLS prophylaxis to the following (high risk) patients:
  • ALL or AML where WBC ≥ 100x10⁹/l
  • Burkitt's lymphoma
  • Lymphoblastic lymphoma
  • Stage III/IV NHL with LDH ≥ 2 x ULN or tumour bulk on CT scan (≥ 8cm)
  • Rarely (discuss with consultant) it may be required for patients with CML in blast crisis or CLL with very high counts or extensive bulky disease. Rasburicase is indicated in this high risk patient group if any of the following factors apply:
    • Pre-existing hyperuricaemia (urate > 0.5mmol/l)
    • Difficulties with fluid balance preventing adequate hydration.
    • Allergy to allopurino.
    • Renal impairment - eGFR <60ml/min or rapidly deteriorating serum creatinine.
    • Patients with CLL treated with venetoclax (see appendix 1).
• Perform up to 6 hourly measurements of urate, LDH, urea, creatinine, electrolytes, calcium, and phosphate until parameters have normalised and no further risk of TLS.
  • Blood samples must be collected into gel tubes (brown top), transported on ice and analysed within 4 hours - Please phone Duty Biochemist on 31899 to inform them that the sample is coming for analysis. This will ensure accurate measurement of uric acid plasma levels.
• If there is evidence of any progression, then the prophylactic dose of rasburicase should be repeated daily until markers of TLS have returned to normal.
• Switch to allopurinol when there is no further risk of TLS.
• Allopurinol should be used as prophylaxis for the 1st 2 cycles of SACT in low risk situations (those not noted above)
• If clinical/biochemical parameters do not improve with above measures, consider increasing rasbiricase to treatment dose (see section 8.0 below) and/or dialysis. Ensure case discussed with consultant.

7.3 Moderate risk patients

Patients considered at moderate risk of TLS and in whom daily monitoring of TLS laboratory parameters is considered appropriate may be treated as out-patients. Such patients could include CLL patients on venetoclax increments (see appendix 1), lymphoma patients, but not fulfilling high risk criteria given above, patients with high bulk haematological malignancies and with a past or current history of gout.

• Start allopurinol up to 7 days prior to administration of SACT.
• Ensure patient is aware/able to drink a minimum 1.5-2L of fluids (not including tea or coffee) daily. If patient non-compliant, consider IV fluids (1000ml sodium chloride 0.18%w/v/glucose4%w/v at a maximum of 100ml/hour)
• SACT Day 1 – bloods first thing (pre-dose) U+Es, Ca, Mg, urate, and phosphate. These need to be taken to lab on ice (as detailed above). No need to wait for results prior to dose administration.
• Administer SACT in accordance with approved SACT protocol.
• For patients with CLL on venetoclax: for first dose (20mg) or 1st dose increment (50mg) only TLS bloods should be repeated 6-8 hours post dose and await results (for further dosing increments once daily, pre-dose bloods only)
• If laboratory TLS (as per Cairo-Bishop definition - see section 5.0), give treatment dose of rasburicase as per section 8.0, admit, and treat as ‘high risk'
• If no evidence of laboratory TLS give Ward 7 appointment time for day 2 and send patient home.
• SACT Day 2 – bloods first thing (24 hours post dose)- U+Es, Ca, Mg, urate, and phosphate. These need to be taken to lab on ice (as detailed above). Await results prior to dose administration. If laboratory TLS (as per Cairo-Bishop definition - see section 5.0) give treatment dose rasburicase as per section 8.0, admit, and treat as high risk.
• If no TLS, continue SACT in accordance with approved SACT protocol.
• Give appointment time for day 3 onwards if necessary (note: patients on venetoclax for CLL will require daily monitoring until increments completed) – day 3 onwards continue as day 2 above, until risk of TLS considered low.
• When TLS risk considered low (D/W registrar or consultant), discontinue daily monitoring, instruct patient to continue allopurinol, and set up further review appointment as appropriate.
• Once patients stabilized on venetoclax for CLL, refer back to consultant OP clinic as appropriate.

7.4 Low risk patients

Prophylaxis:

Give allopurinol 300mg OD (Dose dependent on renal function reduce to 100mg if eGFR <20ml.min)

• If TLS occurs despite prophylaxis, administer rasburicase at treatment dose of 0.2mg/kg, in the following situations:
  • Laboratory evidence of TLS.
  • Clinical evidence of TLS.
  • Rapid change in >1 laboratory marker of tumour lysis but not yet meeting criteria for laboratory TLS.
  • Biochemistry remains abnormal despite 2 prophylactic doses of rasburicase.
• Rasburicase is available as 1.5mg and 7.5mg vials – the dose should be rounded to nearest whole vial. Maximum dose = 15mg.
• If the patient is > 20% above their ideal body weight (IBW) use adjusted body weight: Adjusted body weight = IBW + 0.4 (actual body weight – IBW). Determine IBW from tables below:

Female

Male

• Carefully monitor clinical and biochemical parameters with treatment dosing.
  • Give IV fluids 1000ml sodium chloride 0.18%w/v/glucose4%w/v at a maximum of 100ml/hour.
  • Monitor urine output / fluid intake on a fluid balance chart.
  • Annotate weights chart with ‘weigh patient twice daily’
    • Treat fluid overload/weight gain with furosemide as appropriate.
  • Perform 6 hourly measurements of urate, LDH, urea, creatinine, electrolytes, calcium and phosphate until parameters have normalised and no further risk of TLS.
  • The duration of treatment should be determined by the clinical response, note SmPC recommends treatment duration of >7days is based on clinical adequate monitoring and clinical judgment.
• If clinical/biochemical parameters do not improve with above measures consider dialysis.