When should febuxostat (febuxostat) be given to patients with lymphoma undergoing chemotherapy, particularly those at high risk of tumor lysis syndrome (TLS) due to high tumor burden, intensive chemotherapy regimens, pre-existing impaired renal function, or hyperuricemia?

Timing of Febuxostat Administration in Lymphoma Patients Undergoing Chemotherapy

Primary Recommendation

Febuxostat should be initiated 24 hours before starting chemotherapy in lymphoma patients at intermediate risk for tumor lysis syndrome (TLS), but should NOT be used in high-risk patients who require rasburicase as primary prophylaxis. 1, 2

Risk Stratification Determines Agent Selection

High-Risk Patients: Rasburicase, NOT Febuxostat

• High-risk patients must receive rasburicase instead of febuxostat (or allopurinol) as primary prophylaxis. 1
• High-risk features include:
  • Pre-existing renal impairment, dehydration, or obstructive uropathy
  • Bulky disease or high-grade lymphomas
  • Intensive polychemotherapy regimens
  • Baseline hyperuricemia 1, 3
• Rasburicase achieves significantly lower mean uric acid area under the curve (128±70 mg/dL/hour) compared to allopurinol (329±129 mg/dL/hour; p<0.001) 1
• Only 2.6% of patients receiving rasburicase required dialysis compared to 16% receiving allopurinol 1

Intermediate-Risk Patients: Febuxostat is Appropriate

• Febuxostat 40-60 mg daily should be started 24 hours before chemotherapy initiation in intermediate-risk patients. 2, 4
• Febuxostat demonstrated non-inferiority to allopurinol with a least squares mean difference in uric acid AUC of -33.61 mg h/dL 2
• Successfully reduced median serum uric acid from 8.0 mg/dL at baseline to 3.3 mg/dL by day 5 (p<0.0001) 4

Dosing Regimen

Standard Febuxostat Dosing

• 40 mg daily for patients with renal impairment 4
• 60 mg daily for patients with normal renal function 4
• Continue for 3-7 days after chemotherapy based on ongoing TLS risk 1

Critical Timing

• Must be initiated 24 hours before chemotherapy begins 2
• This allows adequate time for xanthine oxidase inhibition before tumor cell lysis occurs 4

Absolute Contraindication: Never Combine with Rasburicase

Febuxostat must NEVER be administered concurrently with rasburicase due to risk of xanthine accumulation and crystal deposition in renal tubules. 1

Mechanism of Harm

• Febuxostat blocks xanthine oxidase, preventing conversion of xanthine and hypoxanthine to uric acid 1
• Rasburicase generates xanthine and hypoxanthine as intermediate metabolites 1
• Concurrent use causes xanthine accumulation leading to acute obstructive uropathy 1

Sequential Use Protocol

• If rasburicase is used first, wait until rasburicase therapy is completed before starting febuxostat 1
• Rasburicase followed by allopurinol (or febuxostat) showed 78% response rate with time to uric acid control of 4 hours for rasburicase versus 27 hours for allopurinol alone 1

Essential Supportive Measures

Aggressive Hydration is Mandatory

• Initiate aggressive IV hydration ideally 48 hours before chemotherapy 1
• Target urine output ≥100 mL/hour in adults (3 mL/kg/hour in children <10 kg) 1
• Loop diuretics (not thiazides) may be required to achieve target urine output 1

Monitoring Requirements

• High-risk patients require laboratory monitoring every 6 hours for first 24 hours, then every 12 hours for first 3 days 3
• Monitor: uric acid, potassium, phosphorus, calcium, creatinine, BUN, and LDH 3
• Continuous urine output monitoring targeting ≥100 mL/hour 3

Special Considerations and Pitfalls

Xanthine Nephropathy Risk

• Febuxostat elevates serum xanthine levels (as consequence of xanthine oxidase inhibition) 4
• Xanthine levels may reach concentrations reported to cause xanthine nephropathy, though renal impairment was not observed in clinical studies 4
• This risk is magnified if febuxostat is combined with rasburicase 1

Renal Impairment Considerations

• Febuxostat shows no drug accumulation in patients with renal impairment 4
• Serum concentrations at 2 hours post-administration were similar between 40 mg and 60 mg doses (891.8 ± 285.0 ng/ml vs 770.6 ± 242.7 ng/ml, p=0.80) 4
• Use 40 mg dose in patients with baseline renal dysfunction 4

Safety Profile

• No febuxostat-related adverse reactions noted in prospective studies 4
• Grade 3-4 liver dysfunction occurred in 2.6% of febuxostat patients versus 5.1% of allopurinol patients (not statistically significant) 5
• No gout flare or skin rash observed 5

When Febuxostat is NOT Appropriate

Do not use febuxostat in:

• High-risk TLS patients (use rasburicase instead) 1
• Patients currently receiving or scheduled to receive rasburicase 1
• Patients with acute lymphoblastic leukemia in adults or advanced T-cell ALL in pediatric patients (high-risk, requires rasburicase) 3
• Patients with bulky disease and elevated baseline LDH (high-risk) 3