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Pharmacologic Management of Tumor Lysis Syndrome in Adults

Introduction

  1. Tumor lysis syndrome (TLS) constitutes the most frequent oncologic emergency.
  2. It is developed by lysis of tumor cells, during or within 7 days of chemotherapy.
  3. The output of large amounts of potassium, phosphate, and nucleic acid, can result in characteristic electrolyte disturbances and cause the characteristic life-threatening arrhythmias (from electrolyte imbalances) and AKI (from hyperuricemia or hyperphosphatemia).
  4. TLS can occur spontaneously in any tumor type with a high proliferative rate, large tumor burden, or high sensitivity to cytotoxic agents especially clinically aggressive and highly aggressive lymphomas (the Burkitt subtype) and T-cell acute lymphoblastic leukemia (ALL).
  5. The increase in frequency and severity of TLS in hematologic cancers is associated with the emergence of effective targeted anticancer drugs.
Treatment of common electrolyte and lab abnormalities
Hyperkalemia
Happens in initial stages, 12-24 hours post chemotherapy

The most dangerous electrolyte abnormality and usually requires urgent and aggressive treatment as it can quickly develop into an arrhythmia

Standardized treatment consists of short infusion of calcium gluconate or chloride with continuous cardiac monitoring, IV infusion of insulin and glucose, and nebulized beta-2 agonist (albuterol) +/- loop diuretic to promote excretion of potassium and calcium gluconate; start dialysis in refractory cases
Hypocalcemia
Secondary to hyperphosphatemia caused by the release from lysed cells

Can lead to fatal cardiac arrhythmia, tetany, and seizures

Treat symptomatic hypocalcemia with lowest dose of IV calcium gluconate or chloride to relief symptoms, or by correcting serum phosphorus levels; Reserve IV calcium replacement for patients with EKG changes, tetany, and convulsions
Hyperuricemia
Develops 48-72 hours post chemotherapy

Influx of nucleic acids from lysed cells is released into the blood and converted to uric acid by xanthine oxidase.
Renal failure happens due to an increase of uric acid passage and secretions by the renal tubule normally recycled by purine salvage pathways.
Urine alkalinization use is controversial but may be considered in cases of no rasburicase and severe hyperuricemia
Hyperphosphatemia
Typically develops 24-48 hours post chemo when level exceeds renal excretion capacity

Can lead to hypocalcemia

To reduce the risk of hyperkalemia and hyperphosphatemia, continuous modes of renal replacement function are preferred over intermittent hemodialysis
IV Hydration
Avoid calcium and potassium containing fluids due to the risk of hyperkalemia and hyperphosphatemia with calcium phosphate precipitation from tumor breakdown2
Hypouricemic Agents
 AllopurinolRasburicaseFebuxostat
Dose

  Oral: 300 mg/m2/day or 10 mg/kg/day in 3 divided doses, q8h (max 800 mg/day)

  IV: 200-400 mg/m2/day IV as a single dose or in 2-3 divided doses (max 600 mg/day)
Different dosing strategies based on baseline uric acid and risk level  

Comes in 1.5 or 7.5 mg vials; round the dose to the closest number of full vials to prevent waste (a flat dose of 3 mg is commonly used in adults)  

Manufacturer’s labeling: 0.2 mg/kg IV over 30 min once daily for up to 5 days
Oral: 60 mg/day   Doses of up to 120 mg/day PO have been studied in clinical trials
AdministrationHydrate to yield a daily output of at least 2L in adults and neutral or slightly alkaline urine  

Whenever possible, start treatment 1-2 days before chemo induction and continue up to 3-7 d after chemo until lab normalization
Infuse over 30 min; do not administer as an IV bolus  

Infuse through a separate line; if not possible, flush line with at least 15 mL saline prior to and following infusion
Administer with or without meals or antacids
MOAStructural analog of hypoxanthine. Inhibits xanthine oxidase, the enzyme responsible for conversion of hypoxanthine to xanthine and xanthine to uric acidRecombinant form of urate-oxidase, the enzyme that catalyzes uric acid to allantoin (the inactive and more soluble metabolite)Non-purine xanthine oxidase inhibitor
Adverse EffectsAcute gout attacks, hepatotoxicity, delayed hypersensitivity reactionsModerate and common ADRs: antibody formation, constipation, edema, elevated hepatic enzymes, hyperbilirubinemia, hyperphosphatemia, hypophosphatemia, oral ulceration, peripheral edemaModerate and common (>10%) ADRs: gout  

Severe and infrequent ADRs: atrial fibrillation, AV block
Drug Interactions and warningsMajor DDIs: aluminum hydroxide, azathioprine, capecitabine, didanosine, mercaptopurine, pegloticase, warfarin  

Avoid use in patients with the HLA-B*58:01 allele (particularly in certain Asian populations)
Major DDIs:, epinephrine, bupivacaine, lidocaine, penicillin G, prilocaine, ropivacaine , tetracaine  

Contraindicated in patients with G6PD
Fewer drug-drug interactions with febuxostat than with allopurinol  

Major DDIs: azathioprine, mercaptopurine  

Boxed Warning: risk of cardiovascular death
CommentsWorks by decreasing uric acid formation. Does not acutely reduce uric acid levels, hence not the drug of choice in established TLS.  

Reduce dose by 50% in renal impairment due to potential for accumulation  

Use for the prevention* of hyperuricemia in patients at intermediate risk for TLS and without preexisting hyperuricemia  
Drug of choice in established TLS; degrades preexisting uric acid and can normalize serum uric acid within 4 h in adults  

Dose adjustment not needed in patients with renal impairment  

Does not lead to xanthine accumulation  

Substantially declines the need for dialysis during induction therapy for high-risk hematologic malignancies  

Use in patients with preexisting hyperuricemia (uric acid≥7.5 mg/dL), high risk disease, or with intermediate-risk disease unresponsive to allopurinol
Shown similar efficacy at preventing TLS compared to allopurinol in intermediate-high risk groups  

No dosage adjustment necessary for patients with mild-moderate renal impairment  

Good option for patients who cannot tolerate allopurinol and when rasburicase is not available or is contraindicated
* Use of prophylactic measures is indicated for patients without Cairo-Bishop definition of established TLS (Uric acid ≥8mg/dL, potassium ≥6mEq/L, phosphorus ≥6.5 mg/dL for children or ≥4.5 mg/dL for adults, calcium ≤7 mg/dL)

 Overview of Evidence 
Author, yearDesign/ sample sizeIntervention & ComparisonOutcome
Goldman, 2001Multicenter RCT (n=52)Pediatric patients with leukemia or lymphoma and at high risk for TLS received allopurinol (300 mg/m2 or 10 mg/kg PO q8h) vs rasburicase (0.2 mg/kg IV daily) for 5-7 daysmean uric acid AUC(0-96) was 128 +/- 70 mg/dL.hour for the rasburicase group vs 329 +/- 129 mg/dL.hour for the allopurinol group (P <.0001)

86% vs 12% reduction (P <.0001) in initial plasma uric acid levels in the rasburicase vs allopurinol group shown 4 h post 1st dose

The study demonstrated more rapid control and lower levels of plasma uric acid in the rasburicase group
Cortes, 2010RCT (n=275)Rasburicase (0.20 mg/kg/d IV days 1-5) vs rasburicase + allopurinol (rasburicase 0.20 mg/kg/d 1-3 followed by PO allopurinol 300 mg/d 3-5) vs allopurinol (300 mg/d PO d 1-5)  sUA response rate was significantly greater for rasburicase than for allopurinol (P=.001) in the overall study population, those at high risk for TLS (89% vs. 68%; P=0.012), and in patients with baseline hyperuricemia (90% vs. 53%; P=0.15)  

Time to sUA control in hyperuricemic patients was 4 h for rasburicase, 4 h for rasburicase + allopurinol, and 27 h for allopurinol  

Rasburicase was well tolerated and provided more rapid uric acid control than allopurinol alone
Vadhan-Raj, 2012RCT (n=82)Single dose rasburicase (0.15 mg/kg) followed by as needed dosing (max five doses) vs daily dosing for 5 days in adultsUA normalization achieved in 99% of patients within 4 h of the first dose and 84% reached undetectable levels(<0.7mg/dl)  

98% in the daily-dose and 85% in the single-dose group showed sustained UA response  
Single-dose rasburicase was effective in most patients; only a subset of high-risk patients required a second dose
Bellos, 2019Meta-analysis (n=658)Febuxostat (10-120 mg/d) vs allopurinol (100-600 mg/d) in TLS prevention across six studiesFebuxostat achieved a similar response rate as allopurinol (OR: 1.39, 95% CI: [0.55, 3.51])  

Similiar serum uric acid levels resulted between the two groups at day 2 (mean difference (MD): -0.21 mg/dL, 95% CI: [-1.30, 0.88]) and day 7 (MD: -0.43 mg/dL, 95% CI: [-1.38, 0.51]) of treatment  

Elevated LFTs was the most common ADR in both groups
Feng, 2013Meta-analysis (n=269)Ten studies evaluated the response rate and plasma UA level reduction of single dose rasburicase (from 0.05 mg/kg to 0.20 mg/kg) vs daily dosing rasburicase (0.2 mg/kg)Single-dose rasburicase response rate was not significantly different than daily dose rasburicase (88.15% vs 90.18%, P=0.542)  

Single-dose rasburicase was significantly stronger than that of allopurinol given at 300 mg/day PO d1-5 (88.15% vs 66%, P<0.0005)  

Single-dose rasburicase has non-inferior clinical benefit and significant cost savings compared with the daily-dose regimen
Tamura, 2016RCT (n=100)Evaluated the non-inferiority of febuxostat to allopurinol based on AUC of serum UA for a 6-d treatment; Randomized intermediate-high risk patients to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day) taken 24 h before chemotherapyThe least squared mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, 95% CI -70.67 to 3.45  

No differences in safety outcomes between the treatment groups  

The study demonstrated the non-inferiority of febuxostat to allopurinol

Conclusions

  1. The best management of TLS is prevention and is usually based on the following risk stratification:
    • Low risk: observe and monitor S&S, hydration, +/- allopurinol
    • Intermediate risk: monitoring, hydration, and allopurinol (does not acutely reduce uric acid)
    • High risk: monitoring, aggressive IV hydration* and rasburicase (CI in G6PD; use allopurinol)
      • For severe-risk patients, use aggressive fluid hydration to achieve urine output of 80-100 mL/m2 per hour (without CI for volume expansion) +/- loop diuretic (if no evidence of acute obstructive uropathy and/or hypovolemia)
  2. Febuxostat is an alternative oral agent in patients who are at intermediate-high risk for TLS and cannot tolerate allopurinol and when rasburicase is not available or is contraindicated.
  3. Urine alkalinization with sodium bicarbonate has fallen out of favor and is only indicated in patients with metabolic acidosis.
  4. The emergent treatment of TLS involves vigorous hydration and careful monitoring of fluid balance, correcting electrolyte abnormalities, and possible renal replacement therapy.

References

  1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved January 17, 2021, from http://www.micromedexsolutions.com/
  2. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767.
  3. Jones GL, Will A, Jackson GH, et al. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology. Br J Haematol 2015; 169:661.
  4. https://pubmed.ncbi.nlm.nih.gov/11342423/
  5. https://pubmed.ncbi.nlm.nih.gov/20713865/
  6. https://pubmed.ncbi.nlm.nih.gov/22015451/
  7. https://pubmed.ncbi.nlm.nih.gov/30972811/
  8. https://pubmed.ncbi.nlm.nih.gov/23550846/
  9. https://pubmed.ncbi.nlm.nih.gov/27017611/

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