Tumor Lysis Syndrome: What's the Issue with Rasburicase Dosing?

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Tumor Lysis Syndrome:  What's the Issue with Rasburicase Dosing?
Tumor Lysis Syndrome: What's the Issue with Rasburicase Dosing?

It is well known that chemotherapy-related side effects can make the difference between treatment success and treatment failure. Among these treatment-related side effects is tumor lysis syndrome (TLS). Representing a group of metabolic complications including hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia that develops primarily in rapidly proliferating and chemosensitive neoplasms, TLS may interrupt treatment and compromise optimal outcomes.

This side effect most often occurs in patients with leukemia or aggressive lymphomas (i.e., Burkitt's lymphoma and high-grade B-cell lymphoma), but is now being reported in solid tumors with increased frequency. Numerous case reports have recently illustrated TLS occurrence in patients with lower-risk disease as well, such as indolent non-Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes and hepatocellular carcinoma. TLS has often been associated with conventional chemotherapy; however, newer targeted agents have also been reported to precipitate TLS including, but not limited to, imatinib, rituximab, sorafenib, cetuximab, and thalidomide, to name a few.

Managing hyperuricemia is crucial to controlling TLS, but how is this side effect managed? The most common methods of managing hyperuricemia in order to prevent acute renal failure include hydration and the use of allopurinol. Rasburicase (a recombinant urate oxidase enzyme) is another treatment option which catalyzes the enzymatic oxidation of uric acid into its inactive and soluble metabolite allantoin. An advantage of rasburicase is its ability to rapidly normalize uric acid levels by depleting existing uric acid, an effect not seen with allopurinol. Rasburicase is FDA-approved for the initial management of pediatric and adult patients with leukemia, lymphoma, and solid-tumor malignancies who are receiving anticancer therapy expected to result in TLS, and subsequent elevation of plasma uric acid.

But there is a challenge: Compared with allopurinol, rasburicase is costly; therefore, judicious use of the medication is warranted. The challenge with rasburicase has always been issues with dosing. The FDA-approved dosing is 0.2mg/kg as an intravenous infusion daily for up to five days. As a result of the relatively high cost of rasburicase, several small studies were conducted to review cost-efficient drug utilization. Results have demonstrated that a fixed one-time dose of rasburicase is effective at lowering plasma uric acid levels with decreased cost. 

Recent guidelines have been updated to include risk stratification and prophylaxis for TLS. The guidelines now include a change to a one-time dose of rasburicase at (0.1mg/kg to 0.2mg/kg) in patients who are at high-risk for TLS with hydration. Published retrospective studies have utilized a 3mg, 6mg, 7.5mg or weight-based dosing regimens. Collectively, these studies had several limitations including small sample sizes, disproportionate levels of high-risk patients and inconsistent reporting of need for rasburicase re-dosing. 

What is the minimum efficacious dose for administration while maximizing the drug's effect? 

Future studies should hope to reveal dosing measures for maximum efficacy; however, dosing guidelines with vigorous monitoring in moderate- to high-risk patients is the best way to treat and manage hyperuricemia in the face of TLS.

Readers: We'd love to hear from you in the comments section below! If you have a case study or a more extended response to this subject, click here to submit an item for us to publish

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