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Rasburicase: Clearing Uric Acid from the Tumor Lysis Syndrome
By William B. Ershler, MD
Uric acid as a weak organic acid (pka 5.8) is poorly soluble at physiological pH. It presence in serum is derived both from diet and endogenous biosynthesis, and it is excreted primarily by renal (75%) mechanisms under normal circumstances. Humans, and some other primates, differ from lower animals by the absence of urate oxidase (uricase), an enzyme that catalyzes the oxidation of uric acid into water-soluble allantoin. Allopurinol, still considered a mainstay in the management of hyperuricemia, blocks the activity of the enzyme xanthine oxidase and, thereby, decreases the risk of uric acid crystallization, particularly in the kidneys and joints.1,2 The concept of introducing urate oxidase function to metabolize uric acid under conditions of hyperuricemia was first introduced in the 1970s in Europe. At that time, enzyme was purified from cultures of Aspergillus flavus (Uricozyme), but impurities in the preparation were associated with untoward reactions (primarily allergic), although the effect on uric acid levels was clearly demonstrable.3 Using recombinant technology, uricase cDNA (cloned from Aspergillus flavus) was introduced into a genetically modified strain of Saccharomyces cerevisiae, a process that allows a high level of purification. This recombinant form of uricase (rasburicase, Elitek) has been approved by the FDA, initially for use in children with leukemia and lymphoma, but now also for adults at high risk for tumor lysis syndrome (TLS).4,5
The decision to approve rasburicase was initially supported by pediatric trials. Pui et al6 treated 131 children and young adults with newly diagnosed leukemia or lymphoma for a planned 5 to 7 days, but found that initial treatment was met with rapid drop in uric acid. For those who presented with hyperuricemia (n = 65), the mean uric acid level decreased from 9.7 mg/dL to 1.0 mg/dL within 4 hours of treatment, and for those who did not have hyperuricemia the levels dropped from 4.3 mg/dL to 0.5 mg/dL. Furthermore, the toxicity was negligible, and no patients required dialysis. When compared to allopurinol in controlling hyperuricemia in pediatric cancer patients, rasburicase proved more effective in reducing pretreatment uric acid levels.7
Two trials in adults with leukemia and/or lymphoma also support the efficacy and safety of rasburicase. In the first, Bosley and colleagues reported on a multinational study conducted over three years (1999-2001) in which patients at high risk for TLS (both pediatric and adult) were treated with rasburicase 0.2 mg/kg either twice a day for the first 3 days if they were considered high risk for TLS, or once per day for all others.8 After the first 3 days, all patients were continued through a course that extended up to 7 days (median 5 days). All patients responded to treatment. For adults with hyperuricemia (pre-treatment), the uric acid fell from 13.1 mg/dL to 0.3 mg/dL, whereas those who presented without hyperuricemia had their plasma uric acid levels fall from 4.9 mg/dL to 0.3 mg/dL. As with children, toxicity was minimal and no major adverse events were observed. Published in the same year, Coiffier et al treated aggressive non-Hodgkin's lymphoma adult patients (n = 100; median age = 57 years) who were considered at risk for TLS on the basis of both clinical (large tumor burden, adverse IPI score) and laboratory markers (elevated uric acid, LDH, creatinine) with 0.2 mg/kg rasburicase for 3 to 7 days.9 Of the 100 patients, 95 had normalization of uric acid levels and this occurred usually within the first 4 hours of treatment. None of the patients went on to develop TLS. Grade 3 hepatotoxicity was observed, but rapidly reversed, and the drug was discontinued in one patient for clinical reasons other than drug toxicity.
Recommendations: TLS Prevention and Treatment
TLS is a life-threatening condition that occurs in patients with rapidly proliferating, highly chemosensitive tumors. The identification of high-risk patients, and early recognition of the syndrome, is of paramount importance. In this regard, consensus guidelines have been published for diagnosis and treatment.4 Included in these recommendations are treatment with rasburicase for those considered at high risk, and especially for those who are diagnosed with TLS. The current recommended dose is 0.2 mg/kg/day administered intravenously with the first dose given prior to chemotherapy. Expectations are that uric acid levels will fall promptly, but repeated doses for 3-5 days have been commonly administered. Nonetheless, the recently published experience from a single institution suggests that one dose (at 6 mg) is often sufficient to prevent the occurrence of TLS for most patients.10
Hyperuricemia is only one manifestation of TLS, and treatment with rasburicase or allopurinol is itself insufficient to either prevent or treat the disorder. In this regard, aggressive hydration with the maintenance of high urine output and attention to electrolyte, renal, and cardiac function all assume critical importance.
1. Hande KR, et al. Postchemotherapy purine excretion in lymphoma patients receiving allopurinol. Cancer Res. 1981;41:2273-2279.
2. DeConti RC, Calabresi P. Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease. N Engl J Med. 1966;274:481-486.
3. Bomalaski JS, et al. Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies. J Rheumatol. 2002;29:1942-1949.
4. Tosi P, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica. 2008;93:1877-1885.
5. de Bont JM, Pieters R. Management of hyperuricemia with rasburicase review. Nucleosides Nucleotides Nucleic Acids. 2004;23:1431-1440.
6. Pui CH, et al. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol. 2001;19:697-704.
7. Goldman SC, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood. 2001;97:2998-3003.
8. Bosly A, et al. Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer: report of an international compassionate use study. Cancer. 2003;98:1048-1054.
9. Coiffier B, et al. Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe d'Etude des Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult Lymphoma) study. J Clin Oncol. 2003;21:4402-4406.
10. Vines AN, Shanholtz CB, Thompson JL. Fixed-dose rasburicase 6 mg for hyperuricemia and tumor lysis syndrome in high-risk cancer patients. Ann Pharmacother. 2010;44:1529-1537.