A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis

Abstract

Standard therapy in the United States for malignancy-associated hyperuricemia consists of hydration, alkalinization, and allopurinol. Urate oxidase catalyzes the enzymatic oxidation of uric acid to a 5 times increased urine soluble product, allantoin. Rasburicase is a new recombinant form of urate oxidase available for clinical evaluation. This multicenter randomized trial compared allopurinol to rasburicase in pediatric patients with leukemia or lymphoma at high risk for tumor lysis. Patients received the assigned uric acid-lowering agent for 5 to 7 days during induction chemotherapy. The primary efficacy end point was to compare the area under the serial plasma uric acid concentration curves during the first 96 hours of therapy (AUC 0-96 ). Fifty-two patients were randomized at 6 sites. In an intent-to-treat analysis, the mean uric acid AUC 0-96 was 128 ؎ 70 mg/dL.hour for the rasburicase group and 329 ؎ 129 mg/dL.hour for the allopurinol group (P < .0001). The rasburicase versus allopurinol group experienced a 2.6-fold (95% CI: 2.0-3.4) less exposure to uric acid. Four hours after the first dose, patients randomized to rasburicase compared to allopurinol achieved an 86% versus 12% reduction (P < .0001) of initial plasma uric acid levels. No antirasburicase antibodies were detected at day 14. This randomized study demonstrated more rapid control and lower levels of plasma uric acid in patients at high risk for tumor lysis who received rasburicase compared to allopurinol. For pediatric patients with advanced stage lymphoma or high tumor burden leukemia, rasburicase is a safe and effective alternative to allopurinol during initial chemotherapy. (Blood. 2001; 97:2998-3003)

Reduced-dose rasburicase (recombinant xanthine oxidase) in adult cancer patients with hyperuricemia

“…Similarly, a randomized study of rasburicase and allopurinol in children showed faster decline in uric acid with rasburicase therapy without any obvious short-term survival advantage for rasburicasetreated patients. 6 A European multi-center study of rasburicase in 100 patients with aggressive NHL -only 11% of whom were hyperuricemic -found normalization of serum uric acid levels within 4 h of the first dose. 7 The dose of rasburicase used in the study was 0.2 mg/kg daily for 3-7 days (median 3).…”

“…6,7,11 It should be noted that in the United States, rasburicase is approved for therapy only in children. Therefore, there is no recommended dose for adults who may require it under appropriate clinical circumstances.…”

“…7 Rasburicase administration at the recommended dose of 0.2 mg/kg for 3-7 days results in dramatically reduced levels of serum uric acid, usually substantially lower than the lower limit of normal. 6,7 Only one of 12 patients receiving 0.15 mg/ kg rasburicase (25% dose reduction) developed transient hyperuricemia, 7 suggesting that the recommended dose may be higher than necessary. Limited experience suggests that lower doses of rasburicase are also effective in lowering uric acid levels.…”

“…Expression of the gene encoding urate oxidase in yeast yields recombinant enzyme in therapeutically useful quantities. 5 Recombinant urate oxidase (rasburicase) has been found to be useful prophylactically and therapeutically for hyperuricemia in children 6 and adults. 7 Rasburicase administration at the recommended dose of 0.2 mg/kg for 3-7 days results in dramatically reduced levels of serum uric acid, usually substantially lower than the lower limit of normal.…”

Tumour Lysis Syndrome: Implications for Cancer Therapy

“…Rasburicase catalyses the conversion of poorly soluble uric acid into allantoin, which is five to ten times more soluble in urine as compared to uric acid and can be easily excreted by kidneys (Cheson and Dutcher, 2005;Cammalleri and Malaguarnera, 2007;Zojer and Ludwig, 2007). In general, response to rasburicase is rapid and the treatment is well tolerated (Goldman et al, 2001;Patte et al, 2002;Bosly et al, 2003;Coiffier et al, 2003). In patients at highest risk of developing TLS, rasburicase is generally recommended as the preferred prophylaxis (Cairo and Bishop, 2004;Cairo et al, 2007;Zojer and Ludwig, 2007;Mayne et al, 2008).…”