Prevention and treatment of hyperuricemia in hematological malignancies

Abstract

The standard prophylactic and treatment regimen for hyperuricemia in patients with hematological malignancies previously included vigorous hydration, urinary alkalinization, and a xanthine oxidase inhibitor, allopurinol, which blocks the conversion of hypoxanthine and xanthine to uric acid. However, xanthine is less soluble than uric acid, and preexisting uric acid is not affected by allopurinol. The enzyme urate oxidase, not present in mammals, converts uric acid to allantoin, which is 5-10 times more soluble than uric acid. A new recombinant form of urate oxidase, rasburicase, has recently been developed. In a phase I/II study of rasburicase in children and young adults with hematological malignancies, rasburicase was demonstrated to be well tolerated at 0.2 mg/kg/day intravenously, had a mean T1/2 of 21.2 +/- 12.0 hours, and induced a median decrease in uric acid from 9.7 mg/dL to 1.0 mg/dL (P < 0.001). We recently demonstrated, in a randomized prospective trial comparing rasburicase versus allopurinol in children with hematological malignancies at high risk of tumor lysis syndrome, that rasburicase significantly lowered the mean uric acid area under the curve 0 to 96 hours (128 +/- 70 mg/dL/hour vs. 329 +/- 129 mg/dL/hour; P < 0.001) and 4 hours post uric acid by 86% versus 12% (P < 0.001). Furthermore, in the hyperuricemic group, the baseline creatinine level decreased from 144% to 102% by 96 hours following rasburicase compared to an increase from 132% to 147% following allopurinol. Although the difference in effect on creatinine levels is not significant, the study was not designed or powered to question this effect. Lastly, in 510 patients with hematological malignancies at risk for tumor lysis syndrome who received rasburicase, only 2 (0.4%) have developed new renal complications requiring hemodialysis. In summary, in the prevention and treatment of hyperuricemia, patients with hematological malignancies at risk of tumor lysis syndrome appear to benefit significantly from the use of a recombinant urate oxidase (rasburicase).