Management of hyperuricemia in adults: the role of rasburicase
Because hyperuricemia can increase both the risk and the severity of CTLS, management of hyperuricemia that focuses on its prevention and, in cases where it has already emerged, its rapid reversal is an important strategy in reducing TLS-associated mortality and morbidity. The current recommendations for the prevention and management of TLS-associated hyperuricemia have been reviewed in great detail recently.2 Monitoring and clinical judgment generally are adequate for low-risk patients, but patients with higher risk require hydration and antihyperuricemic management with appropriate drug therapy.2 For most patients with an intermediate risk of TLS, prophylactic antihyperuricemic therapy with allopurinol is sufficient, because allopurinol can prevent the buildup of uric acid by blocking the enzymatic conversion of hypoxanthine and xanthine to uric acid (via direct inhibition of xanthine oxidase). However, allopurinol does not modify existing uric acid pools and thus is inadequate for the prevention or management of hyperuricemia in high-risk patients.2 Because a TLS-associated rise in uric acid levels can occur suddenly and rapidly in patients at high risk, effective and safe degradation of uric acid is essential for preventing or reversing life-threatening hyperuricemia.
The effectiveness of rasburicase as antihyperuricemic therapy for adult patients with cancer was demonstrated initially in two international multicenter compassionate-use studies. One study, conducted in the United States and Canada, included 387 adults (and 682 children) with mostly hematologic malignancies who received daily 30-minute IV administrations of rasburicase for 1–7 days at a dose of 0.2 mg/kg.15 All patients who received rasburicase for TLS prophylaxis, including 126 adults, maintained low PUA levels during chemotherapy, and all 212 adults with hyperuricemia at baseline responded to treatment with prompt and impressive reduction in PUA levels, which was maintained for several days.15 Rasburicase generally was well tolerated; only two adults experienced a single episode each of grade 3 toxicity, and no adult experienced grade 4 toxicity.15
The second study—a multicenter compassionate-use study in patients with leukemia or lymphoma from Europe and Australia—included 112 adults (and 166 children) with generally large tumor burdens, as assessed by WBC counts for leukemia and clinical stage and also by serum LDH levels for lymphoma.14 Reduction in PUA levels with rasburicase was statistically and clinically highly significant, resulting in PUA response rates of 100% in both adults and children. Only one adult patient, a 41-year-old man with AML and hyperuricemia at baseline, required hemodialysis because of acute renal failure, although PUA levels returned to normal after treatment with rasburicase. The patient subsequently died of respiratory failure attributable to disease ¬progression.14
The multicenter US registrational trial for the adult indication of rasburicase included 280 patients with hematologic malignancies who were at risk of TLS.55 Patients were randomly assigned to one of three treatments: rasburicase (0.2 mg/kg/d given as a 30-minute IV infusion) for 5 days, rasburicase for 3 days followed by oral allopurinol (300 mg/d) for 2 days, or allopurinol for 5 days. Rasburicase alone achieved significantly greater response rates than allopurinol monotherapy both in patients with a high risk of TLS and in those with baseline hyperuricemia (Table 2). In this clinical trial, control of PUA concentrations was achieved within 4 hours with rasburicase (compared with a median time interval of 27 hours with allopurinol) and was maintained during the 7-day monitoring period after initiation of antihyperuricemic therapy. Although reduction in the incidence of TLS was not an efficacy endpoint of the study, safety data analysis revealed that the occurrence of LTLS or CTLS was less common in the rasburicase than in the allopurinol treatment arm.55
In this large, randomized clinical study, rasburicase was safe and generally well tolerated during the 5-day treatment period. Patients who received rasburicase and those who received allopurinol had a similar incidence of adverse events.55,56 The only drug-related adverse events observed among the 184 patients who received rasburicase (alone or in combination with allopurinol) were potential hypersensitivity reactions in five patients, including irritation at the injection site (one patient); arthralgia, myalgia, and rash (one patient); peripheral edema (one patient); and grade 3 hypersensitivity (two patients). One patient with grade 3 hypersensitivity related to rasburicase discontinued study participation on day 1. No grade 4 hypersensitivity reaction, anaphylaxis, hemolytic reaction, or methemoglobinemia occurred with rasburicase.55
In summary, the results of this phase III randomized controlled study show that rasburicase may be superior to allopurinol in preventing hyperuricemia in adult leukemia/lymphoma patients at high risk of TLS and in achieving rapid and effective control of PUA levels in patients with hyperuricemia. The results support the recommendation within the current TLS management guidelines of using rasburicase for prophylaxis in high-risk patients and for treatment of hyperuricemia of malignancy, as well as in those patients with fully developed LTLS or CTLS (irrespective of PUA levels).17