¹III. Medizinische Klinik, Universitaetsklinikum Mannheim, University of Heidelberg, Mannheim, Germany

Correspondence: Dr M Hummel, III. Medizinische Klinik, Klinikum Mannheim der Universität Heidelberg, Wiesbadenerstrae 7-11, Mannheim D-68305, Germany. Fax: +49 621 3834201

Received 21 July 2003; Accepted 5 September 2003; Published online 2 October 2003.

TO THE EDITOR

Tumor lysis syndrome commonly occurs in patients with acute leukemia and non-Hodgkin's lymphoma with a high tumor burden, even before any antineoplastic treatment is given. Severe complications like hyperkalemia and renal failure induced by uric acid and/or calcium phosphate crystals can arise.

Prophylaxis and treatment standards for tumor lysis syndrome are adequate hydration, correction of electrolyte disturbances, neutralization of urine-pH and allopurinol.¹ Allopurinol blocks the conversion of hypoxanthine and xanthine to uric acid. Xanthine is less soluble than uric acid, even in alkaline urine (150 mg/l xanthine as compared to 2000 mg/l uric acid at pH 7). Therefore, xanthine nephropathy and xanthine stone formation can result.^2,3

Recent studies have shown that rasburicase, a recombinant urate oxidase, is more effective in lowering urate levels as compared to allopurinol and is well tolerated.^1,4,5 The dose of rasburicase used in studies and recommended by the manufacturer for prevention of hyperuricemia is 0.2 mg/kg body weight for the first 5–7 days of chemotherapy. In patients treated with rasburicase, plasma urate levels dropped by 86% within 4 h following the first drug dose.⁴

Costs of a 7-day rasburicase treatment with 0.2 mg/kg in adult patients (70 kg) amount to approximately 7100. As a reduction of plasma urate below the normal range (3.5–7 mg/dl) is not necessary to prevent uric acid nephropathy, we treated patients with lower doses of rasburicase to reduce treatment costs.

We report on the results of four patients (two with advanced lymphoma and two with acute leukemia) with tumor lysis syndrome and renal failure who were successfully treated with recombinant urate oxidase with a lower dose per day and/or shorter treatment duration. All patients were treated in our intensive care unit under close monitoring.

Patient 1 is a 64-year-old male patient with B-CLL. Because of disease progression with lymph node enlargement, the patient received a first course of chemotherapy with fludarabin (60 mg on day 1–3) and cyclophosphamide (500 mg on day 1–3) in October 2002.

On day 5 of chemotherapy, he was admitted to our intensive care unit (ICU) with tumor lysis syndrome (urate 24.6 mg/dl, LDH 1120 U/l, phosphate 4.0 mmol/l) and acute renal failure (BUN 122 mg/dl, creatinine 3.3 mg/dl) (normal range: urate 3.5–7.0 mg/dl, LDH 0–248 U/l, phosphate 0.81–1.53 mmol/l, creatinine 0.7–1.3 mg/dl, BUN 16.7–45.8 mg/dl). He was treated with hydration, sodium bicarbonate and 16.5 mg (0.2 mg/kg) of rasburicase for 3 days. Uric acid levels dropped to 0.1 mg/dl on the next day and remained low during the following days (Figure 1). Renal function improved and at discharge from hospital, plasma urate and creatinine were within the normal range.

Figure 1.

Course of urate, creatinine and LDH in four patients.

Full figure and legend (131K)

Patient 2 is a 66-year-old female patient with a high-grade B-non-Hodgkin's lymphoma of the gastric mucosa, a 9 cm pelvic mass and ascites. The patient was referred to our ICU in March 2003. She presented with tumor lysis syndrome (urate 22.2 mg/dl, LDH 1083 U/l, potassium 6.8 mmol/l (normal range 3.5–5.2 mmol/l), phosphate 2.34 mmol/l) and acute renal failure (creatinine 2.7 mg/dl, BUN 165 mg/dl). Treatment consisted of hydration, sodium bicarbonate and a single dose of 9 mg rasburicase (0.17 mg/kg). Urate dropped from 22.2 to 0.7 mg/dl 1 day after rasburicase treatment and stayed below 1 mg/dl. After 3 days, prephase chemotherapy was started (single dose of vincristine 1 mg and prednisone 100 mg daily). Recurrent hyperuricemia (urate 14.9 mg/dl 2 days after chemotherapy) was treated with hydration and resolved (urate 4.4 mg/dl 2 days later). Renal function recovered with creatinine levels within the normal range, so that after 3 more days, chemotherapy (CHOP regimen: cyclophosphamide, doxorubicin, vincristine and prednisone) in 50% dose reduction could be applied.

Patient 3 is a 49-year-old female patient with B-ALL with extended bone marrow, retroperitoneal, mesenteric, peritoneal, colonic, pulmonary and meningeal manifestation. On computed tomography scan and ultrasound investigation of the abdomen, right ureteric obstruction with hydronephrosis was found. Laboratory investigations showed tumor lysis syndrome (LDH 3630 U/l, urate 33 mg/dl), and acute renal failure (creatinine 5.0 mg/dl, BUN 75.6 mg/dl).

A percutaneous nephrostomy was performed and because of increasing creatinine levels, continuous veno-venous hemofiltration was initiated. Creatinine levels dropped to 2.5 mg/dl and polyuria developed, so that hemofiltration could be stopped after 4 days. A prephase chemotherapy was started (2 mg of vincristine and 100 mg prednisone). The uric acid levels decreased after nephrostomy and hemofiltration, but were still elevated (urate 12.7 mg/dl) and increased after vincristine therapy (16.3 mg/dl). The patient received 1.5 mg rasburicase (0.03 mg/kg). Within 24 h, the uric acid level was in the normal range and remained there in spite of further treatment with CHOP chemotherapy. Creatinine levels decreased and were within the normal range on day 3 after rasburicase treatment.

Patient 4 is a 34-year-old female with newly diagnosed acute myeloid leukemia FAB M 5 B. The patient presented with an initial white cell count of 151 000/l (82% blast cells) and signs of tumor lysis (LDH 854 U/l, urate 14.9 mg/dl) and renal failure (creatinine 2.1 mg/dl, BUN 33 mg/dl). She received one single dose of 1.5 mg rasburicase (0.017 mg/kg) and cytoreductive chemotherapy with cytarabine 190 mg daily was given for 6 days. One day after rasburicase treatment, the uric acid level had dropped to 1.3 mg/dl and stayed below 7.4 mg/dl subsequently. Renal function recovered with normal creatinine levels after 10 days. The first induction chemotherapy course (cytarabine, thioguanine and daunorubicin) could be started.

Treatment with rasburicase is highly effective in reducing urate levels in blood and is well tolerated.^1,4 In a randomized trial in pediatric patients with leukemias and lymphomas, rasburicase (0.2 mg/kg daily for 5–7 days) proved to be more potent and faster-acting as compared to oral allopurinol.⁴ Levels of urate dropped considerably (by up to 86%) in these studies 4 h after the first dose of rasburicase.^1,4

We treated four patients with tumor lysis syndrome, hyperuricemia and renal failure successfully with doses between 0.017 mg/kg as a single dose and 0.2 mg/kg daily for 3 days. All patients showed a fast and marked decline of plasma urate and recovery of renal function after rasburicase treatment. Rasburicase was well tolerated by all patients. Three of four patients had tumor lysis syndrome with acute renal failure before antineoplastic therapy had been started. By treating tumor lysis syndrome and hyperuricemia effectively, chemotherapy could be applied without treatment delay.

Budgets in health care are limited and cost-effectiveness is becoming an increasingly important issue. By successfully treating hyperuricemia and preventing severe renal failure, treatment with rasburicase can be cost-saving in terms of saving costs for intensive care and hemodialysis.⁶ Still, costs for rasburicase are high. If rasburicase is given according to the manufacturer's dosage recommendation, costs are between 5065 and 7091 for 5–7 days for a 70 kg adult patient. We could demonstrate in four patients that lower doses and/or shorter treatment periods can be effective. As lowering of plasma urate to subnormal levels is not needed to prevent renal dysfunction, lower doses of rasburicase may be sufficient. With regard to the high costs of rasburicase, it should be aimed at finding the smallest effective dose.

Rasburicase is highly effective, well tolerated and its elimination does not correlate with renal function.^7,8 Lowering urate levels fast and effectively improves renal function so that chemotherapy can be given early and in full dose. Its use should be encouraged in patients with imminent or manifest tumor lysis syndrome and hyperuricemia. In some patients, lower doses and/or shorter treatment periods than those recommended by the manufacturer can be sufficient. Different dosage regimens might be indicated for different clinical settings, for example single application of rasburicase might be sufficient if patients present with tumor lysis syndrome after chemotherapy, whereas longer treatment may be necessary during chemotherapy treatment.

It is controversial if sodium bicarbonate is necessary in patients treated with rasburicase. Since rasburicase is highly effective, many investigators do not use sodium bicarbonate to facilitate the excretion of phosphorus.

Adapting the dose of rasburicase according to the response of plasma urate levels may be feasible. Repeated use of rasburicase has been reported with good response^5,7 in spite of a 10–20% incidence of antibody generation, most of which are not neutralizing. Further studies in adult and pediatric patients are needed to find appropriate dosage regimens for rasburicase in tumor lysis syndrome and to establish guidelines for its prophylactic use.