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Originally published as JCO Early Release 10.1200/JCO.2003.04.115 on October 27 2003 © 2003 American Society for Clinical Oncology 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) StudyFrom the Centre Hospitalier Lyon-Sud, Pierre-Bénite; Hôpital Saint-Louis, Paris; Centre Hospitalier Universitaire de Brabois, Vandoeuvre les Nancy; Institut Gustave Roussy, Villejuif; Centre Becquerel, Rouen; Hôpital Bon Secours, Metz; Centre Hospitalier du Bocage, Dijon; Centre Hospitalier de Nîmes, Nîmes; Hôpital Henri Mondor, Créteil; Hôpital de Hautepierre, Strasbourg, France; and Université Catholique de Louvain-Mont Godinne, Yvoir, Belgium. Address reprint requests to B. Coiffier, MD, Hématologie, CH Lyon-Sud, 69495 Pierre-Bénite, France; e-mail: bertrand.coiffier{at}chu-lyon.fr.
Purpose: Hyperuricemia and tumor lysis syndrome are well-known complications during induction treatment of aggressive non-Hodgkin’s lymphomas (NHLs). Usual prophylaxis and treatment of hyperuricemia consist of hydration, alkalinization, and administration of allopurinol. This study was designed to evaluate the efficacy and the safety of rasburicase (recombinant urate oxidase) in adult patients with aggressive NHL during their first cycle of chemotherapy. Patients and Methods: A total of 100 patients from Groupe d’Etude des Lymphomes de l’Adulte centers, with diffuse large B-cell lymphoma (n = 79); anaplastic large-cell lymphoma (n = 6); peripheral T-cell lymphoma (n = 8); transformation of indolent lymphoma (n = 5); Burkitt’s lymphoma (n = 1); and lymphoblastic lymphoma (n = 1) were enrolled from May 2001 to June 2002. Before chemotherapy, 66% of patients had elevated lactate dehydrogenase (LDH), including 28% with LDH above 1,000 U/mL. Eleven percent of patients were hyperuricemic (uric acid [UA] > 450 mmol/L or > 7.56 mg/dL). Rasburicase 0.20 mg/kg/d intravenously for 3 to 7 days was started the day before or at day 1 of chemotherapy. UA levels were measured 4 hours after rasburicase injection, then daily during treatment. Results: All patients responded to rasburicase, as defined by normalization of UA levels maintained during chemotherapy. The control of UA was obtained within 4 hours after the first injection of the drug. Creatinine levels and other metabolites were also controlled with the administration of rasburicase. No patient exhibited increased creatinine levels or required dialysis during chemotherapy. Conclusion: Rasburicase is the treatment of choice to control UA and prevent tumor lysis syndrome in adult patients with aggressive NHL.
TUMOR LYSIS syndrome (TLS) is a life-threatening metabolic complication that occurs in malignancies with large tumor burden and highly proliferative cells, including lymphoma and leukemia.1–3 Hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia are the main abnormalities of TLS and occur when the kidneys cannot process and excrete the large amounts of intracellular contents2 released in the bloodstream on cell lysis. Hyperuricemia is caused by the rapid breakdown of nucleic acids either spontaneously in a highly proliferative tumor or after onset of chemotherapy. When renal excretory capacities are exceeded, patients develop acute renal failure secondary to precipitation of uric acid in the renal tubules. Hyperuricemia is the leading disorder responsible for TLS and its consequences. Conventional prophylaxis and treatment of hyperuricemia consists of hydration, administration of allopurinol, and alkalinization, although alkalinization may lead to additional adverse consequences, such as worsening of hyperphosphatemia and hypocalcemia, potentially translating into clinical complications for the patient.3,4
Urate oxidase is an endogenous enzyme found in most mammals but not in humans because of a nonsense mutation in the gene coding region.5 Urate oxidase catalyzes the enzymatic oxidation of uric acid into allantoin, metabolite that are five to 10 times more soluble in urine than uric acid (Fig 1
This article presents the first analysis of efficacy and safety of rasburicase in the control of hyperuricemia in adult patients with aggressive non-Hodgkin’s lymphoma (NHL) at risk of TLS during the induction phase of chemotherapy in a study (GRAAL1) conducted by the Groupe d’Etude des Lymphomes de l’Adulte (GELA).
Study Design GRAAL1 was a phase II, single-arm, open-label study evaluating the benefit of rasburicase in terms of efficacy and safety in adult patients with aggressive NHL with at least one adverse prognostic factor according to the International Prognostic Index9 and at risk of hyperuricemia during the first cycle of chemotherapy. The primary end point was the efficacy of rasburicase in terms of treatment of hyperuricemia and control of uric acid during the induction phase of chemotherapy. The secondary end points were evaluation of the renal protection, the definition of the optimal duration of rasburicase treatment, and safety. The use of allopurinol was allowed if prolongation of hypouricemic treatment beyond 7 days was required. The study was approved by the French Investigational Review Board.
Patient Eligibility Patients were deemed unsuitable for participation if they had a history of significant atopic allergy or documented history of asthma, hypersensitivity to urate oxidase or excipients, known history of glucose-6-phosphate dehydrogenase deficiency, previous treatment with rasburicase or nonrecombinant urate oxidase, pregnancy or lactation, or treatment with any investigational drug within 30 days before the first planned administration of rasburicase.
Treatment Modalities Rasburicase was given at the dose of 0.20 mg/kg/d for 3 to 7 days, starting either before induction chemotherapy or the same day, according to the risk of TLS (per the investigator’s judgment). The minimum duration of treatment was 3 days during chemotherapy, and treatment was prolonged to a maximum of 7 days in total, if uric acid levels or other biologic parameters (creatinine, phosphorus, calcium, and potassium) could not be controlled. Subsequent use of allopurinol was permitted if prolongation of hypouricemic treatment was necessary.
Patient Evaluation
Statistical Analysis
A total of 100 patients were enrolled at 14 GELA centers in France, Belgium, and Switzerland from May 2001 to June 2002. At presentation, 66 of the 100 patients (66%) had elevated LDH. Of these 66 patients, 28 had an LDH value more than 1,000 U/L. Eleven of the 100 patients (11%) had uric acid level more than 450 µmol/L (7.56 mg/dL). Chemotherapy regimens included AEVB10 (43%); CHOP11 (44%); ACE12 (6%); COP- COPADEM13 (4%); and ESHAP14 (3%), and were combined with rituximab in 20% of patients.10–14 Table 1  summarizes patient characteristics at study entry.
Efficacy Results Administration of rasburicase was started the day before initiation of chemotherapy in 12 of 100 patients, 2 days before the initiation of chemotherapy in one patient, and the same day as chemotherapy in the remaining 87 patients. All of the 95 of 100 patients treated at least 3 days responded to treatment. Uric acid levels decreased dramatically within the first 4 hours after administration of rasburicase and were maintained at a low level throughout treatment in all patients (Fig 2 ). Uric acid levels were also rapidly controlled in the subpopulation of patients who were hyperuricemic at presentation.
A total of 81 patients received 3 days of treatment and were controlled satisfactorily. In addition, response was observed in the 10 patients who received rasburicase the day before chemotherapy and received 4 days of treatment. Four patients were treated longer than 4 days: three patients and one patient received 5 and 6 days of rasburicase, respectively, even if they were considered responders after 3 days (two patients) or 4 days (two patients). These four patients were also responders to rasburicase treatment. The five remaining patients who did not receive at least 3 days of treatment had treatment discontinued because of safety reasons (see following section "Safety Results") or, in one patient, an investigator error.
No patient had an increase in creatinine level or required dialysis. In addition, as shown in Figure 3
Safety Results Overall tolerance of rasburicase was excellent. In three patients, rasburicase treatment was stopped earlier than 3 days because of an increase in liver enzymes. This National Cancer Institute grade 3 toxicity was detected during the first 24 to 48 hours of treatment and was rapidly reversible within a few days in all three patients, without sequelae. This toxicity was attributed by the investigators either to rasburicase or to chemotherapy, given that a rapid and transient increase of liver enzymes may be observed and has been reported as part of the biologic changes after anthracycline-containing chemotherapy in patients with diffuse large-cell lymphoma.15 Rasburicase treatment was discontinued in one patient after 2 days of treatment because of NHL-related complications (gastrointestinal hemorrhage).
The actual incidence of TLS in adults with various types of hematologic malignancies is not well appraised even though cases of Burkitt’s lymphoma complicated with TLS are reported in the literature. In a series of 102 pediatric patients with high-grade lymphoma, TLS was reported with a incidence as high as 42%.16 Therefore, the real benefit of prevention is difficult to estimate. A recently published retrospective study on European patients evaluated the incidence of TLS as 6% of the patients with NHL; overall, 1.9% of the global population observed died as a result of TLS-related complications.17 In this series, TLS led to acute renal failure in 45% of the patients, with a need for hemodialysis or hemofiltration in half of the patients. In addition, the outcome was death in 37% of the patients with TLS. The adverse consequences of TLS are also reported for other lymphoid malignancies, such as chronic lymphocytic leukemia treated with fludarabine: even if the overall incidence of TLS is low (estimated at approximately 0.33%), its occurrence seems unpredictable and the outcome of the patients is so poor (30% required dialysis with 40% mortality) that it deserves to be considered seriously when active chemotherapy is initiated in patients with lymphoid diseases.18
The efficacy of rasburicase in children with lymphoma and leukemia is well known and was reported to be statistically superior to that of allopurinol in terms of rapidity of control and levels of uric acid obtained under treatment.7,8,16,19,20 Our study demonstrated that rasburicase is also a highly effective, fast acting, and reliable uricolytic agent for adult patients with aggressive lymphoma. Plasma uric acid levels were controlled in all patients who received rasburicase, including the 11 hyperuricemic patients at baseline, whereas the response rate obtained when using intravenous allopurinol in hyperuricemic adult patients is only 57%, even with prolonged treatment.21 In this study, all of the patients were at risk of TLS, even if only 11% of them were hyperuricemic at presentation; they had a diffuse or bulky disease defined as a tumor size The control of plasma uric acid levels was obtained as fast as 4 hours after the first injection of rasburicase, and uric acid levels as well as levels of other metabolites were normalized and controlled in all patients with 3 to 4 days of treatment with rasburicase. It is important to note that 14 patients required a longer duration of treatment (at least 4 days). This duration of treatment remains shorter than the 5- to 7-day duration previously reported in pediatric patients, with treatment duration of 5 to 7 days.7,20 The same duration of treatment was reported for the majority of adult patients in the US compassionate-use experience.22 In an additional international compassionate-use program, the median treatment duration in adults was 5 days, possibly reflecting a patient population at higher risk of TLS.23 In addition, other biologic parameters involved in TLS were also controlled, demonstrating once again that the dramatic reduction of uric acid levels is the most important parameter for the prevention of TLS. Renal function was preserved, which is of paramount importance in the management of these patients and for the prevention of many complications of chemotherapy. This absence of any metabolic complication in 100 patients with lymphoma in the GRAAL1 study may be favorably compared with the published data in which at least 6% of the patients experienced TLS and its potentially related mortality. This trial was not designed as a randomized study versus allopurinol because of the strong conviction of the GELA that TLS prevention with urate oxidase is a standard of care, on the basis of more than 25 years of experience with urate oxidase. To confirm these results, a prospective randomized study versus allopurinol is currently being conducted in the United States (BENEFIT trial) in adult patients with acute leukemia and NHL at high risk of TLS to assess renal protection through the control of uric acid with urate oxidase. The tolerance of rasburicase was excellent. It is important to note that 20% of patients received rituximab at the same time, which is an emerging standard in the treatment of aggressive lymphoma and had been associated with occurrences of TLS. In addition to the control of TLS in this group at higher risk, no safety issue was observed with the simultaneous use of these two drugs. In summary, rasburicase combined with hydration provides an optimal control of hyperuricemia and prevents its rare but potentially serious complications (such as TLS) in adult patients with aggressive NHL.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: B. Coiffier, Sanofi Synthelabo.
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13. Soussain C, Patte C, Ostronoff M, et al: Small noncleaved cell lymphoma and leukemia in adults: A retrospective study of 65 adults treated with the LMB pediatric protocols. Blood 85:664–674, 1995 14. Soussain C, Souleau B, Gabarre J, et al: Intensive chemotherapy with hematopoietic cell transplantation after ESHAP therapy for relapsed or refractory non-Hodgkin’s lymphoma: Results of a single-centre study of 65 patients. Leuk Lymphoma 33:543–550, 1999[Medline] 15. Bienvenu J, Chvetzoff R, Salles G, et al: Tumor necrosis factor alpha release is a major biological event associated with rituximab treatment. Hematol J 2:378–384, 2001[CrossRef][Medline] 16. Patte C, Sakiroglu O, Sommelet D: European experience in the treatment of hyperuricemia. Semin Hematol 38:9–12, 2001[Medline] 17. Annemans L, Moeremans K, Lamotte M, et al: Incidence, medical resource utilisation and costs of hyperuricemia and tumour lysis syndrome in patients with acute leukaemia and non-Hodgkin’s lymphoma in four European countries. Leuk Lymphoma 44:77–83, 2003[CrossRef][Medline] 18. Cheson BD, Frame JN, Vena D, et al: Tumor lysis syndrome: An uncommon complication of fludarabine therapy of chronic lymphocytic leukemia. J Clin Oncol 16:2313–2320, 1998[Abstract] 19. Pui CH, Jeha S, Irwin D, et al: Recombinant urate oxidase (rasburicase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: Results of a compassionate-use trial. Leukemia 15:1505–1509, 2001[CrossRef][Medline]
20. Pui CH, Mahmoud HH, Wiley JM, et al: Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol 19:697–704, 2001
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5 cm in diameter, lactate dehydrogenase (LDH) level and/or uric acid level above normal upper limits, increase in creatinine level, electrolyte abnormalities, or low urine volume. All patients met the following criteria: age 
re J, et al: CHOP Chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 346:235–242, 2002
