Original article. Introduction

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1 Original article Annals of Oncology 13: , 2002 DOI: /annonc/mdf134 Urate-oxidase in the prevention and treatment of metabolic complications in patients with B-cell lymphoma and leukemia, treated in the Société Française d Oncologie Pédiatrique LMB89 protocol C. Patte 1 *, C. Sakiroglu 1, S. Ansoborlo 2, A. Baruchel 3, E. Plouvier 4, H. Pacquement 5 & A. Babin-Boilletot 6 On behalf of the Société Française d Oncologie Pédiatrique 1 Institut Gustave Roussy, Villejuif, 2 Centre Hospitalier Universitaire, Bordeaux; 3 Hôpital St Louis, Paris; 4 Centre Hospitalier Universitaire, Besançon; 5 Institut Curie, Paris; 6 Institut de Puériculture, Strasbourg, France Received 14 May 2001; revised 7 December 2001; accepted 12 December 2001 Purpose: To evaluate the frequency of metabolic complications and dialysis due to tumor lysis syndrome in patients with B-cell advanced-stage non-hodgkin s lymphoma (NHL) and L3 leukemia at initiation of chemotherapy including the use of urate-oxidase. Patients and methods: Retrospective review of the clinical records of 410 patients with stage III and IV B-cell NHL and L3 leukemia treated in France and prospectively registered in the LMB89 protocol. Results: During the first week of chemotherapy, only 34 of 410 patients recorded metabolic problems that included hypocalcemia (<70 mg/dl) in 24 patients, hyperphosphatemia (>6.5 mg/dl) in 28 and elevation of creatinine 2 SD in 16. Six patients underwent dialysis for life-threatening problems and a seventh as a preventive measure. In the other 27 cases, metabolic problems were successfully resolved using urate-oxidase in combination with alkaline hyperhydration. Among the 410 patients, one case of hemolysis was reported and there was no severe allergic reaction to urate-oxidase. Conclusions: Only 1.7% of patients in our study receiving urate-oxidase during their induction chemotherapy needed renal dialysis. Urate-oxidase was well tolerated, and used as prophylaxis and/or treatment of hyperuricemia and tumor lysis syndrome consistently gave a lower rate of renal and metabolic complications than in other series of similar patients. Key words: B-cell lymphoma, hyperuricemia, L3 leukemia, LMB protocol, tumor lysis syndrome, urate-oxidase Introduction Lymphoproliferative malignancies are frequently associated with acute tumor lysis syndrome (TLS), a massive spontaneous or chemotherapy-induced cytolysis leading to the release of intracellular metabolites [1, 2]. The resulting metabolic disturbances cause significant clinical problems. In particular, hyperuricemia resulting from the breakdown of large quantities of nucleic acids in the lysed tumor cells [3] has been implicated in the eventual development of renal dysfunction, as precipitation of uric acid leading to intraluminal tubular *Correspondence to: Dr C. Patte, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif Cedex, France. Tel: ; Fax: ; patte@igr.fr Listed in the Acknowledgements. obstruction results in acute renal failure [4]. Although the prognosis for patients with B-cell non-hodgkin s lymphoma (NHL) and L3 acute lymphocytic leukemia (ALL) who survive disease-free for 1 year is now generally excellent, these metabolic problems can have a major deleterious impact on morbidity and mortality. For many years the standard pharmacological treatment for hyperuricemia has been allopurinol, which blocks the metabolic conversion of hypoxanthine and xanthine to uric acid [5, 6]. Allopurinol also inhibits de novo purine synthesis, further lowering uric acid concentrations. Although effective, allopurinol treatment has some limitations. Allopurinol administration prevents further synthesis of uric acid but does not degrade the uric acid already present, and is therefore usually given together with alkaline hyperdiuresis to clear renal uric acid crystals, a process that takes up to 10 days and which 2002 European Society for Medical Oncology

2 790 Figure 1. Diagram of the purine catabolism pathway. *Uric acid is the normal end point in humans. might significantly delay the start of chemotherapy. Since xanthine and hypoxanthine are themselves only slightly soluble, their accumulation may be toxic [7 9]. Furthermore, allopurinol inhibits the degradation of the chemotherapeutic agents 6-mercaptopurine and azathioprine, increasing their chemotoxicity and complicating their simultaneous administration in chemotherapeutic regimens [3]. As a result of allopurinol s disadvantages, the enzyme urate-oxidase has been developed as an alternative to catalyze the conversion of uric acid to more soluble allantoin (Figure 1). Urate-oxidase is present in many mammals (excluding humans and other primates), and because it acts at the end of the purine metabolic pathway it does not lead to the accumulation of intermediary metabolites such as xanthine, thus limiting the risk of renal damage [10]. Urate-oxidase extracted from Aspergillus sp. has been available as Uricozyme in France since 1975 [11 13] and in Italy since 1984 [10, 14], and has been routinely used in these countries for the prophylaxis or treatment of severe hyperuricemia following chemotherapy. More recently a recombinant version using the gene cloned from Aspergillus sp. has become available [15]. Little has yet been published to support the clinical use of urate-oxidase in the prophylaxis and treatment of malignancyassociated hyperuricemia and TLS [11 14]. The study reported here retrospectively evaluated the frequency of metabolic complications and dialysis in patients with B-cell NHL and L3 ALL who had undergone chemotherapy in France according to the LMB89 protocol [16] including the use of urate-oxidase. A secondary aim of the study was to compare these results with those of similar patients treated with the same (as in the UK) or similar (in other countries) protocols, all without the concomitant use of urate-oxidase. Patients and methods Patients This study is a retrospective evaluation of early renal and metabolic complications and of the effect of urate-oxidase on patients with B-cell NHL or L3 ALL treated with the LMB89 protocol (July 1989 to May 1996). This protocol followed previous LMB protocols for the treatment of B-cell malignancies in use in France and in some Dutch and Belgian centers since 1981 [17, 18]. In all these protocols, chemotherapy started with a 1-week cytoreductive low-dose regimen (COP) using vincristine (VCR) 1 mg/m 2 and cyclophosphamide (CPM) 300 mg/m 2 on day 1, with 7 days of prednisone 60 mg/m 2 and intrathecal treatment [one dose of methotrexate (MTX) and hydrocortisone for stage III and for central nervous system (CNS)-negative stage IV NHL, or three doses of MTX, cytarabine and hydrocortisone for CNS-positive stage IV NHL or for B-cell ALL]. The first intensive induction course of chemotherapy, COPADM1 [combination of fractionated CPM, VCR, prednisone, Adriamycin and high-dose (HD) MTX (3 g/m 2 in stage III and CNS-negative stage IV, 8 g/m 2 in CNS-positive NHL and in B-ALL)], started on day 8. The metabolic problems due to TLS that may have been present before the start of chemotherapy, and otherwise arose during the first week of treatment, needed to be resolved before COPADM1 could be started. The current recommendations for the management of TLS are: (i) alkaline hyperhydration (3 l/m 2 /day) to obtain a urine output of about ml/m 2 /h and urine ph 7; (ii) urate-oxidase given intravenously over min at a dosage of U/kg/day (the larger dose is given in cases of large tumor mass). These recommendations must be initiated as soon as the diagnosis of NHL or leukemia is suspected and continued as long as there is a risk of TLS, generally over the 5 7 days following the start of treatment. The COP chemotherapy was started only when correct diuresis was achieved, with furosemide if necessary. In the case of urinary tract obstruction by tumor mass, temporary urine diversion by percutaneous nephrostomy or uretera-endoprothesis could be carried out; if these techniques were not immediately available, dialysis was chosen. In cases of known large tumor mass, it was possible to split COP administration over 2 days in an attempt to reduce the acute complications of TLS, and the dose of urate-oxidase could be increased according to the plasma uric acid level. Study design Of the patients registered in the LMB89 study, the following were excluded from this investigation: those who were not treated in France and therefore did not receive urate-oxidase, and those who presented with stage I and II disease and were therefore at lower risk of TLS. For the selected patients, i.e. those with stage III and IV NHL or with ALL, treated in France, the clinical records were reviewed for data on: (i) patient characteristics (age, sex, weight); (ii) NHL and ALL characteristics [histology, primary site, other sites especially kidney involvement, serum lactate dehydrogenase (LDH) level, stage according to Murphy s classification]; (iii) presence of associated problems before the start of treatment (general comments on renal function or other physiological data, without specific documentation); and (iv) occurrence of significant metabolic problems during the first week of treatment. The patients whose records noted the occurrence of metabolic problems during the first week of chemotherapy were selected for detailed analysis. A questionnaire was completed using the information from the patients case report forms on renal function, electrolyte balance [serum phosphate levels >2.1 mmol/l (6.5 mg/dl), calcium <1.75 mmol/l (70 mg/l), potassium >6.5 mmol/l], initial and highest serum uric acid level, urate-oxidase dose, clinical management, need for dialysis and problems during the first COPADM course, especially delay in HD MTX excretion. Renal function impairment was defined as a serum creatinine level >2 standard deviations (SD) above the normal value for the patient s age, as given by the Schwartz formula [19].

3 791 Statistical methodology The results of the retrospective study were tabulated and displayed using descriptive statistics only. Results Study patients Table 1. Baseline characteristics of patients included in study No. of patients (%) Patients eligible for inclusion in the present study 410 Disease status Stage III 257 (63%) Stage IV 57 (14%) L3 acute lymphocytic leukemia 96 (23%) Lactate dehydrogenase <2 normal 145 (35%) 2 normal 234 (57%) Unknown 31 (7.6%) Pleural effusion 83 (20%) Ascites 183 (45%) Kidney involvement 56 (14%) Problems reported before start of chemotherapy Renal failure 21 (5%) Urinary tract obstruction with renal failure 9 (2%) Paraplegia or spina bifida 3 (0.7%) Major electrolyte imbalance 7 (2%) The records of 410 patients with B-cell stage III and IV NHL and ALL, treated in 37 French centers, were reviewed. Some of the characteristics of this group of patients are shown in Table 1. LDH levels raised to over twice the institutional upper normal level were found in 234 patients (57%), indicative of a heavy tumor burden. A large number of the patients had ascites (45%), pleural effusion (20%) or kidney involvement (14%). Initial clinical problems with metabolic or renal disorders and/or urinary tract dysfunction before the start of any chemotherapy were recorded in 41 patients, some of them occurring in the same patient. Renal failure was recorded 21 times (5%); urinary tract obstruction nine times (2%), leading to percutaneous pyelostomy in two patients, vesical catheter in two, double J ureteral catheter in one and a single dialysis course in one patient; major electrolyte imbalance seven times (2%, two patients with hypercalcemia, three with hyperkaliemia, two with hyperphosphatemia); paraplegia or spina bifida three times (0.7%); and ureteral fistula once. All the patients received COP chemotherapy in combination with the measures recommended for the management of TLS. Only 11 of those with recorded initial metabolic problems and 23 others presented significant metabolic problems during the first week after the start of treatment. Patients presenting metabolic problems after start of chemotherapy Description at diagnosis In the first week after the start of chemotherapy, i.e. during the cytoreductive low-dose phase of COP treatment, 34 of 410 patients with metabolic problems were recorded: six girls and 28 boys with ages ranging from 3 to 15 years, and weight from 15.6 to 63 kg. Some of their demographic and baseline characteristics are shown in Table 2. Twenty-two patients had an abdominal and one a maxillary tumor as the primary site, and 11 had ALL. Twenty patients (59%) presented with puncturable ascites, 17 with pleural effusion and 13 with kidney tumor involvement. All but one patient had LDH levels more than twice the normal value, and 13 patients (38%) had levels more than 10 times the normal value; the median LDH level was seven times the normal value. Eight were recorded as having renal insufficiency at diagnosis. After review of the questionnaire, three of these were found to have had creatinine levels <2 SD above the norm and 11 other patients, i.e. a total of 16, already had impaired renal function before the start of COP, including five with oligo-anuria, five with hydronephrosis and six with diffuse kidney tumor involvement. Table 2. Demographic and baseline characteristics of patients with recorded metabolic disorders in the first week of chemotherapy No. of patients (%) Total patients with recorded metabolic disorders 34 Disease status Stage III 11 Stage IV 5 Acute lymphocytic leukemia 18 Lactate dehydrogenase >2 normal 33 >10 normal 13 Median 7 normal Uric acid (22 patients) Median 807 µmol/l Range µmol/l Pleural effusion 17 (50%) Ascites 20 (59%) Impaired renal function Elevated creatinine (>2 SD for the age) 16 Oliguria 5 Hydronephrosis 5 Renal tumor involvement 13

4 792 As uric acid dosage were not available for any time in any center, and because urate-oxidase and hyperhydration were generally initiated immediately on admission of the patient, the initial uric acid level was not known for nine patients and was uncertain in a further two. The other 22 patients showed elevated uric acid levels between 506 and 1800 µmol/l (5.7 and 20.3 mg/dl) with a median of 807 µmol/l (9.1 mg/dl). In 11 patients, the COP course was split over more than 1 day. Metabolic problems after the start of chemotherapy For these 34 patients, a diverse combination of metabolic problems after the start of chemotherapy were reported. Hypocalcemia <1.75 mmol/l (70 mg/dl) was reported in 24 patients (72%), hyperphosphatemia >2.1 mmol/l (6.5 mg/dl) in 28 patients (85%), and creatininemia 2 SD above the norm in 16 patients (47%) (10 in whom it was already recognized and six others). In 21 of the patients the metabolic problems were classified as severe: hyperphosphatemia >3 µmol/l (9.3 mg/dl) in 16 and oliguria or anuria in six and two patients, respectively. Twelve of these cases had life-threatening problems, with levels of phosphate >5 µmol/ml (15.5 mg/dl) in four patients, of potassium 6.5 mmol/l in five patients, and oliguria or anuria in patients as previously noted. Six of the 12 patients with life-threatening problems underwent dialysis: four for oliguria or anuria (associated with hyperphosphatemia in two cases), and two for hyperphosphatemia (associated with hyperkalemia in one patient). Two of these patients initially showed either kidney tumor involvement or renal insufficiency, and four patients had a combination of both problems. In one further case, dialysis was instigated as a preventive measure due to the patient s poor condition (renal insufficiency, staphylococcal septicemia and respiratory problems due to huge ascites and pleural effusion, but without oliguria or electrolyte imbalance). The median number of dialysis courses was three (range two to five). The patients who received dialysis were aged between 4 and 15 years. Five presented with large abdominal tumors (three at stage III, one at stage IV and one ALL) and two with L3 ALL. Their median LDH levels were eight times the upper normal limit (range two to 22 times). In the other 27 cases of patients encountering metabolic problems (including six where they were life-threatening and who did not undergo dialysis), the problems were successfully resolved by treatment using urate-oxidase in combination with alkaline hyperhydration, and hyperdiuresis with furosemide. No patients died. The data review did not investigate the rate at which uric acid levels decreased, only the highest uric acid level achieved and the highest daily dose of urate-oxidase used. Eighteen patients showed good control of uric acid levels [<480 µmol/l (7.65 mg/dl)] on a median urate-oxidase dose of 165 U/kg/day (range ). Conversely, 16 patients whose median dose was only 70 U/kg/day (range ) showed inadequate control of uric acid levels (>480 µmol/l). Subsequent chemotherapy course Among the 34 patients, four (two dialyzed, one with severe metabolic problems but not dialyzed, one without severe metabolic problems but requiring assisted ventilation for 3 days in an intensive care unit) presented delayed excretion of HD MTX given at 8 g/m 2 during the first COPADM course. This was followed by grade 4 mucositis in four patients, severe aplasia with sepsis in two patients, and numerous transfusions required by a further two patients. No patients died. Safety of urate-oxidase In this series of 410 patients there was only one case of hemolysis in a patient with a previously undetected glucose 6-phosphate dehydrogenase (G6PD) deficiency. After stopping urate-oxidase treatment the hemolysis was managed without any further difficulty. No severe allergic reactions were reported from these patients. No data are available on the development of antibodies to urate-oxidase over time. In 31 patients, however, there was subsequent tumor regrowth, relapse or development of secondary hematological malignancy requiring further urate-oxidase treatment, with no reports of significant immunological reaction. Discussion Out of a total 410 patients in the LMB89 series with stage III or IV B-cell lymphoma or ALL, only 34 (8%) had reports of metabolic problems after the start of chemotherapy, 21 (5%) displayed severe metabolic problems, of which 12 (2.9%) were life-threatening, and only seven (1.7% of all the study patients, 0.7% of patients in stage III and 2.6% of patients in stage IV and with ALL) required dialysis as a result of TLS. It should be noted that some patients were successfully treated without dialysis on the standard urate-oxidase-containing regimen even though they showed the same clinical changes, including alteration of renal function, oliguria, hyperphosphatemia and hyperkalemia, that led to the implementation of dialysis in other patients. No patient died as a consequence of metabolic problems or further problems related to renal function impairment. These efficacy data may be compared with the data from published United Kingdom Children Cancer Study Group (CCSG) and USA Pediatric Oncology Group studies [20 22]. No metabolic data are given in the report of 112 patients with stage III and CNS-negative stage IV treated with the UKCCSG9002 protocol identical to the LMB89 group B protocol [19]. In the series treated with the UKCCSG9003 protocol identical to the LMB89 group C protocol, however, of 63 patients with CNS-positive stage IV and ALL, 10 (16%) required dialysis [21]. Five of them subsequently died of toxicity (infection with or without renal failure). Furthermore, COPADM first or second courses had to be delayed or modified for 28 patients because of poor clinical condition or

5 793 Table 3. Comparison of chemotherapy studies with/without urate-oxidase LMB89 (France) UKCCSG (UK) a POG (USA) b Disease stages included III + IV + ALL IV + ALL IV + ALL IV + ALL Patient number Patients receiving dialysis 7 (1.7%) 4 (2.6%) 10 (16%) 28 (23%) a UKCCSG, United Kingdom Children Cancer Study Group. Data from Atra et al. [21]. b POG, Pediatric Oncology Group. Data from Bowman et al. [22]. ALL, acute lymphocytic leukemia. associated complications, mainly infectious or metabolic. Of these 28 patients, seven relapsed and four died from toxicity. These data underline the improvement in long-term survival with prevention of renal damage during chemotherapy. The study from the USA [22], which used an initially more aggressive chemotherapy regimen, i.e. without a low-dose cytoreductive phase, showed a nine-fold higher recourse to dialysis compared with the data reported here (Table 3). Treatment of 123 patients with stage IV small non-cleaved cell NHL or B-cell ALL showed that early renal and metabolic dysfunction led to a requirement for dialysis in 28 patients (23%). Six patients died from metabolic problems. Thus, compared with 11% and 23% of children with stage IV NHL and ALL in protocols using chemotherapy and allopurinol, without urate-oxidase, in our series only 2.6% of similar patients receiving chemotherapy plus urate-oxidase needed renal dialysis. Although there might be differences in the indications for dialysis in different studies, these results suggest that urate-oxidase results in better management of metabolic and renal complications. The potential impact of the increased use of urate-oxidase in patients with lymphoid malignancies at risk of TLS is emphasized by a retrospective analysis of 1192 children diagnosed with NHL of any stage [23], in which 63 patients (5%) were reported to have suffered from impaired renal function and/or TLS either before or during the initial treatment. Dialysis was necessary for 25 patients (40% of all patients with impaired renal function) and a total of nine patients (14%) died after the first course of chemotherapy due to sepsis (seven patients) or electrolyte imbalances (two patients). The authors of this paper note that patients at advanced stages of the disease and with a large tumor mass are at high risk of renal failure, and that the prophylactic use of urate-oxidase in patients with advanced-stage NHL might reduce the incidence of TLS. Our retrospective data show that good control of hyperuricemia [<480 µmol/l (7.65 mg/dl)] was achieved on a median urate-oxidase dose of 165 U/kg/day. Lower dosages (median 70 U/kg/day) gave inadequate control (uric acid >480 µmol/l). Clinical experience showed that dosage must be adjusted in line with the observed serum uric acid level. In patients with a known large tumor mass, the dosage may need to be increased substantially above the recommended dose of 100 U/kg/day in order to obtain full efficacy. Clinical practice has shown that the decrease in uric acid levels is obtained rapidly, although the present study cannot provide data to support this. Pui et al., 1997 [24] showed in eight patients with B-ALL or advancedstage B-NHL that plasma uric acid levels were <1 mg/dl (88 µmol/l) after 4 days of treatment with urate-oxidase Urate-oxidase was well tolerated in the series of patients reported here, with one case of hemolysis revealing a previously unknown G6PD deficiency, and with no hypersensitivity reaction. Previous studies with urate-oxidase have reported varying rates of allergic reactions, from 0% to 4.5% [24], reflecting differences in the underlying allergic status of the patients involved. This retrospective study was not designed to evaluate pharmacoeconomics benefits of urate-oxidase or to collect treatment-related costs. The low incidence of dialysis, of metabolic complications and toxicity-related deaths, however, when compared with similar cohorts of patients not receiving urate-oxidase, may suggest a pharmacoeconomic benefit of the use of this drug in the described patient population. From our experience in pediatric hemato-oncology, we could propose the following guidelines for an optimal use of urate-oxidase: patients with very high risk of TLS [i.e. patients with ALL or myeloblastic leukemia with a white blood cell (WBC) count >100000/mm 3 ; patients with stage III/IV Burkitt lymphoma and increased LDH level and/or high uric acid level, renal involvement and impaired renal function; patients with L3 leukemia; patients with stage III/IV lymphoblastic lymphoma and a significant tumor mass (>10 cm) and/or pleural effusion and impaired renal function] will systematically be treated with urate-oxidase. Urate-oxidase in these cases will be started before initiation of chemotherapy and given as long as tumor lysis persists, for a duration of 5 7 days under chemotherapy. In cases where tumor lysis is very intense (during the first 3 days of chemotherapy) the number of daily injections may be increased, according to the plasma uric acid levels and to the other biological parameters. The use of urate-oxidase should also be closely considered in the following patients: patients with acute leukemia and WBC count between and /mm 3 and/or extensive tumor mass, high uric acid level, renal involvement, impaired renal function or high proliferation index, as well as patients with other stage III/IV Burkitt and lymphoblastic lymphoma. Urate-oxidase should be avoided in patients with G6PD

6 794 deficiency and given with caution in patients with history of severe allergies. A recombinant urate-oxidase (rasburicase; Fasturtec ) has recently been approved in Europe for the prevention and treatment of acute hyperuricemia in patients with hematological malignancies. Recombinant DNA techniques result in a welldefined product of higher purity compared with the enzyme extracted from Aspergillus flavus used in Uricozyme, potentially translating into a reduced risk of allergic reactions. Conclusion The retrospective study reported here shows that urateoxidase in the prophylaxis and treatment of hyperuricemia and TLS in patients with B-cell ALL or advanced lymphoma consistently leads to a low rate of metabolic and renal complications and recourse to dialysis. Using this treatment regimen, many patients who would normally be considered at high risk of TLS showed no symptoms of it, nor of hyperuricemia. The ability of urate-oxidase to prevent the delays that are caused by hyperuricemia or impaired renal function represents a major clinical advantage, since the rapid continuation or resumption of chemotherapy is of paramount importance in the treatment of these patients with a high tumor mass. Of the original 34 patients who showed metabolic problems in this study, only four experienced delay in continuing chemotherapy. Most of the patients in the study reported here, and in the UK and USA studies, had excellent prognoses in the absence of renal complications, so that preservation of renal function is an important clinical objective in this patient population. Using urate-oxidase before and during the initial exposure to cytoreductive therapy may therefore have a two-fold impact on overall survival in patients with a large tumor burden: first by its beneficial effect on the renal response to TLS and subsequent need for dialysis, and secondly by allowing patients to continue or restart chemotherapy more rapidly, a crucial consideration for patients in late-stage disease who are also those most at risk of TLS. Acknowledgements The authors are grateful to P. Rigaudy and J. Leach Scully for editorial assistance. Sanofi-Synthelabo, Paris, France was the grant supporter. Participating institutions and investigators: Institut G. 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