1Institut Gustave Roussy, Villejuif, 2Centre Hospitalier Universitaire, Bordeaux; 3Hôpital St Louis, Paris; 4Centre Hospitalier Universitaire, Besançon; 5Institut Curie, Paris; 6Institut de Puériculture, Strasbourg, France
Received 14 May 2001; revised 7 December 2001; accepted 12 December 2001.
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Abstract |
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To evaluate the frequency of metabolic complications and dialysis due to tumor lysis syndrome in patients with B-cell advanced-stage non-Hodgkins 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
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Introduction |
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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 might significantly delay the start of chemotherapy. Since xanthine and hypoxanthine are themselves only slightly soluble, their accumulation may be toxic [79]. 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 allopurinols 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 [1113] 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].
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Patients and methods |
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The current recommendations for the management of TLS are: (i) alkaline hyperhydration (3 l/m2/day) to obtain a urine output of about 100120 ml/m2/h and urine pH 7; (ii) urate-oxidase given intravenously over 1530 min at a dosage of 50100 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 57 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 Murphys 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 patients age, as given by the Schwartz formula [19].
Statistical methodology
The results of the retrospective study were tabulated and displayed using descriptive statistics only.
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Results |
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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.
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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 patients 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 66375). Conversely, 16 patients whose median dose was only 70 U/kg/day (range 30105) 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/m2 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.
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Discussion |
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These efficacy data may be compared with the data from published United Kingdom Children Cancer Study Group (CCSG) and USA Pediatric Oncology Group studies [2022]. 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 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.
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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 advanced-stage 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 >100 000/mm3; 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 57 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 50 000 and 100 000/mm3 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 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 well-defined product of higher purity compared with the enzyme extracted from Aspergillus flavus used in Uricozyme®, potentially translating into a reduced risk of allergic reactions.
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Conclusion |
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Acknowledgements |
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Footnotes |
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Listed in the Acknowledgements.
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References |
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