Urate oxidase in the prophylaxis or treatment of hyperuricemia: The United States experience

Urate Oxidase Hyperuricemia:

in the Prophylaxis or Treatment The United States Experience

of

Ching-Han Pui Nonrecombinant urate oxidase (Uricozyme@, Sanofi-SynthQlabo, Inc, Paris, France) is a highly effective uricolytic agent, but its use is associated with hypersensitivity reaction manifested mainly by bronchospasm in approximately 5% of patients. Recently, several multi-institutional studies have evaluated the efficacy and safety of a recombinant urate oxidase (rasburicase). In a phase l/II study, all 131 patients with newly diagnosed acute lymphoblastic leukemia (ALL) or stage III/IV non-Hodgkin’s lymphoma (NHL) experienced rapidly decreased plasma uric acid concentrations after receiving recombinant urate oxidase. Serum creatinine levels also decreased significantly. Toxicity was negligible, and none of the patients required dialysis. In a phase Ill trial, children with newly diagnosed ALL or stage III/IV NHL were stratified and randomized to receive recombinant urate oxidase or allopurinol. Results showed that the 27 patients who received recombinant urate oxidase had a significantly lower plasma uric acid concentration and a more rapid decline in serum creatinine level than did the 25 who took allopurinol. One patient in the recombinant urate oxidase group had hemolysis of unknown cause, and one in the allopurinol group required hemofiltration for hyperphosphatemia. To further assess the safety profile of recombinant urate oxidase, the data on 245 patients (173 children and 72 adults) who received this agent in a compassionate-use program were reviewed retrospectively. The drug produced dramatic decreases in uric acid concentrations in all patients. Nine patients (four children and five adults) had mild adverse reactions that were drug-related or of unknown etiology. These data suggest that recombinant urate oxidase is safe and effective in the prophylaxis and treatment of hyperuricemia associated with malignancy or chemotherapy. Semin Hematol38(suppllO):l3-21. Copyright 0 2001 by W. 8. Saunders Company.

L

EUKEMIA AND LYMPHOMA patients are at risk of hyperuricemia, either prior to or as a result of induction chemotherapy.7J1,12J5,21 Hyperuricemia has been associated with acute renal failure and delays in chemotherapy, especially in patients with large tumor burden and mature B-cell or T-cell neoplasia.19 The current standard therapy for hyperuricemia in the United States consists of allopurinol, urinary alkalinization, hydration, and osmotic diuresis.20 Allopurinol, through the inhibition of the enzyme xanthine oxidase, blocks de novo uric acid formation, with no direct effect on circulating uric acid levels. Allopurinol increases the renal load of the uric acid precursors hypoxanthine and xanthine.2 Unlike hypoxanthine, xanthine is actually less soluble than uric acid14 and can lead to xanthine nephropathy. 1.3.10 In contrast to allopurinol, urate oxidase enzymatically oxidizes uric acid to allantoin, a metabolite readily excreted by the kidneyq5 with a 5 to IO-fold greater solubility than uric acid.20 Urate oxidase is present in most mammals but not in humans.23 Previous studies with a nonrecombinant form of urate oxidase (Uricozyme@, Sanofi-Synthelabo Inc, Paris, France) purified from cultures of Aspergillus jlavus have shown it to be more effective than allopurinol in correcting hyperuricemia.17,20 However, nonrecombinant urate oxidase is associated with acute hypersensitivity reactions in some cases (even in patients

with no history of allergy), making the drug a less than optimal choice.19 Since 1996, recombinant urate oxidase (rasburicase, SR29142 from Sanofi-Synthelabo Inc) has become available for clinical trials and appears to be an effective treatment option, with a lower toxicity profile than nonrecombinant urate oxidase. The experience with urate oxidase in the United States is summarized as follows. Use of Nonrecombinant

Urate

Oxidase

To determine the toxicity profile and efficacy of nonrecombinant urate oxidase, we retrospectively reviewed the data of 134 children (126 with newly diagnosed non-B-cell acute lymphoblastic leukemia [ALL], five with B-cell ALL, and three with stage III/IV B-cell non-Hodgkin’s lymphoma [ NHL]) From the St.&de Children’s Research Hospital, and Depmtment ofPediatrics, University of Tennessee, College of Medicine, Memphis, TN. Supported in part by National Institutes of Health Grants No. CA21 765, CA51 001, CA58297, CA60419, CA78224, and CA36401, by a Center ofExcellence grantfrom the State of Tennessee, by a grant from Sanoj-Synthelabo, Inc, and by the American Lebanese Syrian Associated Charities (ALSAC), Address reprint requests to Ching-Hon Pui, MD, St. Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105. Copyright 0 2001 by W.B. Saunders Company 0037-1963/01/3804-1005$35.00/O doi:10.1053/shem.2001.29018

13

14

Ching-Hon Pui

treated at St. Jude Children’s Research Hospital between February 1994 and December 1996.20 The blood levels of uric acid and other indicators of tumor lysis at diagnosis and during treatment in the 126 patients with non-B-cell ALL were compared with findings in 129 similarly treated historical controls who had received allopurinol to control hyperuricemia between December 1991 and February 1994. Patient

Characteristics

Children with non-B-cell ALL who received urate oxidase had a median age of 5.6 years, a leukocyte count of 11.7 X log/L, blood levels of lactic dehydrogenase of 1,243 U/L, uric acid of 4.3 mg/dL, phosphorus of 4.9 mg/dL, blood urea nitrogen (BUN) of 8.0 mg/dL, creatinine of 0.5 mg/dL, calcium of 9.4 mg/ dL, and T-cell immunophenotype of 14.3%. The historical control group had similar presenting features, with a median age of 5.7 years, a leukocyte count of 13.8 X log/L, blood levels of lactic dehydrogenase of 957 U/L, uric acid of 4.3 mg/dL, phosphorus of 4.7 mg/dL, BUN of 8.0 mg/dL, creatinine of 0.5 mg/dL, calcium of 9.4 mg/dL, and T-cell immunophenotype of 15.5%. Patients were excluded from receiving nonrecombinant urate oxidase if they had a history of allergy or glucose-6-phosphate dehydrogenase (GGPD) deficiency. Treatment Subjects with non-B-cell ALL receiving nonrecombinant urate oxidase and historical controls were treated in two consecutive “Total Therapy” studies for newly diagnosed ALL. All 129 historical controls and 29 patients treated with urate oxidase were enrolled in the first Total Therapy study. The remaining patients treated with urate oxidase were enrolled in the second Total Therapy study. In the first study, patients were stratified and randomized to high-dose methotrexate (1 g/m2 intravenously over 24 hours) or fractionated methotrexate (30 mg/m’ every 6 hours for six doses) as upfront therapy. In the second study, patients were stratified and randomized to upfront 6-mercaptopurine (1 g/m’ intravenously over 6 hours), or high-dose methotrexate (1 g/m’ intravenously over 24 hours) or fractionated methotrexate (30 mg/m2 every 6 hours for six doses) followed by an infusion of 6-mercaptopurine (1 g/m2 intravenously over 6 hours). Prednisone, vincristine, and daunorubicin were administered 96 hours after methotrexate and 72 hours after 6-mercaptopurine. During the first 96 hours, patients in the second study received more chemotherapy than those in the first study. Hence, patients treated with urate oxidase were exposed to more chemotherapy in the first 96 hours than those treated with allopurinol.

During the first week, all B-cell ALL or NHL patients received one dose of cyclophosphamide (300 mg/m2), one dose of vincristine (2 mg/m’), and 7 days of prednisone (60 mg/m2/d>. Intrathecal treatment consisted of one dose of methotrexate and hydrocortisone for stage III NHL patients or three doses of methotrexate, cytarabine, and hydrocortisone for stage IV NHL patients or those with B-cell ALL. Supportive care included hydration fluid with NaHCO, to prevent methotrexate toxicities. Nonrecombinant urate oxidase diluted in saline was administered at 100 U/kg/d intravenously over 30 minutes for 5 days. Historical controls received allopurinol at 300 mg/m2/d orally for 5 to 13 days. Some patients received oral phosphorus binder as indicated. Laboratory

Determinations

To measure uric acid levels, plasma was collected in an EDTA tube. During sampling, transport, and preparation of the assay, temperatures were held at 0°C to 4°C to prevent enzymatic degradation of uric acid by urate oxidase ex vivo. Samples were assayed based on the oxidation of uric acid in the presence of exogenous urate oxidase to form allantoin and hydrogen peroxide. Hydrogen peroxide then reacted with a leuco dye in the presence of peroxidase to produce a colored compound that is measured by reflectance spectrophotometry. The lower limit of sensitivity was 0.5 mg/dL. Results Patients treated with urate oxidase had rapid and significantly greater decreases in their blood uric acid levels relative to 129 historical controls. The median maximal level of blood uric acid during treatment was 2.3 versus 3.9 mg/dL (P < .OOl), respectively. In the urate oxidase group, 50.9% of patients had uric acid levels below 1 mg/dL after day 1, compared with 1% in the allopurinol group (P -=z .OOl). After day 2, 46.8% versus 1.8% had uric acid levels below this amount (P < .OOl). The urate oxidase group also had lower minimal uric acid levels than the allopurino1 group (median, 0.6 v 2.3 mg/dL, respectively; P < .OOl). Urate oxidase-treated patients also had lower levels of creatinine (median, 0.6 v 0.7 mg/dL; P = .Ol) and BUN (11 v 24 mg/dL; P < ,001) after treatment. Clinical responses to urate oxidase were also observed in eight patients with newly diagnosed B-cell ALL or advanced-stage NHL. Each of the five patients with B-cell ALL and the three with advanced-stage NHL experienced a sharp decrease in uric acid levels, dropping below 1 mg/dL, after 4 days of treatment despite receiving antineoplastic chemotherapy. One

Urute Oxidasefor Hyperuricemia

patient had temporary problems with renal function, with creatinine levels increasing from 1.4 mg/dL to 2.1 mg/dL on day 3. Levels returned to normal on day 6. Although nonrecombinant urate oxidase is an effective uricolytic agent, it is associated with acute hypersensitivity reactions even in patients with no prior history of allergy. Six (4.5%) of the 134 children given urate oxidase had allergic reactions, manifested primarily by urticaria, bronchospasm, and hypoxemia. All of the adverse reactions occurred within a median of 6 minutes following the first infusion of urate oxidase. All side effects cleared within 1 to 12 hours with treatment. A 12-year-old African-American boy with T-cell ALL developed methemoglobinemia 2 hours after administration of the first dose of urate oxidase. The child completely recovered without treatment 4 days later and was subsequently diagnosed to have GGPD deficiency. In conclusion, nonrecombinant urate oxidase is effective in reducing uric acid levels but is also associated with a relatively high rate of hypersensitivity reactions. Phase I/II

Clinical Trial of Recombinant Urate Oxidase

Recombinant mate oxidase may be an effective option with a better safety profile, according to the results of a phase I/II clinical trial. At multiple centers across the United States and Canada, recombinant urate oxidase was administered to 131 patients with leukemia or lymphoma, presenting with hyperuricemia or at high risk of developing the condition, between March 1996 and October 1997.i9 Eligibility

Criteria

Eligibility criteria included a recent diagnosis of Bcell ALL, ALL with an initial leukocyte count of at least 50 X log/L or a lymphomatous presentation and a large tumor burden, stage III or IV small noncleaved cell (B-cell) or lymphoblastic NHL with a large tumor burden, or any leukemia or NHL with a plasma uric acid concentration of at least 8 mg/dL and a serum creatinine or lactate dehydrogenase concentration exceeding twice the upper limit of normal. Exclusion criteria included a history of clinically significant atopic allergy, bronchial asthma, or GGPD deficiency. Patients were also excluded if they had received one dose of allopurinol within 24 hours, or two doses or more within the preceding 7 days, or were pregnant or lactating. Patient Characteristics Of the 131 patients (88 boys and 43 girls) who were treated, 17 had stage III and three had stage IV small noncleaved cell (B-cell) NHL; five had B-cell ALL; 33

15

Table 1. initial Tumor Burden of Study Cohort in the Phase l/II Trial Median category

B-precursor ALL* T-cell ALL B-cell ALL or NHL Lymphoblastic NHL

N

63 33 2.5

10

WBC

(X10$/L)

61.3 143.6 9.6 7.9

Median LDH (U/L)

1218 3489 1532 569

* One patient had AML. Abbreviations: WBC, white blood cell count; LDH, lactic dehydrogenase.

had T-cell ALL; 62 had B-cell precursor ALL; one had acute myeloid leukemia; and four had stage III and six stage IV NHL. All patients in the study had either high serum lactate dehydrogenase concentrations or hyperleukocytosis at diagnosis, indicative of a high tumor burden (Table 1). Hyperuricemia was present at diagnosis in 65 patients (50%) and renal impairment (indicated by an abnormally high serum creatinine level) in 28 patients (21%). Fourteen patients had previously received allopurinol; seven of these patients had hyperuricemia (plasma uric acid levels of 6.9 to 16.3 mg/dL) prior to treatment with recombinant urate oxidase (Table 2). Treatment Recombinant urate oxidase, isolated as a cDNA clone from Aspergillus flavus and biosynthesized in the yeast Saccharomyces cerevisiae, was administered intravenously each day for 5 to 7 days, under the auspices of the Food and Drug Administration, Investigational New Drug (IND) 49626. Dosing every 12 hours was allowed during the first 48 hours of initiating administration. Each dose of recombinant urate oxidase was diluted in 50 mL of preservative-free normal saline and administered intravenously over 30 minutes, within 2 hours after preparation of the drug. Chemotherapy was initiated as soon as 4 hours after the administration of the first dose of recombinant urate oxidase. Chemotherapy administration was based on institutional or collaborative group protocols. The study was divided into two phases: a dosevalidation phase for determination of the effective dose, and an accrual phase for confirming the efficacy and safety profiles of the drug. The initial dose of 0.15 mg/kg of body weight in the first phase was based on phase I/II clinical trial results in normal volunteers, as well as the equivalent dose of the nonrecombinant urate oxidase.16 The dosage was then increased incrementally by 0.05 mg/kg to one that corrected hyperuricemia (6.5 mg/dL in patients younger than 13 years of age, and 7.5 mg/dL in patients 213 years)

16

Chin.@lon Pui

Table 2. Initial Blood Chemistries at Presentation the Phase l/II Trial Category Uric acid (mg/dL) Creatinine (mg/dL) Phosphorus (mg/dL) Potassium (mEq/L)

of Patients in

Median

Range

% Abnormal

6.5 0.6 4.7 3.9

1.4-33.8 0.15-2.5 1.5-10.7 2.7-5.5

50 21 5 2

within 48 +- 2 hours post-treatment and prevented hyperuricemia in 14 consecutive patients for up to 24 hours post-treatment. Upon achieving dose validation, no further dose escalations were allowed, and the accrual phase began with at least 76 patients treated. The failure rate in the accrual phase with this dosage was predicted to be less than 20%. Laboratory Determinations Using a previously described assay, plasma concentrations of uric acid were measured at 4 hours, at 12 hours postadministration of the initial dose of recombinant urate oxidase, and every 12 hours thereafter, while taking precautions to keep all collected samples on ice until assayed, to prevent degradation by urate oxidase ex vivo.20 If below the limit of detection, the uric acid concentration was assumed to be 0.5 mg/dL. Complete and differential blood cell counts were obtained daily, along with blood levels of creatinine, phosphorus, and potassium. Creatinine concentrations greater than 0.4, 0.7, 1.0, 1.2, or I.3 mg/dL were judged to be abnormal for infants 12 months or younger, children 10 years or younger, adolescents 18 years or younger, females 18 years or older, or males 18 years or older, respectively. Phosphorus concentrations greater than 6.3 mg/dL, potassium concentrations greater than 5.0 mEq/L, lactate dehydrogenase greater than 300 U/L, and calcium greater than 10.5 mg/dL or less than 8 mg/dL were all considered abnormal6 Vital signs were measured before and at 15 and 30 minutes after the start of each infusion. Urine was collected over a 24-hour period in toilet-trained individuals during and after treatment for up to 8 days. A validated liquid chromatographymass spectroscopy/mass spectroscopy method was used to determine urinary concentrations of allantoin, with a lower limit of quantification of 14.6 Fg/mL.4 Results Recombinant urate oxidase, administered during the dose-ranging phase of the study, effectively corrected or prevented hyperuricemia (based on the parameters described above) in the first 11 patients tested, but failed to do so (with a transient increase in uric

acid concentration from 9.7 mg/dL at 4 hours to 10.7 mg/dL at 48 hours) in the 12th patient, a 13-year-old boy with stage III small noncleaved cell NHL and a presenting uric acid level of 21.1 mg/dL. According to study design, the dosage of recombinant urate oxidase was then increased to 0.20 mg/kg, which proved effective in the subsequent 14 patients and was the dosage used in the accrual phase. At either dose, the recombinant enzyme produced rapid, dramatic decreases in uric acid plasma concentrations in all 131 patients, regardless of whether or not they presented with hyperuricemia. The median uric acid level at diagnosis was 5.7 mg/dL (2.6 to 33.8 mg/dL), decreasing to 0.5 mg/dL (0.08 to 15.4 mg/ dL) by 4 hours after the first recombinant urate oxidase treatment (P < .OOOl). In the 65 patients presenting with hyperuricemia, the median level decreased from 9.7 to 1 mg/dL (Fig 1A). In the remaining 66 nonhyperuricemic patients (at presentation), uric acid levels decreased from 4.3 to 0.5 mg/dL (Fig 1B). Notably, even with intensive cytoreductive chemotherapy, the median uric acid concentration remained at or near 0.5 mg/dL throughout the course of the study. Serum phosphorus concentrations were normal in both initial hyperuricemic (Fig lC> and nonhyperuricemic patients (Fig 1D) 48 hours after the end of treatment. Serum potassium concentrations were relatively stable during the entire course of treatment. Renal function improved despite ongoing tumor lysis. Serum creatinine concentrations decreased significantly after day 1 of treatment in both patient groups (Fig 1E and F) and were within the normal range by day 6 of treatment. The median half-life of recombinant urate oxidase in plasma was 16 + 6.3 (SD) hours for the 0.15 mg/kg dose and 21.1 t 12.0 hours for the 0.20 mg/kg dose. Plasma concentration of recombinant urate oxidase v time is shown in Fig 2. Sequential daily urinary allantoin excretion rates for days 1 through 6 posttherapy initiation are shown in Fig 3. The rate of allantoin excretion (allantoin is not a natural metabolite of uric acid in humans) peaked at day 3 and was significantly higher in the 46 patients who presented with hyperuricemia at diagnosis. The treatment was well tolerated. None of the 131 patients developed life-threatening metabolic derangements or required dialysis after the start of recombinant urate oxidase therapy. One patient had mild nausea and vomiting, attributed to the use of recombinant urate oxidase, and another patient who presented with a white blood cell count of 160 X log/L (consisting of 82% eosinophils) and pneumonia at diagnosis developed bronchospasm and hypoxemia 3 hours after the initiation of recombinant urate oxidase therapy. This patient had received chemo-

t&ate Oxidasefor Hyperuricemia

17

Nonhyperuricemic

Hyperuricemic A

E

0.8

ic

0.7

T5

0.6 -

a .I!

B c’

1.0

1.o 0.9i 0.8

.99

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0.7 t

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0.6 0.5

0.5

25

0.9 0.4

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0.2 -

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4 hr

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2

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01

1

Baseline

1

2

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Baseline

6

t

1

3

4

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6

F

* Figure 1. Levels of uric acid, phosphorus, and creatinine in either hyperuricemic or nonhyperuricemic patients following treatment with recombinant urate oxidase. Reprinted with permission.i3

2

50

*

T

50

1

i

i

" 3

therapy several hours before. The patient recovered fully within 3 days, after receiving oxygen and treatment with a bronchodilator. Antibody formation against either recombinant urate oxidase or its epitopes were noted in two of 12 patients (17%) receiving the product at 0.15 mg/kg/ dose and 15 of 109 (14%) patients receiving 0.20 mg/kg/dose at the completion of therapy. No relationship could be demonstrated between the detec-

i

I

4

6

i

4 0 L Baseline

;

+ 1

2

l

+

‘I

3

4

** Iri 5

6

Days from Start of Treatment

tion of antibodies tients.

and the clinical

status

of the pa-

Phase III Randomized Study to Compare Relative Efficacy of Recombinant Urate Oxidase With Allopurinol The safety and efficacy of recombinant urate oxidase (rasburicase) was compared with those of allopurinol

Ching-Han Pui

18

6000 r

s‘ E 3l 5 2

-e---c-c---

5000 4000

Day 1, 0.15 mglkg Day 5, 0.15 mglkg Day 1, 0.20 mglkg Day 5, 0.20 mg/kg

T,,z=21 plk12.0

,-,

"0

I

4

8

72

16

20

24

Time (hours) in a phase III randomized study.9 Patients had either stage III or IV NHL, ALL with a white blood cell count greater than 25 X log/L, or uric acid greater than 8 mg/dL. Treatment Patients were stratified according to disease stage and uric acid level, then randomized to receive allopurino1 (n = 25) or recombinant urate oxidase (n = 27). Rasburicase was administered at a O&mg/kg daily dose, while oral allopurinol was administered at the standard dose (300 mg/m2/d>.

s

200

2 5 5

180

Figure 2. Plasma concentration of recombinant urate oxidase v time. Reprinted with permission.ig

Results As shown in Fig 4, the 27 patients treated with recombinant urate oxidase had a more rapid and profound decrease in uric acid levels v that seen in the 25 allopurinol-treated patients. Table 3 provides further comparison of both drugs’ prophylactic effect on hyperuricemia. Initial uric acid levels were similar between the recombinant urate oxidase subgroup (n = 17) and the allopurinol-treated (n = 16) subgroup (5.2 + 1.2 mg/dL v 4.6 k 0.9 mg/dL, respectively). Uric acid plasma levels in the recombinant urate oxidase subgroup were significantly lower (0.78 k

m

Hyperuricemic

0

Nonhyperuricemic

(n=46)

160 140

.-c A? c =

a

+

Figure 3. Sequential daily urinary allantoin excretion rates for- days 1 through 6 posttherapy initiation. Reprinted with permission.19

120 100 80

t

0

1

2

3

4

Days from Start of Treatment

5

6

(n=46)

Urate Oxidasefor Hyperuricemia

n=25

0

Figure 4. Comparison of plasma uric acid levels over time in patients treated with allopurinol or rasburicase. Reprinted with permission.g

I

0

I

I

I

I

,

I

I

I

2

3

4

5

6

7

8

9

Days From Start of Treatment

0.4 mg/dL) than those in the allopurinol-treated subgroup (3.92 2 0.95 mg/dL), 4 hours after treatment. Furthermore, area under the plasma concentrationversus-time curve (AUC) exposure (for hours 0 to 96 post-therapy initiation) to uric acid was significantly lower in the recombinant urate oxidase subgroup (107.9 mg.h/dL) versus the allopurinolgroup (265.9 mg * h/dL). All of the recombinant urate oxidase subgroup patients recorded normal uric acid levels at 48 hours posttherapy initiation versus 91% in the allopurinol-treated patient subgroup. Similar results were noted in patients presenting with hyperuricemia (Table 4). Patients had similar levels of uric acid at diagnosis. The recombinant urate oxidase patient subgroup (n = 10) recorded significantly lower uric acid levels (1.35 t 1.05 mg/ dL) 4 hours post-therapy initiation versus those of the allopurinol-treated group (n = 9; 8.8 t 2.9 mg/ dL). The recombinant urate oxidase-treated subgroup of patients recorded lower exposure levels to uric acid based on AUC over the 0- to 96-hour period post-therapy initiation. In addition, recombinant urate oxidase-treated patients took only a median of

4.1 hours to record normal uric acid levels, versus 19.2 hours for their allopurinol-treated controls. Sequential changes in the levels of uric acid, creatinine, and phosphorus in patients presenting with hyperuricemia are illustrated in Fig SA for the recombinant urate oxidase-treated subgroup and in Fig 5B for the allopurinol-treated subgroup. Favorable decreases in phosphorus, creatinine, and uric acid can be seen in the recombinant urate oxidase subgroup, while transient increases in phosphorus and creatinine, along with a less rapid and dramatic decrease in uric acid levels, are seen in the allopurinol-treated subgroup. One patient in the recombinant urate oxidase subgroup developed hemolysis of uncertain cause. In the allopurinol group, one patient required hemofiltration for hyperphosphatemia.

Table 3. Comparison of Prophylactic Efficacy Between Rasburicase and Allopurinol in a Phase Ill Trial

Table 4. Comparison of Treatment Efficacy Between Rasburicase and Allopurinol in a Phase III Trial

Uric Acid (mg/dL)

Rasburicase (N = 17)

At diagnosis At 4 h

0.78

5.2 i

1.2

i 0.4

A&-ee

107.9

Normal at 48 h

100%

AHopurinoB (N = 16) 4.6 t 0.9 3.92

t 0.95

265.9

91%

Experience With Recombinant Uratz Oxidase Under a Compassionate-Use Protocol Between January 1999 and December 2000,173 children and 72 adults were treated under a compassion-

Uric Acid (mg/dL)

At diagnosis At 4 h AU’%ea

Time to normal

Rasburicase (N = 10)

Allopurinol (N = 9)

10.4

I! 1.6

9.6 -c 2.7

1.35

-+ 1.05

8.8 -t 2.9

162.4 4.1 h

440

19.2 h

20

Ching-Hon Pui

A

0

B

Rasburicase

12

36

60

84

108

132 144

0

Allopurinol

12

36

Time from Start of Treatment (hours)

ate-use protocol.18 As expected, a dramatic and significant reduction in their uric acid levels was noted. Repeated administrations were also effective in all 11 evaluable patients. Four children and five adults had mild adverse reactions that were drug-related or of unknown etiology, including pruritus, hives, rash, wheezing, edema, vomiting, myalgia, and headache. Conclusion While nonrecombinant urate oxidase may produce hypersensitivity reactions such as urticaria, bronchospasm, and hypoxemia, recombinant urate oxidase appears to be an effective and well-tolerated uricolytic agent. Its potent uricolytic effect facilitates the excretion of phosphorus and results in improved renal function. Research to date shows the drug compares favorably to standard treatment with allopurinol. Use of the recombinant urate oxidase allows timely delivery of chemotherapy and may improve the outcome in patients with leukemia and lymphoma. Recombinant urate oxidase is a preferred initial treatment agent for patients with extreme hyperuricemia, especially in those with B-cell ALL or advanced-stage B-cell NHL. As with other oxidative agents, it should not be used in patients with GGPD deficiency. Additional studies are needed to determine its safety profiles in patients with a history of allergy. References 1. Ablin A, Stephens BG, Hirata T, et al: Nephropathy, xanthinuria, and erotic aciduria complicating Burkitt’s lymphoma treated with chemotherapy and allopurinol. Metabolism 21: 771-778, 1972 2. Andreoli SP, Clark JH, McGuire WA, et al: Purim excretion during tumor lysis in children with acute lymphocytic leukemia receiving allopurinol: Relationship to acute renal failure. J Pediatr 109:292-298, 1986

60

84

108 132 144

Figure 5. Sequential changes in levels of uric acid, creatinine, and phosphorus among hyperuricemic patients treated with either rasburicase or allopurinol.

3. Band PR, Silverberg DS, Henderson JF, et al: Xanthine nephropathy in a patient with lymphosarcoma treated with allopurinol. N Engl J Med 283:354-357, 1970 4. Berthemy A, Newton J, Wu D, et al: Quantitative determination of an extremely polar compound allantoin in human urine by LC-MS/MS based on the separation on a polymeric amino column. J Pharm Biomed Anal 19:429-434, 1999 5. Brogard JM, Coumaros D, Franckhauser J, et al: Enzymatic uricolysis: A study of the effect of a fungal mate-oxydase. Rev Eur Etudes Clin Biol 17:890-895, 1972 6. Choukair MK: Blood chemistries/body fluids, in Siberry GK, Iannone R (eds): The Harriet Lane Handbook: A Manual for Pediatric House Officers (ed 15). St Louis, MO, Mosby, 1996, pp 119-130 7. Cohen LF, Balow JE, Magrath IT, et al: Acute tumor lysis syndrome: A review of 37 patients with Burkitt’s lymphoma. Am J Med 68:486-491,198O 8. DeConti RC, Calabresi P: Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease. N Engl J Med 274:481-486, 1966 9. Goldman SC, Holcenberg JS, Finklestein JZ, et al: A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 97:2998-3003, 2001 10. Greene ML, Fujimoto WY, Seegmiller JE: Urinary xanthine stones-d rare complication of allopurinol therapy. N Engl J Med 280:426-427, 1969 11. Holland P, Holland NH: Prevention and management of acute hyperuricemia in childhood leukemia. J Pediatr 72:358-366, 1968 12. Jones DP, Mahmoud H, Chesney RW: Tumor lysis syndrome: Pathogenesis and management. Pediatr Nephrol 9:206-212, 1995 13. Jones DP, Stapleton FB, Kalwinsky D, et al: Renal dysfunction and hyperuricemia at presentation and relapse of acute lymphoblastic leukemia. Med Pediatr Oncol 18:283-286, 1990 14. Klinenberg JR, Goldfinger SE, Seegmiller JE: The effectiveness of the xanthine oxidase inhibitor allopurinol in the treatment of gout. Ann Intern Med 62:639-647, 1965 15. Krakoff IH, Murphy ML: Hyperuricemia in neoplastic disease in children: Prevention with allopurinol, a xanthine oxidase inhibitor. Pediatrics 41:52-56, 1968 16. Mahmoud HH, Leverger G, Patte C, et al: Advances in the management of malignancy-associated hyperuricaemia. Br J Cancer 77:18-20, 1998 (suppl4)

Urate Oxidasefor Hyperuricernia

17. Masera G, Jankovic M, Zurlo MG, et al: Urate-oxidase prophylaxis of uric acid-induced renal damage in childhood leukemia. J Pediatr 100:152-155, 1982 18. Pui C-H, Jeha S, Camitta B: Recombinant urate oxidase (rasburicase) in the prevention and treatment of malignancyassociated hyperuricemia: The compassionate use experience. Blood 96:719a, 2000 (suppl 1, abstr) 19. Pui C-H, 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 19:697704,200l 20. Pui C-H, Relling MV, Lascombes F, et al: Urate oxidase in

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