recombinant urate oxidase (rasburicase) for the treatment of hyperuricemia in pediatric patients...

Pediatr Blood Cancer 2006;46:439–445

Recombinant Urate Oxidase (Rasburicase) for the Treatment ofHyperuricemia in Pediatric Patients With HematologicMalignancies: Results of a Compassionate Prospective

Multicenter Study in Korea

Hee Young Shin, MD, PhD,1,2 Hyoung Jin Kang, MD, PhD,1 Eun Sil Park, MD,1

Hyoung Soo Choi, MD, PhD,1 Hyo Seop Ahn, MD, PhD,1,2* Sun Young Kim, MD,3

Nak Gyun Chung, MD, PhD,3 Hack Ki Kim, MD, PhD,3 So Youn Kim, MD,4 Hoon Kook, MD, PhD,4

Tai Ju Hwang, MD, PhD,4 Kwang Chul Lee, MD, PhD,5 Sun Min Lee, MD,6 Kun Soo Lee, MD, PhD,6

Keon Hee Yoo, MD,7 Hong Hoe Koo, MD, PhD,7 Mee Jung Lee, MD,8 Jong Jin Seo, MD, PhD,8

Hyung Nam Moon, MD, PhD,8 Thad Ghim, MD,8 Chuhl Joo Lyu, MD, PhD,9

Won Sik Lee, MD,10 and Yong Mook Choi, MD, PhD11

INTRODUCTION

Hyperuricemia is a feature of the tumor lysis syndrome

(TLS), and results from the rapid destruction of malignant

cells and the release of their intracellular contents into the

extra-cellular space. TLS is a metabolic disorder that can

include hyperuricemia, hyperphosphatemia, hypocalcemia,

hyperkalemia, and creatinine increase. Subsequently, renal

elimination capability is exceeded and this may lead to

the precipitation of uric acid and calcium phosphate in the

kidney and acute renal failure [1], which is one of the

most feared acute complications in the treatment of

hematologic malignancies [2–7]. In the absence of preven-

tion and/or treatment of hyperuricemia, the frequency of

acute renal failure in TLS associated with the precipitation

of uric acid crystals in renal tubules may be as high as

30% in Burkitt lymphoma patients, and renal sequelae

may be irreversible [8]. Therefore, renal protection is of

paramount importance for delivering optimal planned

chemotherapy.

The concomitant use of hydration (with or without urinary

alkalinization) and allopurinol remains a standard treatment

Background. Hyperuricemia accompanying tumor lysis syn-drome is a serious complication in neoplasia with rapid proliferationand destruction. To confirm the efficacy of recombinant urateoxidase (rasburicase) and its safety profile, a phase IV compassionateuse prospective study was performed in Korean pediatric patientswith hematologic malignancies. Procedure. Rasburicase was admi-nistered at 0.2 mg/kg/day once daily for 3–5 days (twice dailyallowed during the first 72 hr) by intravenous route for hyperuricemia(uric acid>7.5 mg/dl). The study period was 5 weeks and consistedof a baseline assessment within 48 hr before the administration of

rasburicase, 3–5 days of assessment during treatment and a follow-up assessment at 4 weeks after its final administration. Results. Theuric acid endpoint (�7.0 mg/dl) was reached in 97.3% (36/37) of thepatients and uric acid levels were significantly reduced in all patients(P<0.001). Drug related toxicities were mild and reversible withoutany grade 4 or serious adverse event associated with rasburicase.Conclusion. This study confirms that rasburicase is a safe andeffective agent for the treatment of hyperuricemia associated withhematologic malignancies in pediatric patients. Pediatr BloodCancer 2006;46:439–445. � 2005 Wiley-Liss, Inc.

Key words: compassionate study; hematologic malignancy; hyperuricemia; pediatric patients; rasburicase; tumor lysis syndrome

� 2005 Wiley-Liss, Inc.DOI 10.1002/pbc.20555

——————Abbreviations: TLS, tumor lysis syndrome; DIC, disseminated

intravascular coagulation.

1Department of Pediatrics, Seoul National University College of

Medicine, Seoul, Republic of Korea; 2Cancer Research Institute, Seoul

National University College of Medicine, Seoul, Republic of Korea;3Department of Pediatrics, College of Medicine, The Catholic

University of Korea, Seoul, Republic of Korea; 4Department of

Pediatrics, Chonnam National University Medical School, Gwangju,

South Korea; 5Department of Pediatrics, Korea University College of

Medicine, Seoul, Republic of Korea; 6Department of Pediatrics,

Kyungpook National University School of Medicine, Daegu, South

Korea; 7Department of Pediatrics, Sungkyunkwan University

School of Medicine, Samsung Medical Center, Seoul, Republic of

Korea; 8Department of Pediatrics, University of Ulsan, Asan Medical

Center, Seoul, Republic of Korea; 9Department of Pediatrics,

Yonsei University College of Medicine, Seoul, Republic of Korea;

——————10Sanofi-Synthelabo Korea Co., Ltd., Seoul, Republic of Korea;11Department of Pediatrics, Kyung Hee University College of

Medicine, Seoul, Republic of Korea.

The following are now working at the following institutions; Sun

Young Kim, Chungnam National University College of Medicine,

Daejeon, South Korea; Mee Jung Lee, Dankook University College of

Medicine, Cheonan, South Korea; and Sun Min Lee, Sungsam

Hospital, Daegu, South Korea.

Grant sponsor: Sanofi-Syntherlabo Korea.

*Correspondence to: Hyo Seop Ahn, Division of Hematology/

Oncology, Department of Pediatrics, Cancer Research Institute,

Seoul National University College of Medicine, Address: #28

Yongon-dong, Chongno-gu, Seoul 110-744, Korea.

E-mail: [email protected]

Received 10 January 2005; Accepted 28 June 2005

for hyperuricemia in countries where urate oxidase is not

available [9]. Allopurinol (4-hydroxypurinol) is an inhibitor

of the liver enzyme xanthine oxidase, which catalyzes the

breakdown of purines to uric acid. Hence, allopurinol inhibits

the ongoing formation of uric acid, but it does not degrade

pre-formed uric acid. Allopurinol administration also results

in the accumulation of upstream purine metabolites, notably

xanthine, which is even less soluble than uric acid and can

also cause renal failure [6,10].

Urate oxidase catalyzes the enzymatic oxidation of uric

acid to allantoin, a readily-excretable substance, which is 5–

10 times more soluble than uric acid. It is an endogenous

enzyme found in most mammals, but not in humans because

of a nonsense mutation in the coding region in the gene,

which occurred during hominoid evolution [11] Moreover,

rasburicase (Fasturtec), a recombinant form of urate oxidase,

has been shown to be a more effective agent than allopurinol

for correcting hyperuricemia in a multicenter randomized

trial [12].

This compassionate use study was undertaken to evaluate

the efficacy and safety of rasburicase for the treatment of

hyperuricemia and to provide a treatment opportunity by

supplying the study drug to Korean pediatric patients with

hematologic malignancies.

MATERIALS AND METHODS

Study Patients

From March 2003 to December 2003, a total of 38

pediatric patients were enrolled in this clinical study at 8

centers in the Republic of Korea. One patient was excluded

from the data analysis because the diagnosis was not a

hematologic malignancy. All the other 37 patients are

currently evaluable for efficacy analysis. Eligibility criteria

included acute hyperuricemia (uric acid> 7.5 mg/dl) in

pediatric patients (less than 18 years old) before/during

chemotherapy for hematologic malignancies with a mini-

mum life expectancy of 3 months, and signed written

informed consent from parents. The exclusion criteria were

hypersensitivity to uricase or any of the following: a known

history of glucose-6-phosphate reductase (G6PD) deficiency,

previous treatment with rasburicase or uricozyme, or

treatment with any other investigational drug within 30 days

before the planned first administration of rasburicase. The

institutional review board of each participating center

approved this study.

Treatment Design

This clinical study was an open-label, prospective, multi-

center, non-comparative, compassionate use, phase IV study.

The study period for each patient was 5 weeks and consisted

of a baseline assessment within 48 hr before the administra-

tion of the study drug, 3-5 days of assessment during

treatment, and a follow-up assessment at 4 weeks after the

final administration of the study drug. The dosage of

rasburicase (Fasturtec) was 0.2 mg/kg/day, once daily for

3-5 days by the intravenous route. However, the dose might

be repeated at 12-hr intervals during the first 72 hr of

chemotherapy if hyperuricemia persisted, or if the patient

was considered to be at significant risk of tumor lysis

complications (e.g., a large tumor, pre-existing hyperurice-

mia, or renal impairment). Adverse events that occurred

between the baseline and 1 week (7 days) after the

completion of rasburicase administration, were observed

and recorded. Outcomes of adverse events were observed

until the end of the 5-week study duration. All patients

receiving treatment with another hypouricemic agent

(allopurinol) at study entry discontinued the therapy before

beginning rasburicase treatment. All patients received

hydration according to the standard clinical practice at each

center. However, the use of alkalinized hydration (using

NaHCO3) was left to the discretion of the investigator.

Statistical Analysis

All patients who received at least one dose of rasburicase

were included in the analysis of safety. All the patients for

whom both pre- and post-treatment uric acid levels were

available, were included in the analysis of efficacy as well.

The efficacy rate of rasburicase in the treatment of

hyperuricemia was evaluated by assessing the number of

responses (defined as the achievement of the uric acid level

�7.0 mg/dl) per number of subjects included after the

completion of administration, and relevant frequencies,

percentages, and 95% exact confidence intervals were

analyzed. The difference of uric acid levels before treatment

and after the completion of the administration was evaluated.

The blood levels of creatinine, calcium, phosphorus, and

potassium were also evaluated before treatment and after the

completion of the administration. In order to compare

differences in uric acid, creatinine, calcium, phosphorus,

and potassium levels, we used a non-parametric method

(Wilcoxon signed rank test). The safety of rasburicase was

evaluated by analyzing all adverse events and clinical

laboratory values. Toxicity grades of adverse events were

classified according to NCI Common Toxicity Criteria 2.0

[13]. Investigators at each center categorized the relation-

ships between toxicities and the study drug as follows:

(definitely/probably/possibly/probably not/undetermined).

RESULTS

Patient Characteristics

The median age of enrolled patients was 8 (0–16)

years and the most common malignancy was acute

lymphoblastic leukemia (62.2%). There were three patients

with extreme hyperleucocytosis (WBC> 200� 109/l).

Presenting characteristics of the 37 patients are shown in

Table I.

Pediatr Blood Cancer DOI 10.1002/pbc

440 Shin et al.

Treatment and Response

Although the planned treatment duration was 3–5 days,

two patients received rasburicase treatment for only 1 day.

The first patient expired on the day of rasburicase adminis-

tration (day 1) due to disseminated intravascular coagulation

(DIC). In the second patient, rasburicase treatment was

discontinued from day 2 inadequately but the uric acid level

was maintained in normal range even after the discontinua-

tion. Rasburicase was skipped only on day 2 inappropriately

in one patient. A total of three patients received rasburicase

twice, at 12-hr interval, for only 1 day as their uric acid levels

did not return to normal after single dose.

Uric acid levels were checked one to six times within 24 hr

after the administration of rasburicase in all patients. The uric

acid endpoint (�7.0 mg/dl) was reached in 36 of the 37

patients with an efficacy rate of 97.3% (95% exact confidence

lower limit: 87.8%). Seven patients were treated for 5 days

owing to persisting risk of tumor lysis syndrome after 3 days

of rasburicase treatment. Among them, five patients received

chemotherapy from day 3 and one patient from day 2.

Remaining one patient had huge mediastinal mass (lympho-

blastic lymphoma), which persisted after 3 days of

chemotherapy with concomitant rasburicase administration.

In two patients, transient reappearance of hyperuricemia was

observed on day 3 and day 4, respectively after the

chemotherapy started from day 3 of rasburicase administra-

tion. One patient had acute lymphoblastic leukemia with

leukocyte count of 94.71� 109/L, and the other patient had

Burkitt lymphoma. Response rates by treatment day are

presented in Table II.

The uric acid levels were reduced in all patients including

three patients with extreme hyperuricemia (uric acid> 20

mg/dl) after the administration of rasburicase (Fig. 1). Uric

acid, phosphorus, and creatinine levels were significantly

decreased regardless of whether they received hemodialysis

(P< 0.0001, respectively). But the levels of calcium and

potassium were not changed after the administration of

rasburicase (Fig. 2).

Patients Requiring Hemodialysis

Four patients required hemodialysis. All four patients

presented with acute renal insufficiency at diagnosis before

rasburicase treatment. Three achieved resolution of hyper-

uricemia after rasburicase treatment. Among these, one

patient discontinued dialysis after the beginning of rasburi-

case but two patients continued dialysis for 1 or 2 days

owing to persistent azotemia. One who did not respond

to rasburicase (after 2 hr) died on that day due to DIC

(Table III).

Treatment Toxicities

During study drug administration, 33 patients (89.2%)

received concomitant chemotherapy. A total of 115 adverse

TABLE I. Characteristics of Analyzed 37 Patients

Age

0–4 13

5–9 12

10–14 11

15–18 1

Gender

Male 26

Female 11

ECOG Score

�1 17

2, 3, 4 20

Diagnosis

Non Hodgkin lymphoma 7

Burkitt (stage IV) 3

Anaplastic large T/null-cell (stage III) 1

Lymphoblastic (stage IV) 1

NK cell (stage IV) 2

Leukemia 30

Acute lymphoblastic 23

Acute myeloid 6

Acute mixed 1

Chemotherapy during 5 weeks of study period

Performed 35

First line 29

Relapsed or recurrent 6

Not performed (early death) 2

Start of chemotherapy

Before the treatment of rasburicase 17

During the treatment of rasburicase 16

Day 1 2

Day 2 7

Day 3 7

After the treatment of rasburicase 2

2 days after the final dose of rasburicase 1

3 days after the final dose of rasburicase 1

Previous treatment of hyperuricemia

Yes 34

Hydration 34

Alkalinization 33

Allopurinol 10

No 3

WBC (�109/L)

Median 8.31

Range 0.31–316.10

LDH (IU/L)

Median 1787

Range 180–24900

Uric acid (mg/dl)

Median 9.1

Range 7.7–57.9

TABLE II. Number of Responders After Treatment in a Total of37 Patients

Treatment

day

No. of treated

patients

No. (%) of

responders

1 37 32 (86.5)

2 34 34 (100)

3 34 33 (97.1)

4 7 6 (85.7)

5 7 7 (100)


Rasburicase for Hyperuricemia 441

events occurred in 32 patients (86.5%) with an average of 3.1

events per patient. Analysis showed that gastrointestinal

disorders (n¼ 37, 32.2%), and blood and lymphatic system

disorders (n¼ 14, 12.2%) occurred frequently. These were

usually associated with chemotherapy and the progression of

underlying diseases. The most frequently reported adverse

event was a headache (n¼ 11, 9.6%) followed by vomiting

(n¼ 9, 7.8%) and abdominal pain (n¼ 9, 7.8%). Five patients

(13.5%) experienced serious adverse events, including three

cases of death (n¼ 1, pulmonary hemorrhage, n¼ 2, DIC).

However, no serious adverse event was judged to be related to

the study drug.

Adverse events judged to be related with the study drug

(definitely/possibly/probably/undetermined categories) nu-

mbered 19 (16.5%) in total, whereas 96 events (83.5%) were

not related with the drug, thus demonstrating that most

adverse events were not related with the study drug. Of the

adverse events judged to be related, the ‘probably’ category

included SGOT/SGPT elevation (n¼ 4), nausea (n¼ 2),

vomiting (n¼ 2), and headache (n¼ 1), and the ‘possibly’

category included headache (n¼ 4), nausea (n¼ 2), vomiting

(n¼ 1), hyperbilirubinemia (n¼ 1), hypokalemia (n¼ 1),

and weight loss (n¼ 1) (Table IV). The cause of weight loss

was also associated with severe nausea and vomiting

occurring after rasburicase administration. All patients with

adverse events judged to be related with the study drug did

not discontinue rasburicase administration and recovered

without sequelae during the 4-week follow-up period after

the last administration of rasburicase.

DISCUSSION

Rasburicase is a safe and highly effective uricolytic agent

in patients with leukemia or lymphoma, including pediatric

patients with extreme hyperleucocytosis [14,15]. The results

of a study that compared the efficacy and safety of

rasburicase and allopurinol in patients with hematologic

malignancies at high risk of tumor lysis during induction/

reduction chemotherapy, demonstrated that more rapid

control and lower levels of uric acid were achieved in

patients who received rasburicase compared to allopurinol

[12].

Rasburicase is now available in Europe, Australia, United

States, and Southeast Asia for the prevention and treatment of

tumor lysis associated hyperuricemia. Before commerciali-

zation, compassionate use programs were conducted in these

geographic areas [16–18]. But the experience of rasburicase

has not yet been reported in East Asia, including China,

Japan, and Korea.

The results of the current study further support the high

efficacy of this drug in line with the United States

compassionate use study that showed a 98% efficacy rate in

pediatric cancer patients with hyperuricemia [18], and a

multi-national compassionate use study showing a 100%

efficacy rate in both adult and pediatric cancer treatment

groups [17]. A significant reduction in uric acid levels

between baseline and follow-up after final dose in the present

study including three patients with extreme hyper-

leucocytosis, also indicates that rasburicase is a highly

effective uricolytic agent, as previously reported [15]. A

significant reduction of phosphorus and creatinine levels was

also observed after final dose of rasburicase regardless of

whether patients received hemodialysis, which can be

considered as secondary effect of rasburicase.

Rasburicase was effective in patients with hyperuricemia

before chemotherapy, but the normalized uric acid levels

could be re-elevated after beginning chemotherapy, as in the

present study. Close monitoring of uric acid level and

continuous rasburicase treatment are necessary for patients at

high risk of tumor lysis syndrome after beginning che-

motherapy.

During the adverse event observation period from the first

day of administration to 1 week after treatment, a total of 115

adverse events occurred. Most events were related to

concomitant chemotherapy and the progression of under-

lying disease. One patient with huge mediastinal lymphoma

experienced grade 4 hyperkalemia with hyperphosphatemia,

hypocalcemia, azotemia, and an elevated creatinine level

after chemotherapy began, although he received potassium-

free hydration and the uric acid level was maintained in the

normal range by rasburicase. This patient did not receive

dialysis and recovered after slow administration of calcium

gluconate and continuous hydration.

Rasburicase could not prevent the complications of tumor

lysis syndrome that were secondary to hyperphosphatemia,

which is the second major cause of tumor lysis-associated

renal failure. Furthermore, alkalinization of the urine

increases the risk of calcium phosphate deposition (uric acid

is more soluble in an alkaline urine, but calcium phosphate is

more soluble in an acidic urine) [19]. Urinary alkalinization

facilitates renal clearance of uric acid, but close patient

monitoring is required during rasburicase treatment.

Fig. 1. Baseline Assessment of uric acid levels before the adminis-

tration, assessment during the 3–5 days of treatment period, and

assessment after the 4-week follow-up period. Uric acid levels were

reduced in all patients after the administration of rasburicase. In two

patients, the transient reappearance of hyperuricemia was observed after

the beginning of chemotherapy during the period of rasburicase

administration.


442 Shin et al.

Fig. 2. Uric acid, phosphorus, calcium, potassium, and creatinine levels at baseline and within 24 hr after final dose of rasburicase in all patients

(n¼ 37, A) or in patients who didn’t receive hemodialysis (n¼ 33, B). The box plots show median values (break in box), mean values (triangles),

interquartile ranges (25th to 75th percentile), and outlying values (vertical lines). Uric acid, phosphorus, and creatinine levels were significantly

decreased regardless of whether they received hemodialysis (P< 0.0001). But the level of calcium and potassium were not changed after the

administration of rasburicase.



Hemodialysis was performed in four patients (11.1%) due

to acute renal insufficiency that had occurred before the

administration of rasburicase. In three of them, uric acid and

creatinine levels were dramatically reduced after adminis-

tration of rasburicase, but in two of them, azotemia persisted.

This result also implies that factors other than uric acid could

compromise kidney function in tumor lysis syndrome, and

that in this case, renal insufficiency might not be improved by

the sole use of rasburicase, which again underlies the need for

close renal function monitoring during the treatment.

Urticaria occurred in one patient 3 days after the final

administration of rasburicase, though it was not associated

with the study drug. The non-recombinant form of urate

oxidase, uricozyme, is extracted from Aspergillus flavus, and

is a highly active uricolytic agent, but its use is associated

with hypersensitivity reaction in approximately 4.5% of

patients [20]. In the present study, patients received a

recombinant form of the enzyme, rasburicase, and no allergic

reaction was observed in any patient, thus demonstrating a

low prevalence of hypersensitivity to rasburicase, which is in

line with previous reports [12,16].

G6PD deficiency is contraindicated for the use of

rasburicase. One of the by-products of the breakdown of

uric acid to allantoin is hydrogen peroxide, which can induce

hemolytic anemia or methemoglobinemia in patients with

G6PD deficiency [14]. G6PD deficiency is very rare in Korea

[21,22]. During rasburicase treatment, no hemolytic event

occurred in the present study.

Based on these efficacy and safety results, we confirm that

rasburicase is a safe and highly effective drug for the

treatment of hyperuricemia in pediatric patients with

hematologic malignancies.

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TABLE III. Patients that Received Hemodialysis

Patient

number

Baseline features After final rasburicase treatment

OutcomeAge/sex Diagnosis

BUN/creatinine

(mg/dl)

Uric acid

(mg/dl)

BUN/creatinine

(mg/dl)

Uric acid

(mg/dl)

3 3/M Burkitt lymphoma 53.0/2.0 8.2 9.0/0.4 0.5 Recovered

19a 2/M NK cell lymphoma 34.2/1.4 14.9 31.0/1.4 10.5b Death

(DIC)

21 11/M Acute lymphoblastic

leukemia

93.4/4.4 8.0 45.4/1.6 0.1 Recovered

33a 0/M Acute lymphoblastic

leukemia

116.0/3.9 57.9 59.0/0.6 0.5 Recovered

aPatients who continued hemodialysis after initiation of rasburicase treatment owing to persistent azotemia; bUric acid level started to decrease in

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treatment.

TABLE IV. Adverse Events Judged to be Related With theStudy Drug

Adverse Events Toxicity grade No. of patients (%)

Nausea 1 3 (8.1)

2 1 (2.7)

Vomiting 1 1 (2.7)

2 2 (5.4)

SGOT/SGPT elevation 2 1 (2.7)

3 3 (8.1)

Hyperbilirubinemia 2 1 (2.7)

Hypokalemia 3 1 (2.7)

Weight loss 1 1 (2.7)a

Headache 1 2 (5.4)

2 2 (5.4)

aWeight loss owing to severe nausea and vomiting after rasburicase

administration.


444 Shin et al.

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