Gout and Nucleic Acid Metabolism Vol.41 No.

2（2017） 183

原著２

Successful use of rasburicase for management of tumor lysis

syndrome after the approval of febuxostat for cancer-associated
hyperuricemia: A single-institution experience
Mihoko Morita1）* Kana Oiwa1）*
Kei Fujita1） Eiju Negoro1）
Miyuki Okura1） Yasufumi Matsuda1）
Katsunori Tai1） Naoko Hosono1）
Misato Kawamichi2） Takanori Ueda1）
Takahiro Yamauchi1）

Abstract dL) (P<0.0001, by paired t test). Serum creatinine

Tumor lysis syndrome (TLS) is a life threatening
- levels also decreased from 1.2±0.4 to 0.8±0.2 mg / dL
complication caused by the massive death of (P=0.0001, by paired t test), suggesting that controlling
cancer cells upon chemotherapy. Lowering serum UA might potentially improve the renal function. Not
uric acid (S UA) levels is crucial to controlling
- all patients demonstrated a concomitant reduction in
TLS. Febuxostat was approved for use in treating lactate dehydrogenase levels, which suggested that
chemotherapy associated hyperuricemia in May 2016.
- S- UA was successfully controlled by rasburicase
Rasburicase and febuxostat are now the major UA- despite the residual amount of cancer cells. Thus,
reducing agents ; the former for high risk, the latter for rasburicase was successfully used for appropriate
intermediate risk. The present study retrospectively patients after the febuxostat era.
evaluated the efficacy of rasburicase in cancer patients
in our institution after the approval of febuxostat of Introduction
this use (June 2016 – January 2017). The primary Tumor lysis syndrome (TLS) is a life-threatening
endpoint was the normalization of S-UA at the end complication caused by the sudden and massive death
of rasburicase administration. Rasburicase was used of cancer cells upon chemotherapy1 6）. Intracellular
-

in 12 patients with hematological malignancies in the metabolites are rapidly released from lysed cells
designated period. Eight patients were at high risk of to the circulating blood, which include proteins,
TLS, while 2 patients had already developed TLS. potassium, phosphorus, and nucleic acids. This may
The median dose administered was 0.2 mg / kg, and result in hyperkalemia, hyperphosphatemia, and
the median duration was 5 days. The S UA at the
- hyperuricemia, thereby inducing renal insufficiency,
baseline (10.4±3.0 mg / dL, mean±SD) was decreased cardiac arrhythmias, seizures, neurological disorders,
below the normal levels in all patients (0.3±0.2 mg / and ultimately death1 6）. However, TLS is preventable
-

受付：2017年5月7日，受理：2017年9月20日
1 ）Department of Hematology and Oncology
2 ）Department of Pharmacy, University of Fukui
* MM and KO equally contributed to the present study.
Key words: Tumor lysis syndrome ; rasburicase ; hematological malignancy ; hyperuricemia.
Correspondence to: Takahiro Yamauchi, Department of Hematology and Oncology, Faculty of Medical Sciences,
University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Fukui 910-1193, Japan.
184
at an early stage, and for this purpose, it is needed to
evaluate the risk of TLS in each patient.
Japanese TLS guidance, which was published by the
Japanese Society of Medical Oncology in 2013, shows
a medical decision tree to assign a low (TLS frequency
<1%), intermediate (TLS frequency 1-5%), and high
risk (TLS frequency >5%) of TLS to patients with
cancer . This originates from International TLS expert
7）
consensus panel guideline . Patients are classified into
3）
low-, intermediate-, and high-risk groups based on
the type of malignancy, white blood cell count, lactate
dehydrogenase (LD) level, type of therapy, presence
of renal dysfunction, and levels of uric acid (UA),
phosphorus, and potassium. This risk stratification
enables the appropriate management of each group7）.
The major component of the management of TLS
is the reduction in serum uric acid (S-UA) level by
drugs that decrease the production of UA or degrade
UA7）. Hyperuricemia results from the rapid catabolism
of purine containing nucleic acids derived from
- The present study retrospectively evaluated
collapsed cancer cells, since purine nucleotides are
converted to hypoxanthine, xanthine, and finally
to UA by xanthine oxidase 6）. Two UA - lowering
agents, a conventional xanthine oxidase inhibitor,
allopurinol, and a recombinant uricase, rasburicase,
are recommended ; the former for intermediate risk
for TLS and the latter for high risk or the patients who
already develop TLS7）.
Allopurinol sometimes induces skin rashes,
h ype rs e n si t i vi t y, a nd hep ati c dysf unct ion 8,9）.
Importantly, some patients at risk of TLS are
complicated by renal dysfunction, which would be a
limitation to the use of allopurinol, because the drug
is primarily excreted from the kidney. A non-purine
analog, febuxostat, is a more selective and potent
inhibitor of xanthine oxidase than allopurinol, exhibits
less adverse reactions, and possesses renal and hepatic
excretion pathways10）. This suggested that febuxostat
would be a more appropriate agent than allopurinol for
TLS. Our previous studies demonstrated its excellent
痛風と核酸代謝　第 41 巻　第 2 号（平成 29 年）
UA-lowering efficacy in patients at an intermediate
risk for TLS11,12）. The agent was approved for the use
in the management of hyperuricemia associated with
cancer chemotherapy, which is TLS, in May of 2016
in Japan. Thus, febuxostat and rasburicase are now the
major agents employed in the management of TLS.
Rasburicase is a recombinant form of Aspergillus-
derived urate oxidase expressed in a Saccharomyces
cerevisiae vector13,14）, which metabolizes UA to the
much more soluble allantoin. The approved method of
administration in Japan is 0.2 mg / kg once daily as an
intravenous infusion over 30 minutes for maximally
7 days (RASURITEK. Interview Form, 2012). The
UA-lowering efficacy of rasburicase is quite prompt
and potent 13,14）. Nevertheless, the use of rasburicase
is limited only once due to its immunogenicity.
Therefore, rasburicase and febuxostat should be
separately used for patients depending on the risk of
TLS.
the efficacy of rasburicase in cancer patients in
our institution after the approval of febuxostat for
managing TLS. Rasburicase might be used more
properly for selected patients after the introduction
of febuxostat, because the former is expensive and
immunogenic.
Patients and Methods
Patients.
This was a retrospective observation study.
Patients admitted to the University of Fukui Hospital
between June 2016 and January 2017 were evaluated.
They were all newly diagnosed with hematological
malignancies and received rasburicase intravenously
during induction chemotherapy.
Evaluation of TLS.
The risk classification for TLS was made based
on Japanese TLS guidance7）. Diseases at a high risk
for TLS included acute myeloid leukemia / acute
Gout and Nucleic Acid Metabolism Vol.41 No.2（2017）
lymphoblastic leukemia with a peripheral white blood
cell count >100,000 /μL, diffuse large B cell non - All statistical analyses were performed using
Hodgkin's lymphoma with elevated LD or a bulky
mass, and Burkitt lymphoma7）. TLS is divided into
laboratory TLS and clinical TLS. Laboratory TLS
is defined according to 2 abnormal serum values
among UA, potassium, and phosphorus 7）. Clinical
TLS requires the presence of clinical manifestations
(increased creatinine, cardiac arrhythmia, and seizure)
in addition to laboratory TLS. The treatment algorithm
was based on the guidance .7）
Categorizing the type of hyperuricemia.
Hyperuricemia is categorized into the following
3 types : "UA- overproduction type," "UA-
underexcretion type," and "combined type," according
to the guidelines for the management of hyperuricemia
and gout published in Japan in 2010 . Urinary UA
15）
excretion and UA clearance rate were determined
for the categorization (urinary UA excretion > 0.51
mg / kg / h and UA clearance rate > 7.3 mL / min for
overproduction type ; urinary UA excretion < 0.48
mg / kg / h or UA clearance rate < 7.3 mL / min for
underexcretion type ; UA excretion > 0.51 mg / kg /
h and UA clearance rate < 7.3 mL / min for combined
type).
Assessments of UA-lowering efficacy of
rasburicase.
Rasburicase was administered to patients within
24 h of the initiation of induction chemotherapy for
underlying diseases. The standard method of drug
administration is 0.2 mg / kg / day for maximally
7 days, which is covered by the national health
insurance system in Japan. The dose and duration of
administration was modified by the level of S- UA
according to the physicians' decision. The primary
endpoint was the normalization of S-UA ( ≤ 7 mg / dL)
at the end of rasburicase treatment.
185
Statistical analyses.
Microsoft Excel 2013 software (Microsoft, Redmond,
WA, USA). All graphs were generated using GraphPad
Prism software (version 6.0) (GraphPad Software,
Inc., San Diego, CA, USA).
Results
Patient backgrounds.
Rasburicase was used in a total of 12 patients
between June 2016 and January 2017 (Table 1). Their
median age was 73 years (range, 43-86 years) with
3 males and 9 females. Eight patients were at a high
risk of TLS, while 2 patients already developed TLS.
The diagnosis included acute leukemias and malignant
lymphomas. Rasburicase was also administered to the
patients with multiple myeloma. The TLS guidance
classified multiple myeloma as a low-risk disease for
TLS (less than 1%), but our recent study indicated that
multiple myeloma treated with bortezomib developed
TLS more frequently (17.5%) than the estimated
low risk 16）. Rasburicase was therefore used in these
patients.
Categorization of hyperuricemia.
Six patients (No. 1, 3, 8, 10, 13, and 14) were
examined for the categorization of hyperuricemia.
All patients exhibited the overproduction of UA,
with one patient of combined type (Table 2). This is
in accordance with the mechanism of hyperuricemia
induced by TLS.
Method of administration of rasburicase.
Within 24 h of the initiation of chemotherapy,
rasburicase was administered at different doses for
various durations adjusted to patients (Table 3). Most
of the patients received the standard dose (0.2 mg / kg).
The median duration of administration was 5 days.
186 痛風と核酸代謝　第 41 巻　第 2 号（平成 29 年）

Table 1 Patient characteristics

Age WBC LD UA Cr K P TLS LTLS /
No. Dx eGFR
/ Sex (x102/µL) (IU / L) (mg/dL) (mg /dL) (mEq /L) (mg/dL) risk CTLS
1 43 / M AML 1,179 2,627 5.5 1.13 3.5 3.5 55.2 High (-)/(-)
2 66 / F DLBCL 69 513 6.6 0.84 4.3 4.6 46.1 High (-)/(-)
3 73 / F MM 48 1,263 10.3 1.27 3.9 3.0 44.3 Low (-)/(-)
4 61 / M ATL 393 533 12.2 1.99 3.8 4.6 28.2 High (-)/(-)
5 86 / F MM 617 236 12.9 1.32 4.0 2.3 29.5 Low (-)/(-)
6 86 / F PTCL 234 559 4.5 0.92 4.6 4.0 40.4 High (-)/(-)
7 52 / M DLBCL 206 6,310 7.0 1.02 4.0 5.5 59.8 High (-)/(-)
8 83 / F DLBCL 127 286 9.5 1.35 5.4 4.7 － － (+) / (+)
9 72 / F DLBCL 80 351 13.4 1.89 4.2 4.8 20.9 － (+) / (+)
10 74 / F ALL 26,400 4,884 12.3 0.91 3.9 2.4 46.2 High (-)/(-)
11 66 / F Burkitt 89 644 13.1 0.87 3.7 3.1 50.2 High (-)/(-)
12 80 / F AML 2,480 1,308 10.8 1.52 2.9 3.7 25.3 High (-)/(-)
Dx, diagnosis ; AML, acute myeloid leukemia ; DLBCL, diffuse large B-cell lymphoma ; ATL, adult T-cell leukemia ; MM,
multiple myeloma ; ALL acute lymphoblastic leukemia ; Burkitt, Burkitt lymphoma ; LD, lactate dehydrogenase ; UA, uric
acid ; Cr, creatinine ; eGFR, estimated glomerular filtration rate (mL / minute / 1.73 m2) ; TLS, tumor lysis syndrome ; LTLS,
laboratory TLS ; CTLS, clinical TLS. -, not determined.

Table 2 Classification of hyperuricemia Table 3 Chemotherapies and the

administration of rasburicase
No. U-UA C-UA Type of hyperuricemia
Rasburicase
1 0.98 21.6 Overproduction No. Anticancer agents
(mg/kg) (days)
3 0.88 11.0 Overproduction
8 0.51 3.3 Combined 1 Ara-C 0.20 5
10 0.78 10.0 Overproduction 2 CPA, ADR, VCR, DEX, RIT 0.20 6
13 1.27 21.8 Overproduction 3 BOR, DEX 0.18 4
14 1.90 12.5 Overproduction 4 CPA, ADR, VCR, PSL 0.20 7
5 BOR, DEX 0.20 10
U-UA, urinary uric acid excretion (normal range : 0.483-
6 CPA, ADR, VCR, PSL 0.20 3
0.509 mg / kg) ; C-UA, uric acid clearance (normal range :
7.3-14.7 mL / min). 7 CPA, ADR, VCR, DEX, RIT 0.20 7
8 CPA, ADR, VCR, PSL, RIT 0.14 3
9 CBDCA, IFO, ETOP, RIT 0.20 4
10 CPA, ADR, VCR, PSL 0.20 6
11 CPA, ADR, VCR, PSL 0.20 5
12 Ara-C, DNR 0.20 5
Ara-C, cytarabine ; DNR daunorubicin ; CPA,
cyclophosphamide ; VCR vincristine ; ADR, Adriamycin ;
D EX , dexamethas one ; P S L, pr ednis olone ; RIT,
rituximab ; BOR, bortezomib ; CBDCA, carboplatin ; IFO,
ifosfamide ; ETOP, etoposide.
Gout and Nucleic Acid Metabolism Vol.41 No.2（2017） 187

UA-lowering efficacy. drug administration (Figures 1E,F). This suggested

The primary endpoint was the normalization that S -UA was successfully controlled by rasburicase
of S - UA (≤7.0 mg / dL) at the end of rasburicase despite the residual amount of cancer cells.
treatment. The baseline S UA was 10.4±3.0 mg /
-

dL (mean±SD), and S-UA at the end of rasburicase Discussion

administration was 0.3±0.2 mg / dL (mean±SD)
(P<0.0001, by paired t test) (Table 4, Figure 1A). All
patients therefore met the primary endpoint. The renal
function was also evaluated in the same manner. The
baseline S-Cr was 1.2±0.4 mg / dL (mean±SD), and
S Cr at the end of rasburicase administration was
- was administered mostly to patients with a high risk
0.8±0.2 mg / dL (mean±SD) (P=0.0001, by paired
t test)(Table 4, Figure 1B). Estimated glomerular
filtration rate values are also elevated after rasburicase
treatment in most patients (Table 4, Figure 1C). These
results suggested that controlling UA might potentially
improve renal function. Moreover, the change in LD
values was also determined. LD is one of surrogate
markers to estimate the tumor burden. LD values
entirely decreased after the initiation of chemotherapy
(from 601.5 to 551.5, the means), but not all patients
demonstrated LD reduction (Table 4, Figure 1D).
Potassium and phosphorus normalized at the end of
The present study retrospectively evaluated
the indication and efficacy of rasburicase for
the management of TLS after febuxostat had
been approved for controlling cancer - associated
hyperuricemia. The study revealed that rasburicase
of TLS or the patients who already developed TLS
(Table 1). They were not candidates for the use of
febuxostat. Despite the residual cancer cells, S- UA
was dramatically reduced with the improvement of
renal dysfunction (Table 4, Figure 1).
We previously investigated the clinical efficacy of
febuxostat for the management of intermediate risk of
TLS12）. Ten patients (4 males, 6 females ; median age,
67 years ; age range, 52-79 years) with hematological
malignancies were treated with febuxostat along with
the induction chemotherapy. The dose of febuxostat
was modified according to the renal function ; 60 mg /

Table 4 Parameters after the completion of administration of anticancer agents

WBC LD UA Cr
No. eGFR
(x102 / µL) (IU / L) (mg / dL) (mg / dL)

1 3 1,108 0.4 0.69 100.3

2 126 566 0.2 0.54 84.5
3 88 1,975 0.4 0.89 －
4 66 312 0.9 1.22 －
5 343 244 0.2 1.03 26.6
6 75 537 0.2 0.64 65.6
7 54 2,743 0.4 0.83 76.5
8 4 197 0.2 0.94 －
9 12 290 0.8 0.98 41.1
10 148 3,075 0.3 0.6 72.9
11 96 713 0.3 0.67 66.9
12 11 471 0.2 0.49 －
Dx, diagnosis ; LD, lactate dehydrogenase ; UA, uric acid ; Cr, creatinine ; eGFR, estimated glomerular
filtration rate (mL / minute /1.73 m2). -, not determined.
188 痛風と核酸代謝　第 41 巻　第 2 号（平成 29 年）

A All patients B All patients C All patients

15 2.5 120

Creatinine(mg/dL)
100
Uric acid(mg/dL)

2.0
10 80
1.5

eGFR
60
1.0
5 40
0.5 20
0 0.0 0
base line EOT base line EOT base line EOT

D All patients E All patients F All patients

10000 6 6

Phosphorus(mg/dL)
Potassium(mEq/L)

4 4
LD(IU/L)

1000
2 2

0 0
base line EOT base line EOT base line EOT

Figure 1. The reduction in serum levels of uric acid (UA) (A), creatinine (Cr) (B), eGFR (C),
lactate dehydrogenase (LD) (D), potassium (E), and phosphorus (F) during induction
chemotherapies with the concomitant use of rasburicase in all the patients. The values
were determined at baseline and at the end of rasburicase administration. eGFR,
estimated glomerular filtration rate (mL/minute/1.73 m2). EOT, end of treatment.

day for patients with a estimated glomerular filtration dL with the white blood cell count of 1,900 /μL after
rate >90 mL / minute / 1.73 m2 and 40 mg / day ≤ 90 5 - day drug administration. This indicated that 60
mL / minute / 1.73 m . The primary endpoint was the
2
mg febuxostat effectively lowered S - UA (from 6.9
reduction of S UA to ≤ 7.5 mg / dL by day 5. The
- to 3.0 mg / dL for 5 days) in a cancer chemotherapy
median S- UA at base line was 8.0 mg / dL, and the setting. Nevertheless, the efficacy of rasburicase is
median S-UA on day 5 after chemotherapy was 3.3 apparently much stronger (Table 4, Figure 1) than that
mg / dL, indicating successful control of S-UA during of febuxostat, suggesting rasburicase as the first choice
chemotherapy. In addition, after the official approval for managing TLS cases such as progressing renal
of febuxostat for TLS, we had one representative dysfunction or hyperuricemia > 10 mg / dL.
patient (67 years, male, acute myeloid leukemia) with Multiple myeloma is a neoplastic proliferation
an intermediate risk of TLS, who received 60 mg of plasma cells in bone marrow. The disease
febuxostat along with induction chemotherapy using induces anemia, bone fractures, hypercalcemia,
cytarabine and daunorubicin. S - UA was 6.9 mg / renal dysfunction, and amyloidosis. The TLS
dL and a white blood cell count was 29,000 /μL (80% risk of multiple myeloma is regarded to be
blasts) at the start. S UA was reduced to 3.0 mg /
- low by Japanese TLS guidance and other
Gout and Nucleic Acid Metabolism Vol.41 No.2（2017）
TLS guidelines 2,3,7）. There have been significant
advancements in the treatment of multiple myeloma in
the past 10 years17）, and new classes and combinations
of drugs, including proteasome inhibitor bortezomib
and immunomodulatory drugs, have led to the
increased survival of patients. Our recent study
demonstrated that TLS occurred in 13 (10.5%) out of
124 chemotherapy courses (bortezomib, thalidomide,
lenlidomide, adriamycin, and prednisolone) in
patients with multiple myeloma16）. The incidences of
TLS further increased to 17.5% in myeloma patients
receiving bortezomib - containing regimens. TLS
occurred more frequently in the patients with elevated
uric acid, creatinine, or beta-2-microglobulin levels at
the baseline. Because 2 patients (No.3, 5) with multiple
myeloma had hyperuricemia and received bortezomib-
containing regimen, rasburicase not febuxostat
would be an appropriate agent for them. The prompt
reduction of S - UA was beneficial, especially in
patients with myeloma, because it improved the renal
function (Table 4, Figures 1B,C).
The present study demonstrated that rasburicase
was used in cancer patients with high risk or already
having TLS. Since many, new molecularly targeted
agents has been introduced to many cancer types, the
incidence of TLS may increase in cancers that have
previously been regarded as low risk diseases. The
risk classification may change by the recruitment of
new treatment modalities. Rasburicase and febxostat
will be properly selected by the TLS risk. The present
study did not reveal the most appropriate dose and
schedule for rasburicase administration. Moreover, all
the patients with TLS might not respond to rasburicase
treatment, although its UA- lowering effect is quite
potent. We had one leukemic patient (74 years, male)
with laboratory TLS, who was treated with rasburicase
(0.2 mg / kg, 2 days) for his hyperuricemia (S- UA
17.2 mg / dL) before the initiation of the induction
chemotherapy. S - UA was unsuccessfully reduced
to 7.0 mg / dL. This patient was not included in this
189
study because he did not meet the inclusion criteria
of the study period. Close attention should thus be
paid to this oncologic emergency despite the use of
rasburicase. Careful monitoring of S-UA levels may
individualize the dose and duration. Rasburicase
should be used in proper quantities in the right patients
to fulfil the chemotherapy without interruption for
maximal anticancer effects.
Disclosure statement
The authors indicated no conflict of interest
regarding the present study.
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