Introduction
Tumor lysis syndrome (TLS) is considered to be an
oncological emergency that may result in severe metabolic
abnormalities, including hyperuricemia, hyperkalemia,
hyperphosphatemia and hypocalcemia, in patients with rapidly
proliferating and chemosensitive malignancies, such as high-grade
lymphoma or acute lymphoblastic leukemia (1,2). The
prevention and management of TLS includes aggressive hydration and
reduction or increase in the excretion of uric acid (UA) (3).
Allopurinol or febuxostat decrease the production of
UA by inhibiting the enzyme xanthine oxidase and blocking the
oxidation of xanthine. Therefore, following allopurinol or
febuxostat administration, there is a time lag prior to the
reduction in UA levels. By contrast, rasburicase, a recombinant
urate oxidase, catalyzes the conversion of UA to allantoin, rapidly
reducing UA levels (4). Although
several studies have been conducted with the use of fixed,
low-dose, or single-dose rasburicase (5–7), the
manufacturer recommends a dose of 0.2 mg/kg daily to be
administered for up to 7 days in Japan.
The objective of this retrospective review was to
examine the incidence of TLS in patients with hematological
malignancies treated with rasburicase and to evaluate the dose and
duration of rasburicase administration.
Patients and methods
Patients
A total of 52 patients with hematological
malignancies who received rasburicase at the Ogaki Municipal
Hospital (Ogaki, Japan) between August, 2011 and July, 2016 were
enrolled. The study protocol was reviewed and approved by the
Ethics Committee at Ogaki Municipal Hospital (20161124–6).
Patient background
The backgrounds of patients who received rasburicase
were investigated to determine their gender, age, weight,
rasburicase administration, diagnosis, concomitant therapy for TLS,
TLS risk category, spontaneous TLS, serum UA, potassium, phosphate,
calcium and creatinine levels prior to and following rasburicase
administration.
Incidence of TLS
The incidence of laboratory TLS (LTLS) and clinical
TLS (CTLS) were examined. The TLS risk was classified based on the
report by Calio et al (8).
First, patients were required to have ≥2 of the following
abnormalities: Increased UA, increased potassium, increased
phosphate, or decreased calcium, in order to be defined as having
LTLS within 3 days prior to or up to 7 days after the initiation of
chemotherapy. CTLS was diagnosed in patients with abnormalities
such as increased serum creatinine level, seizures and cardiac
dysrhythmia or death while experiencing LTLS.
Comparison among TLS risk
categories
Hematological malignancies were classified into
high-risk disease (HRD), intermediate-risk disease (IRD) and
low-risk disease (LRD) groups based on their TLS risk. The
rasburicase daily dose, duration and total dose were evaluated and
compared among different groups. In addition, serum UA, potassium,
phosphate, calcium and creatinine levels were evaluated at
baseline, at 24 h and 7 days after rasburicase administration.
Comparison of incidence of LTLS
The same comparison was performed between the LTLS
and non-LTLS groups.
Cost simulation
The difference in the total cost of rasburicase at
the dose administered in the present study and at the weight-based
dose approved in Japan was assessed. A simulation of the estimated
cost if all patients were administered rasburicase for 5 days was
also created. The costs were calculated using Japanese medicine
prices as of November, 2016.
Statistical analysis
The data were analyzed using JMP software, version
5.0.1J (SAS Institute Japan Ltd., Tokyo, Japan). The Mann-Whitney
U-test was used for the comparison of the patient backgrounds
between the LTLS and the non-LTLS groups. The Kruskal-Wallis test
was used for comparisons among each TLS risk categories. The
recorded P-values were two-sided and P<0.05 was considered to
indicate a statistically significant difference.
Results
Patient background
The baseline characteristics of the 52 patients who
received rasburicase are listed in Table
I. The median daily dose of rasburicase administered to all
patients was 7.5 mg/day (interquartile range, 7.5–9.0 mg/day) and
the daily weight-based dose was 0.147 mg/kg/day (interquartile
range, 0.126–0.178 mg/kg/day). The administration duration was 3
days (interquartile range, 3–4 days) and the total dose was 22.5 mg
(interquartile range, 22.5–30.0 mg). A total of 17 patients (32.7%)
had leukemia and 35 (67.3%) had malignant lymphoma; 19 patients had
HRD (36.5%), 23 had IRD (44.2%) and 10 had LRD (19.2%) in the TLS
risk categories; 5 patients (9.6%) had spontaneous TLS (presence of
TLS prior to chemotherapy initiation).
 | Table I.Baseline characteristics of the study
patients (n=52). |
Table I.
Baseline characteristics of the study
patients (n=52).
| Characteristics | Study population, n
(%) |
|---|
| Gender |
|
| Male | 27 (51.9) |
|
Female | 25 (48.1) |
| Age, years |
|
| Median
(interquartile range) | 68 (58–76) |
| Weight, kg |
|
| Median
(interquartile range) | 57.6 (49.2–63.
2) |
| Rasburicase
administration |
|
| Daily
dose, mg/day | 7.5 (7.5–9.0) |
| Daily
weight-based dose, mg/kg/day | 0.147
(0.126–0.178) |
| Duration,
days | 3 (3–4) |
| Total
dose, mg | 22.5 (22.5–30.0) |
|
Weight-based dose | 13 (25.0) |
| Single
fixed dose (7.5 mg/day) | 33 (63.5) |
| Diagnosis |
|
|
Leukemia |
|
| Acute
lymphoblastic leukemia | 8 (15.4) |
| Acute
myelogenous leukemia | 8 (15.4) |
| Chronic
myelogenous leukemia | 1 (1.9) |
|
Lymphoma |
|
| Diffuse
large B-cell lymphoma | 18 (34.6) |
|
Peripheral T-cell
lymphoma | 3 (5.8) |
| Mantle
cell lymphoma | 2 (3.8) |
|
Follicular lymphoma | 2 (3.8) |
|
Angioimmunoblastic T-cell
lymphoma | 2 (3.8) |
|
Anaplastic large-cell
lymphoma | 2 (3.8) |
| Adult
T-cell lymphoma | 1 (1.9) |
| Hodgkin's
disease | 1 (1.9) |
| Other
lymphomas | 4 (7.7) |
| Concomitant therapy
for TLS |
|
|
Allopurinol or febuxostat | 26 (50.0) |
|
Hydration | 52 (100.0) |
| TLS risk
category |
|
| High-risk
disease | 19 (36.5) |
|
Intermediate-risk disease | 23 (44.2) |
| Low-risk
disease | 10 (19.2) |
| Spontaneous
TLSa |
|
|
Laboratory TLS | 5 (9.6) |
Incidence of TLS
The incidences of TLS are listed in Table II. Overall, 24 patients (46.2%)
developed LTLS. Among these, 30 (57.7%) had hyperuricemia, 6
(11.5%) had hyperkalemia, 17 (32.7%) had hyperphosphatemia and 18
(34.6%) had hypocalcemia. Additionally, 2 of the patients (3.8%)
developed CTLS (only increased serum creatinine level).
| Table II.Incidence of tumor lysis syndrome. |
Table II.
Incidence of tumor lysis syndrome.
| Findings | N (%) |
|---|
| Laboratory TLS | 24 (46.2) |
|
Hyperuricemia | 30 (57.7) |
|
Hyperkalemia | 6
(11.5) |
|
Hyperphosphatemia | 17 (32.7) |
|
Hypocalcemia | 18 (34.6) |
| Clinical TLS | 2 (3.8) |
| Increased
creatinine level | 2 (3.8) |
|
Seizures | 0 (0.0) |
| Cardiac
dysrhythmia | 0 (0.0) |
|
Death | 0 (0.0) |
Comparison among TLS risk
categories
A comparison of the rasburicase doses and laboratory
data in the HRD, IRD and LRD groups is shown in Table III. There was no significant
difference among the groups.
| Table III.Comparison of the rasburicase
treatment doses and laboratory data among tumor lysis syndrome risk
categories. |
Table III.
Comparison of the rasburicase
treatment doses and laboratory data among tumor lysis syndrome risk
categories.
|
| HRD | IRD | LRD | P-value |
|---|
| Rasburicase
administration |
| Daily
dose, mg/day | 7.5 (7.5–9.0) | 7.5 (7.5–7.5) | 7.5 (7.5–7.5) | 0.928 |
| Daily
weight-based dose, mg/kg/day | 0.152
(0.147–0.181) | 0.140
(0.124–0.174) | 0.132
(0.116–0.181) | 0.495 |
| Duration,
days | 3 (3–4) | 3 (3–4) | 4 (3–4) | 0.382 |
| Total
dose, mg | 27.0 (22.5–33) | 22.5 (22.5–34.5) | 22.5 (22.5–30.0) | 0.392 |
| Serum UA, mg/dl |
|
Baseline | 5.5 (4.0–10.7) | 5.6 (2.9–7.9) | 4.5 (3.8–6.0) | 0.516 |
| 24 h
after rasburicase administration | 0.1 (0.1–0.1) | 0.1 (0.1–0.2) | 0.1 (0.1–0.1) | 0.271 |
| 7 days
after rasburicase administration | 2.1 (1.6–3.0) | 2.1 (1.3–3.0) | 1.9 (1.3–3.6) | 0.895 |
| Serum potassium,
mEq/l |
|
Baseline | 4.0 (3.6–4.1) | 4.2 (3.7–4.5) | 4.1 (4.0–4.2) | 0.438 |
| 24 h
after rasburicase administration | 3.9 (3.7–4.2) | 4.2 (3.8–4.4) | 4.1 (3.9–4.3) | 0.540 |
| 7 days
after rasburicase administration | 4.2 (3.6–4.4) | 3.9 (3.6–4.6) | 4.2 (4.1–4.3) | 0.810 |
| Serum phosphate,
mg/dl |
|
Baseline | 3.0 (3.0–3.5) | 3.6 (3.0–3.9) | 3.0 (3.0–3.5) | 0.263 |
| 24 hl
after rasburicase administration | 3.6 (3.0–4.4) | 3.7 (2.9–4.6) | 3.0 (2.8–3.3) | 0.161 |
| 7 days
after rasburicase administration | 3.0 (2.7–4.3) | 3.6 (3.0–4.2) | 3.0 (2.8–3.3) | 0.277 |
| Serum calcium,
mg/dl |
|
Baseline | 8.7 (8.5–8.9) | 8.5 (8.3–8.9) | 8.6 (8.4–8.9) | 0.962 |
| 24 h
after rasburicase administration | 8.5 (8.0–8.9) | 8.3 (7.6–8.6) | 8.4 (8.3–8.7) | 0.493 |
| 7 days
after rasburicase administration | 8.4 (7.7–8.8) | 8.4 (7.8–8.6) | 8.6 (8.2–8.7) | 0.466 |
| Serum creatinine,
mg/dl |
|
Baseline | 0.61 (0.56–1.06) | 0.68 (0.57–0.93) | 0.63 (0.52–0.83) | 0.541 |
| 24 h
after rasburicase administration | 0.58 (0.52–1.03) | 0.59 (0.46–0.92) | 0.58 (0.43–0.75) | 0.367 |
| 7 days
after rasburicase administration | 0.57 (0.47–0.77) | 0.51 (0.47–0.61) | 0.54 (0.51–0.70) | 0.971 |
Comparison between LTLS and non-LTLS
groups
A comparison between the LTLS and the non-LTLS
groups is shown in Table IV. The
baseline data for serum UA and creatinine levels in the LTLS group
were significantly higher compared with those of the non-LTLS
group. Additionally, the data obtained 24 h after rasburicase
administration for serum phosphate and creatinine levels in the
LTLS group were significantly higher compared with those in the
non-LTLS group. There was no significant difference in serum
potassium at any point (baseline, 24 h, or 7 days after rasburicase
administration).
| Table IV.Comparison of rasburicase treatment
doses and laboratory data between laboratory and non-laboratory TLS
groups. |
Table IV.
Comparison of rasburicase treatment
doses and laboratory data between laboratory and non-laboratory TLS
groups.
|
| Laboratory TLS
(n=24) | Non-laboratory TLS
(n=28) | P-value |
|---|
| Rasburicase
administration |
| Daily
dose, mg/day | 7.5 (7.5–9.0) | 7.5 (7.5–9.0) |
0.410 |
| Daily
weight-based dose, mg/kg/day | 0.144
(0.121–0.176) | 0.151
(0.128–0.182) |
0.440 |
|
Duration, days | 3 (3–3) | 3 (3–4) |
0.987 |
| Total
dose, mg | 22.5
(22.5–31.5) | 22.5
(22.5–30.0) |
0.528 |
| TLS risk
category |
|
|
0.022 |
|
HRD | 11 (45.8) | 8.0 (28.6) |
|
|
IRD | 12 (50.0) | 11.0 (39.3) |
|
|
LRD | 1 (4.2) | 9.0 (32.1) |
|
| Serum UA,
mg/dl |
|
Baseline | 9.1 (5.9–12.7) | 3.8 (2.6–4.7) | <0.001 |
| 24 h
after rasburicase administration | 0.2 (0.1–0.2) | 0.1 (0.1–0.1) |
0.698 |
| 7 days
after rasburicase administration | 2.8 (1.9–3.9) | 1.8 (1.0–2.3) |
0.008 |
| Serum potassium,
mEq/l |
|
Baseline | 4.2 (3.7–4.5) | 4.0 (3.7–4.2) |
0.172 |
| 24 h
after rasburicase administration | 4.2 (3.8–4.5) | 4.0 (3.8–4.3) |
0.070 |
| 7 days
after rasburicase administration | 4.1 (3.7–4.4) | 4.2 (3.7–4.4) |
0.280 |
| Serum phosphate
(mg/dl) |
|
Baseline | 3.5(3.1–4.0) | 3.1 (3.0–3.8) |
0.171 |
| 24 h
after rasburicase administration | 3.8 (3.0–4.8) | 3.0 (2.9–3.7) |
0.002 |
| 7 days
after rasburicase administration | 3.8 (3.0–4.7) | 3.0 (2.8–3.8) |
0.029 |
| Serum calcium,
mg/dl |
|
Baseline | 8.8 (8.3–9.2) | 8.5 (8.3–8.9) |
0.023 |
| 24 h
after rasburicase administration | 8.3 (7.7–8.8) | 8.4 (8.3–8.7) |
0.753 |
| 7 days
after rasburicase administration | 8.2 (7.7–8.8) | 8.6 (8.1–8.8) |
0.183 |
| Serum creatinine,
mg/dl |
|
Baseline | 0.88
(0.68–1.34) | 0.57
(0.47–0.68) | <0.001 |
| 24 h
after rasburicase administration | 0.84
(0.59–1.31) | 0.49
(0.44–0.62) | <0.001 |
| 7 days
after rasburicase administration | 0.64
(0.51–0.83) | 0.51
(0.44–0.58) |
0.059 |
Discussion
TLS consists of serious, potentially fatal
complications in patients with hematological malignancies
undergoing anticancer chemotherapy. Allopurinol has been used for
several years for the prevention of TLS-related hyperuricemia.
Recently, rasburicase was found to confer a potential advantage
over allopurinol with its rapid onset of action, reducing the
pre-existing pool of UA within a few h (9).
In the present study, patients with HRD as well as
those with IRD received rasburicase. Although the baseline serum UA
level of 29 patients (55.8%) exceeded the normal range, it declined
to undetectable levels within 24 h after rasburicase
administration. Only 1 patient who received a single dose of
rasburicase had an increased serum UA level above the normal range
at 7 days. The incidence of LTLS was very high (46.2%); however, no
patients developed renal events requiring dialysis or emergence of
clinical TLS. All the patients who experienced LTLS had spontaneous
hyperuricemia that presented prior to chemotherapy initiation.
Therefore, rasburicase administration is very important for such
patients.
There was no significant difference in the daily
dose, weight-based daily dose, administration duration, or total
dose of rasburicase in terms of TLS risk classification and between
the LTLS and non-LTLS groups. The approved rasburicase dose in
Japan is 0.2 mg/kg/day for up to 7 days. However, several studies
indicated that a shorter treatment duration or low-dose rasburicase
was also effective. Vadhan-raj et al reported that
single-dose rasburicase (0.15 mg/kg/day) was effective for the
prevention of hyperuricemia; however, 12.5% of high-risk patients
required a second dose. McBride et al reported that a 6-mg
dose of rasburicase may represent an optimal balance of
cost-effectiveness and efficacy (6).
Campara et al reported that a single low (0.15 mg/kg) dose
of rasburicase based on optimal body weight was sufficient to lower
urate levels and appeared as effective as the significantly higher
doses for multiple days (10).
Herrington et al had adjusted their hyperuricemia algorithm
to determine the 3- or 6-mg low-dose rasburicase on the baseline UA
level (11). Owing to the relatively
high cost associated with its use, rasburicase is typically
administered at low doses and for <5 days in patients with
malignancies attributed to lead exposure to minimize the cost of
treatment.
In the present study, the daily dose of rasburicase
was 7.5 mg/day (interquartile range, 7.5–9.0 mg/day) and the daily
weight-based dose was 0.147 mg/kg/day (interquartile range,
0.126–0.178 mg/kg/day), which was lower than the manufacturer's
recommended rasburicase dose. Additionally, the duration of
rasburicase administration was short. The median duration was 3
days (interquartile range, 3–4 days), ranging from 1 to 9 days.
Only 3 patients (5.7%) received single-dose rasburicase; they did
not require a second dose, and no patient developed serious TLS. If
rasburicase was administered at weight-based doses in all 52
patients in this study, the cost would increase by ~1.5-fold, from
Ұ10,817,291 to Ұ15,712,580, and by ~2.1-fold, to Ұ22,502,255, if
administered for 5 days. To the best of our knowledge, rasburicase
is effective for the prevention of TLS in patients with
hematological malignancies, even at a low dose and with short-term
administration. Patients should be closely monitored, as
rasburicase administration may be deemed necessary according to
clinical judgment, based on the biological abnormalities.
In addition, serum creatinine and phosphate levels
were significantly higher in the LTLS group after 24 h of
rasburicase administration. Although the serum UA level decreased
with rasburicase after chemotherapy, it is crucial to monitor serum
creatinine and phosphate levels within 24 h.
In summary, the results of our study indicate that
there is no significant association between rasburicase daily dose,
duration, or post-administration laboratory data and TLS risk
classification. Factors that may indicate the onset of TLS and are
important to monitor include serum UA, creatinine and phosphate
levels. Rasburicase was highly effective for the prevention and
management of hyperuricemia, even at a low-dose (7.5 mg/day) and
with a short duration of administration (3 days), which is below
the manufacturer's recommended dose. Clinicians should administer
rasburicase based on their clinical judgment, taking into
consideration the cost-effectiveness of this therapy.
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