Keywords
Low dose - rasburicase - tumor lysis syndrome
Introduction
Tumor lysis syndrome (TLS) is an oncological emergency associated with potentially
life-threatening metabolic abnormalities.[1] Hyperuricemia is a feature of TLS and is treated with hydration, urine alkalinization,
and allopurinol. Allopurinol inhibits the conversion of hypoxanthine to xanthine and
xanthine to uric acid (UA) by inhibiting xanthine oxidase. It has no direct effect
on existing UA. Rasburicase being a recombinant urate oxidase is highly efficacious
in TLS. Rasburicase lowers UA rapidly to very low levels at the labeled dose of 0.15–0.2
mg/kg daily for 5 days by converting UA to allantoin which is rapidly excreted. Despite
this dramatic effect on UA, rasburicase has not been shown to have any beneficial
impact on survival. There are various studies suggesting the effectiveness of a reduced
dose of rasburicase (3 mg to 6 mg single dose). In a developing country like India
where affordability is one of the major limitations to medical care, the use of rasburicase
at the dose recommended by the US Food and Drug Administration (FDA) is not always
possible. There is no convincing data from India suggesting the efficacy of a lower
dose of rasburicase (1.5 mg or 3 mg) in the treatment of TLS.
Objectives
The objective is to study the efficacy of a reduced dose of rasburicase (1.5 mg or
3 mg) in adult patients with TLS.
Materials And Methods
A retrospective review from January 2015 to June 2016 was conducted in adult oncology
patients who received rasburicase. We evaluated the efficacy of a reduced dose of
rasburicase (1.5 mg or 3 mg) in patients aged 18–72 years presenting with clinical
or laboratory TLS[1]
[Table 1] to our institution. These patients were administered rasburicase, hydration (3 L/m2/day), and chemotherapy on day 1. Patient's biochemistry parameters such as serum
UA, serum potassium, serum creatinine, and serum calcium were studied before and after
giving rasburicase. All the patients with TLS [Bishop and Cairo definition of clinical
and/or laboratory TLS is shown in [Table 1] received 1.5 mg of rasburicase on the 1st day, and the response was studied in terms of decrease in UA levels or decrease in
serum creatinine levels. Those patients who did not achieve normal UA level within
24 h of 1.5 mg of rasburicase were given one more dose of rasburicase (1.5 mg). All
patients were also evaluated for the change in serum creatinine, serum calcium, and
serum potassium levels, postrasburicase administration.
Table 1
Bishop and Cairo criteria for TLS
|
Laboratory tumor lysis
|
Clinical tumor lysis
|
|
2 or more of the following criteria
|
Laboratory tumor lysis plus
|
|
within 3 days prior to or 7 days
|
1 or more of the following
|
|
after initiation of chemotherapy
|
Seizure
|
|
Uric acid : ≥ 8 mg/dl or 25%
|
Cardiac dysthymias or
|
|
increase from baseline
|
sudden death
|
|
Potassium: ≥6 mEq/l or 25%
|
Creatinine >1.5 times of
|
|
increase
|
age adjusted reference
|
|
Phosphorus: ≥4.5 mg/dl or 25%
|
range
|
|
increase from baseline
|
|
|
Calcium: ≤7 mg/dl or 25%
|
|
|
decrease from baseline
|
|
Results
The median UA level was 9.9 mg/dl (8.2–13.4 mg/dl). A total of 90 patients received
low-dose rasburicase. Out of 90 patients, 54 patients (60%) had normalization of UA
levels after 1.5 mg of rasburicase and 16 (18%) patients required 3 mg of rasburicase
for bringing down the UA level to normal. The low serum UA levels were maintained
even on the 3rd day of rasburicase. Twenty patients (22%) did not achieve normal UA levels even with
3 mg of rasburicase although they had more than 50% reduction in UA levels. All the
patients who did not acheive normal UA levels after 3 mg rasburicase had high risk[2]
[Table 2] of TLS. Rasburicase was well tolerated, and there was no death due to TLS among
the patients studied. Out of 90 patients, 48 patients (53%) had elevated creatinine
due to TLS. The median serum creatinine level was 3.8 mg/dl (1.9–5.4 mg/dl). Thirty-one
patients (64%) had normalization in the serum creatinine levels after rasburicase.
Two patients of Burkitt's lymphoma required hemodialysis due to acute renal failure.
The cost of one dose (1.5 mg) of rasburicase was Rs. 6000 as compared to the usual
FDA recommended dose (0.15 mg/kg/day) which comes out to be Rs. 36,000 per day.
Table 2
Risk stratification of TLS patients
|
Low risk
|
Intermediate risk
|
High risk
|
|
LDH - Lactate dehydrogenase; ULN - Upper limit of normal; NHL - Non-Hodgkin’s lymphoma;
CML - Chronic myeloid leukemia;
|
CLL - Chronic lymphocytic leukemia; AML - Acute myeloid leukemia; ALCL - Anaplastic
large cell lymphoma; GCT - Germ cell tumor;
|
SCLC - Small cell lung cancer; TLC - Total leukocyte count, ALL - Acute lymphoblastic
leukemia
|
|
Multiple myeloma
|
Neuroblastoma, GCT, SCLC
|
AML with TLC >100,000/mm3
|
|
CML
|
CLL with TLC >50,000/mm3
|
ALL with TLC >100,000/mm3 or LDH >2 × ULN
|
|
CLL with TLC <50,000/mm3
|
AML with either TLC >25,000-1,00,000/ mm3 or with LDH >2 × ULN
|
Stage III/IV Burkitt’s lymphoma, any stage Burkitt’s lymphoma with LDH >2 × ULN
|
|
Hodgkin’s lymphoma
|
Intermediate-grade NHL with LDH >2 × ULN
|
Stage III/IV lymphoblastic lymphoma or any stage lymphoblastic lymphoma with LDH >2
× ULN
|
|
AML with TLC <25,000/mm3 and LDH <2*ULN
|
ALL with TLC <100,000/mm3 and LDH <2 × ULN
|
Intermediate-risk disease with renal dysfunction
|
|
Adult ALCL
|
Burkitt’s lymphoma with LDH <2 × ULN
|
Intermediate-risk disease with elevated serum uric acid or potassium levels
|
Discussion
TLS and hyperuricemia are serious complications with significant morbidity and potential
mortality in patients with hematologic malignancies undergoing anticancer therapy.
Allopurinol has been used for many years in the prevention and management of TLS-related
hyperuricemia. However, allopurinol should be administered for ≥3 days for the achievement
of significant reduction in UA levels. Rasburicase offers a potential advantage over
allopurinol by its rapid onset of action, reducing preexisting pool of UA within few
hours.[3] The results of our study demonstrate that a fixed low-dose rasburicase is a highly
effective agent for the management of hyperuricemia associated with TLS. We also find
that the cost of rasburicase reduces by one-sixth when using a fixed low dose for
TLS. All patients at potential risk and majority of high-risk patients responded to
a reduced dose, indicating that in appropriately monitored patients, single dose followed
by dosing as needed can be cost saving. Our results are similar to the results of
Hummel et al.[4] wherein fifty patients were studied to evaluate the efficacy of low-dose rasburicase
in TLS [Table 3].[4],[5],[6],[7],[8],[9],[10],[11]
Table 3
Other studies on efficacy of low dose rasburicase
|
Study
|
n
|
Malignancy
|
Dose of rasburicase
|
Number of doses
|
|
NHL - Non-Hodgkin’s lymphoma; AML - Acute myeloid leukemia; CML - Chronic myeloid
leukemia; CLL - Chronic lymphocytic leukemia;
|
GCT - Germ cell tumor; ALL - Acute lymphocytic leukemia; CMML - Chronic myelomonocytic
leukemia; MDS - Myelodysplastic syndrome;
|
CMP - Common myeloid progenitors; DLBCL - Diffuse large B-cell lymphoma; ALL - Acute
lymphoblastic leukemia
|
|
Lee et al.
[5]
|
3
|
ALL
|
0.08-0.26 mg/kg
|
1
|
|
McDonnell et al.
[6]
|
11
|
3 NHL B-cell, 1 Burkitt’s lymphoma, 3 AML, 1 CMML, 1 MDS
|
0.0232-0.1361 mg/kg
|
1
|
|
Liu et al.
[7]
|
8
|
3 AML, 2 ALL, 2 NHL, 1 CML
|
0.141-0.118 mg/kg
|
1
|
|
Trifilio et al.
[8]
|
43
|
20 plasma cell dyscrasias, 10 NHL, 1 AML, 3 CLL, 1 MDS
|
3 mg
|
1, except for 6 additional doses (2 doses, 1.5 mg; 4 doses, 3 mg)
|
|
Hutcherson et al.
[9]
|
11
|
|
0.045-0.1 mg/kg
|
1, except for 1 additional dose (0.1 mg/kg)
|
|
Hummel et al.
[4]
|
50
|
14 NHL, 9 AML, 1 CLL, 6 CMP/MDS 5 ALL, 5 multiple, 4 solid tumor
|
0.031-0.11 mg/kg
|
Given as 1 (25 of 50 patients) to 3 doses
|
|
Reeves and Bestul.[10]
|
17
|
14 NHL, 3 AML
|
1.5 mg
|
1
|
|
Campara et al.[11]
|
21
|
9 AML, 3 NHL, 3 multiple myeloma, 3 myelofibrosis, 2 chronic leukemia, 1 plasma cell
leukemia
|
0.11-0.24 mg/kg
|
1
|
|
Our study
|
90
|
7 multiple myeloma, 10 CLL, 6 CML, 22 ALL, I7 GCT, 09 Burkitt’s lymphoma, 08 AML,
11 DLBCL
|
1.5 mg
|
1 or 2 doses depending on the response to single dose
|
Conclusion
As per our knowledge, this is the largest study conducted for evaluating the efficacy
of low-dose rasburicase. A reduced dose of rasburicase at 1.5 mg single dose (repeated
only if necessary clinically) is very efficacious in TLS. We conclude that a low dose
of rasburicase (1.5 mg or 3 mg) is cost saving and effective in reducing serum UA
(especially for low-risk and intermediate-risk TLS) and the higher dose as recommended
by the US FDA probably is required only for patients with high risk of TLS.
