|Year : 2014 | Volume
| Issue : 2 | Page : 180-183
Efficacy of rasburicase (recombinant urate oxidase) in the prevention and treatment of malignancy-associated hyperuricemia: An Indian experience
R Digumarti1, S Sinha2, SS Nirni3, SG Patil4, RM Pedapenki5
1 Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, India
2 Department of Medical Oncology, MNJ Institute of Oncology and Regional Cancer Centre, Hyderabad, India
3 Department of Medical Oncology Indo-American Cancer Institute and Research Centre, Hyderabad, India
4 Department of Medical Oncology, Bangalore Institute of Oncology, Bangalore, India
5 Department of Medical Oncology, King George Hospital, Visakhapatnam, Andhra Pradesh, India
|Date of Web Publication||7-Aug-2014|
Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad
Source of Support: Virchow Biotech Private Limited, Hyderabad extended financial support to conduct this study.,, Conflict of Interest: None
Clinical trial registration CTRI/2009/091/000283
Background: Patients with hematological malignancies that are highly proliferative and have high tumor burden are at high risk of developing hyperuricemia and tumor lysis syndrome (TLS), spontaneously and while undergoing chemotherapy. Aim: To assess the safety and efficacy of a new generic formulation of recombinant rasburicase in prevention and treatment of malignancy-associated hyperuricemia. Materials and Methods: An open-label, multicenter, phase-III study was conducted on 100 eligible patients with high risk for TLS. Rasburicase was administered 0.2 mg/kg intravenously over 30 min, daily, for 4 days. The outcome measures were percentage of reduction in plasma uric acid at 4 h after rasburicase, plasma uric acid area under the curve (AUC) 0-96 h and incidence of adverse events. Results: Eighty eight patients completed the study period of 10 days. After rasburicase administration, there was a 75.3 ± 28.5% of reduction in plasma uric acid at 4 h as compared to baseline. The plasma uric acid AUC 0-96 h was 259.9 ± 215.5 mg/dL h. Safety of rasburicase was assessed on the basis of changes in vitals, hematological, and biochemical parameters from baseline to termination. Except for the plasma uric acid level, there was no significant difference in any of the parameters. Mild to moderate adverse events were reported in 29 patients. Three patients had serious adverse events (SAEs) unrelated to rasburicase. Conclusions: These results demonstrated that recombinant rasburicase that is indigenously developed is effective for prevention and management of hyperuricemia in patients who are at high risk of developing TLS.
Keywords: Hyperuricemia, rasburicase, tumor lysis syndrome, uric acid, urate oxidase
|How to cite this article:|
Digumarti R, Sinha S, Nirni S S, Patil S G, Pedapenki R M. Efficacy of rasburicase (recombinant urate oxidase) in the prevention and treatment of malignancy-associated hyperuricemia: An Indian experience. Indian J Cancer 2014;51:180-3
|How to cite this URL:|
Digumarti R, Sinha S, Nirni S S, Patil S G, Pedapenki R M. Efficacy of rasburicase (recombinant urate oxidase) in the prevention and treatment of malignancy-associated hyperuricemia: An Indian experience. Indian J Cancer [serial online] 2014 [cited 2019 Aug 25];51:180-3. Available from: http://www.indianjcancer.com/text.asp?2014/51/2/180/138299
| » Introduction|| |
Tumor lysis syndrome (TLS) is a life-threatening metabolic disorder characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. It occurs when tumor cells undergo rapid disintegration spontaneously or in response to cancer chemotherapy.  Apart from hydration, diuresis and alkalinization, allopurinol was the standard drug used to prevent TLS. However, during the last decade, rasburicase, recombinant urate oxidase, was developed. Rasburicase promptly reduces the existing uric acid pool and prevents accumulation of xanthine and hypoxanthine. It does not require alkalization, facilitating phosphorous excretion.  Several studies evaluated the effects of rasburicase versus allopurinol on plasma uric acid levels and established the superior efficacy of rasburicase over allopurinol in the prevention and treatment of TLS and its associated complications. ,,,,
Considering these obvious clinical advantages and to make it available as a cost-effective drug, a new formulation of rasburicase was developed indigenously. It is produced from genetically modified strain of Escherichia coli cloned with cDNA from a strain of Aspergillus falvus. The enzyme is a tetrameric protein with identical subunits of molecular masses of about 34 KDa. Its safety was established in experimental animals through a series of preclinical studies. In the present clinical trial, its safety and efficacy were evaluated in patients at high risk for TLS.
| » Materials and Methods|| |
An open-label, multicenter, phase III study was conducted, with the approval of Drugs Controller General of India (DCGI), at five centers in India, between February 2010 and January 2012.
The study was initiated at each centre after obtaining approval of the study protocol from the ethical committee of the respective institution. The study was conducted in accordance with ICMR Guidelines for Biomedical Research on Human Subjects, Schedule Y Guidelines, ICH-GCP and the Declaration of Helsinki. The study was registered in Clinical Trial Registry (CTRI/2009/091/000283). Written informed consent was obtained from each participant/guardian before enrolment into the study. Serious adverse events were documented and communicated to the ethics committee and DCGI.
Male and female patients, above 1 year of age and below 75 years of age, were eligible to participate, if they gave a written informed consent; had stage III or IV non-Hodgkin lymphoma (NHL) or acute lymphoblastic leukemia (ALL), with a peripheral WBC count of >25,000 cell/cu.mm, or, any leukemia or lymphoma with plasma uric acid level of at least 8 mg/dL; patients who met Eastern Cooperative Oncology Group (ECOG) performance scale of ≤3 and scheduled to receive chemotherapy were included. Patients were excluded, if they had significant allergy or asthma, or hypersensitivity to urate oxidase; glucose-6-phosphate dehydrogenase (G6PD) deficiency; psychiatric or co-morbid unstable medical conditions; exposure to rasburicase; and/or use of allopurinol within previous 7 days; pregnant and lactating women were also excluded.
Rasburicase, developed by Virchow Biotech Private Ltd., was first reconstituted in the solvent provided. Briefly, 1 mL of reconstituting solvent was added to each vial containing 1.5 mg of rasburicase and mixed by swirling very gently without the use of vortex. The required dose of rasburicase (0.2 mg/kg body weight) was added to an infusion bag containing 0.9% sterile normal saline, to achieve a final total volume of 50 mL and it was administered to eligible patients intravenously over 30 min daily, for 4 days.
All patients were allowed to continue on their chemotherapy protocols/schedules as determined by the individual investigators.
Vitals (blood pressure, respiratory rate, pulse rate, and temperature), hematology (complete blood picture, hemoglobin, and platelet count) and biochemical parameters (serum lactate dehydrogenase, creatinine, potassium, and phosphorus) were measured throughout the treatment from days 1 to 5 and day 10. G6PD was done at the time of screening to rule out G6PD deficiency. ECG was monitored daily. Adverse events (AE) were recorded and graded for severity, that is, mild, moderate, and severe.
Blood samples for uric acid levels were collected at baseline and after the first dose of rasburicase at 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, and 240 h and just before administration of next dose of rasburicase. Since rasburicase causes enzymatic degradation of the uric acid within blood samples kept at room temperature, the samples were collected into prechilled tubes containing heparin as anticoagulant and were immediately stored in an ice water bath. The tubes were centrifuged in a precooled centrifuge (4°C) and plasma separated. The plasma uric acid levels were measured within 4 h after sample collection by using the modified uricase method.
The outcome measures included percentage of reduction in plasma uric acid at 4 h after uric acid-lowering therapy; plasma uric acid area under the curve AUC 0-96 h and incidence of adverse events. The AUC 0-96 h was calculated by using the trapezoidal rule. 
Patients who received at least one dose of rasburicase and had uric acid levels measured both at pre-and post-treatment were included for efficacy analysis. All patients who received at least one dose of rasburicase were included for safety analysis. The SPSS 19.0 statistical package was used. Data are shown as mean ± standard deviation and median (range). The efficacy variables that included percentage of reduction in plasma uric acid at 4 h after uric acid-lowering therapy and plasma uric acid AUC 0-96 h were analyzed using descriptive statistics. All the vitals, hematology, and biochemical parameters were evaluated before and after administration of rasburicase, using paired t-test. Statistical significance was considered at P < 0.05. Subgroup analysis was done using non parametric Mann-whitney U test for percentage reduction in plasma uric acid at 4 h and AUC 0-96 h for significant differences between children and adults.
| » Results|| |
One hundred forty eight patients with high risk for TLS were screened at five centers. Amongst them, 100 patients, who met the eligibility criteria, were enrolled into the study. Their demographic characteristics are presented in [Table 1]. Eighty eight patients completed the study period of 10 days. Since nine patients were lost to follow-up and three patients died, they could not complete the study. The disposition of patients is presented in [Figure 1].
The mean plasma uric acid levels in 100 patients at baseline were 7.4 ± 4.6 mg/dL (median 6.3; range 0.3-26.6 mg/dL). After 4-h postrasburicase administration, the plasma uric acid levels decreased significantly to 2.2 ± 3.8 mg/dL (P < 0.0001). It was maintained at a normal level (≤7.5 mg/dL) for 3 to 5 days in 94% of patients [Figure 2]. There was a 75.3% reduction in mean plasma uric acid at 4 h after study drug administration. On the other hand, the percentage of reduction in median plasma uric acid concentrations from baseline (6.3 mg/dL) to 4 h (0.5 mg/dL) was 92.1%. The mean AUC uric acid during the first 96 h of therapy, calculated using trapezoidal rule, was 259.9 ± 215.5 mg/dL/h.
Subgroup analysis was done on two parameters, namely percentage reduction in plasma uric acid at 4 h and AUC 0-96 h for significant differences between children and adults. The results are presented in [Table 2]. The median age of children was 11 years (range 2 to 18) and that of adults was 36 years (range 18 to 75). There was no significant difference in percentage reduction in plasma uric acid at 4 h and AUC 0-96 h between children and adults.
|Table 2: Percentage of reduction in plasma uric acid at 4 h and AUC0-96 h (mg/dL.h) in children and adults|
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Majority of patients tolerated the administration of rasburicase well. The compliance was excellent. Ninety seven of the study subjects received the prescribed dose of rasburicase for 4 days, and 88% of patients completed the study period of 10 days.
Safety of rasburicase was assessed based on adverse events, changes in vitals, hematological, and biochemical parameters from baseline to termination. There were no significant changes in any of the vitals, hematological, and biochemical parameters from baseline to termination, except in total leukocyte count, plasma uric acid and lactate dehydrogenase levels.
Among the 100 patients, who received the rasburicase, 29 patients experienced 55 mild (89.6%) to moderate (5.2%) adverse events, which included headache, fever, chills etc., [Table 3]. None of the patients required hemodialysis due to renal failure, which is a common complication of TLS. During the study period of 10 days, three patients (5.2%) died due to cardio respiratory failure secondary to acute leukemia. These were reported as SAEs. However, in the opinion of the investigators, the deaths were unrelated to rasburicase.
| » Discussion|| |
TLS and its associated metabolic complications account for high morbidity and mortality.  A number of studies have established the superior efficacy of rasburicase over allopurinol in prevention and treatment of malignancy-associated hyperuricemia. ,,, However, its prohibitive cost restricted its widespread use. Therefore, in this study, the safety and efficacy of indigenously developed recombinant urate oxidase (rasburicase), was evaluated in patients at high risk for TLS.
Since an active control group with allopurinol was not included (as opined by the DCGI), the results of this study with test drug were compared with historical studies to demonstrate the efficacy of rasburicase. The mean percentage of reduction in plasma uric acid levels from baseline to 4 h was 75.3, which was 6-fold higher than that reported with historical control of allopurinol (12%).  However, it was around 10% lower compared to the reported mean percentage of reduction (86%) with rasburicase.  This could be due to differences in baseline plasma uric acid levels, concomitant chemotherapy administration and the hematologic malignancies in patients studied. However, the percentages of reduction in median plasma uric acid levels from baseline to 4 h are comparable to published results. Over the 100 patients studied, there was a 92.1% (range 22.9% to 99.2%) reduction in median plasma uric acid levels from baseline to 4 h. Similar percentage of reduction (91.2%) in median plasma uric acid levels from baseline (5.7 mg/dL) to 4 h (0.5 mg/dL) was reported by Cortes et al., in 131 patients. In this study, there were 69 patients without hyperuricemia (<8 mg/dL) at presentation. In these patients also, the percentage of reduction in median plasma uric acid levels from baseline to 4 h was 93.9%, which is comparable to a published report (88.4% on 66 patients). 
In this study, subanalysis of data revealed that patients with AML had 83.4% of reduction in plasma uric acid levels after rasburicase administration from baseline to 4 h. In a recent study, Cortes et al. also reported comparable percentage reduction (87%) in AML patients.  In this study, 94% of patients had achieved and maintained normal plasma uric acid levels (≤7.5 mg/dL) for 3-5 days, which was comparable (87%) to the study of Cortes et al. in 92 patients. 
Currently, rasburicase is approved at a dosage of 0.15 to 0.2 mg/kg once a day for 5 days. Recently the efficacy of single fixed dose of rasburicase (3-6 mg) was evaluated. , Though the results are encouraging and it would be cost effective, these need to be confirmed on a larger sample size.
Rasburicase was well tolerated and there were no serious adverse events (SAEs) except in three patients. The drug was safe, as assessed by vitals, hematological, and biochemical test results, which showed no change, from baseline to termination. Changes in total leukocyte count and lactate dehydrogenase levels were most likely to be due to response to chemotherapy.
Fifty five mild to moderate adverse events, such as headache, fever, chills etc., were reported by 29 patients. There was no renal failure or need for hemodialysis due to TLS in any of the patients. During the study period of 10 days, three patients died who were reported as SAEs. However, investigators considered these SAEs as not related to rasburicase. In a meta-analysis, conducted on five trials, which included 336 patients in treatment group and 458 patients in the control group, adverse events were reported in 20% of patients.  In this study, AEs were reported in 32 patients (32%).
| » Conclusions|| |
These results demonstrated that the recombinant rasburicase developed in India is safe and effective for prevention and management of hyperuricemia both in children and adults who are at high risk of developing TLS.
| » Acknowledgment|| |
The authors gratefully acknowledge Dr. U. Srihari (NIMS, Hyderabad) and Dr. P. S. Dattatreya (Indo-American Cancer Institute and Research Center, Hyderabad) for participating in the study. Dr. M. Vishnu Vardhana Rao (National Institute of Nutrition, Hyderabad) provided statistical assistance for data analysis.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]