|Year : 2016 | Volume
| Issue : 4 | Page : 136-140
Efficacy of single-dose rasburicase in the management of tumor lysis syndrome: a case series from a regional cancer center in western India
Sandeep R Kukkar, Harsha P Panchal, Asha S Anand, Apurva A Patel, Sonia P Parikh, Sandip A Shah
Department of Medical and Paediatric Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
|Date of Web Publication||18-Jan-2017|
Dr. Sandeep R Kukkar
Medical OPD Room No. 80, Gujarat Cancer and Research Institute, New Civil Campus, Asarwa, Ahmedabad, Gujarat
Source of Support: None, Conflict of Interest: None
Background: Tumor lysis syndrome (TLS) is an oncological emergency. Rasburicase (recombinant urate oxidase) has been proven to be an effective therapy for prevention of TLS and its serious consequences in patients with hematological malignancies such as acute leukemias with high white blood cells count, Burkitt lymphoma, and lymphoblastic lymphoma with high tumor burden. The US Food and Drug Administration recommended daily dosing regimen for 5 days is unaffordable by each and every patient in developing countries such as India. Recently, the conducted studies have clearly shown a similar efficacy for a single dose of rasburicase. Herein, we report a case series of 15 patients, including children and adults with hematologic malignancies, in whom TLS was managed by a single dose of rasburicase.
Materials and Methods: We retrospectively analyzed the efficacy of single-dose rasburicase (SDR) (0.15 mg/kg intravenous infusion over 30 min) in patients with hematologic malignancies at risk for TLS. The drug was administered in five adult and 10 pediatric patients admitted to the Gujarat Cancer and Research Institute between January 2013 and December 2014.
Results: The study included 15 patients, out of which 10 were pediatric (8 male:2 female) and five were adults (5 male:0 female). Patients with hematologic malignancies having Eastern Cooperative Oncology Group performance status 0–2 and at high risk or potential risk for TLS were selected. The median ages in pediatric and adult groups were 7.7 years and 32 years, respectively. The presence of hyperuricemia (plasma uric acid (UA) levels ≥7.5 mg/dl) or a diagnosis of very aggressive lymphoma or leukemia based on the World Health Organization classification of hematopoietic and lymphoid neoplasms in patients was classified as high-risk. Rasburicase was administered in a single dose of 0.15 mg/kg intravenously over 30 min. Patients were evaluated by clinical examination and blood biochemical tests at frequent intervals. Plasma samples for UA were collected at baseline before rasburicase, 6–24 h post-rasburicase, 48 h post-rasburicase, and daily during treatment. The blood samples for UA during the course of treatment were collected in prechilled tubes containing heparin and immediately immersed and transported on ice. The blood samples were analyzed within 4 h of collection. Serum electrolytes, blood urea nitrogen, creatinine, calcium, and phosphorous were monitored daily during this period. A single dose of rasburicase produced a rapid and sustained therapeutic effect of lowering the plasma UA levels in all the 15 patients. Renal parameters normalized within 72 h. UA levels remained below 4 mg/dl throughout the administration of chemotherapy until discharge, and none of the patients required a repeat dosing of rasburicase.
Conclusion: SDR is a highly economical and clinically effective way of managing patients with TLS and could serve as an alternative to the 5-day treatment in a resource-limited country such as India.
Keywords: Hematologic malignancy, hyperuricemia, single-dose rasburicase, tumor lysis syndrome
|How to cite this article:|
Kukkar SR, Panchal HP, Anand AS, Patel AA, Parikh SP, Shah SA. Efficacy of single-dose rasburicase in the management of tumor lysis syndrome: a case series from a regional cancer center in western India. J Appl Hematol 2016;7:136-40
|How to cite this URL:|
Kukkar SR, Panchal HP, Anand AS, Patel AA, Parikh SP, Shah SA. Efficacy of single-dose rasburicase in the management of tumor lysis syndrome: a case series from a regional cancer center in western India. J Appl Hematol [serial online] 2016 [cited 2020 Jan 20];7:136-40. Available from: http://www.jahjournal.org/text.asp?2016/7/4/136/198510
| Introduction|| |
Tumor lysis syndrome (TLS) syndrome is an oncological emergency characterized by the rapid release of intracellular metabolites from lysed malignant cells into the blood stream resulting in metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, causing acute renal failure, which may lead to cardiac arrhythmias, seizures, and death.,, Hyperuricemia, a common manifestation of TLS, results from rapid catabolism of purine-containing nucleic acids from tumor cells and can lead to renal insufficiency when uric acid (UA) precipitates into the renal tubules and distal collecting system., Rasburicase (recombinant urate oxidase) has been proven to be an effective therapy for prevention of TLS and its serious consequences in patients with hematological malignancies such as acute leukemias with high white blood cells count, Burkitt lymphoma, and lymphoblastic lymphoma with high tumor burden. Rasburicase rapidly reduces UA levels by catalyzing the conversion of the existing pool of UA into allantoin, which is 5–10 times more soluble in urine than UA and thereby decreases the need for dialysis for TLS-mediated renal failure., The US Food and Drug Administration (FDA) recommended daily dosing regimen of rasburicase for 5 days is unaffordable to each and every patient in developing countries such as India. Recently, several smaller noncontrolled studies involving retrospective case series have clearly shown a similar efficacy for single dose of rasburicase, which is beneficial to minimize the cost.,,,,,,,, Herein, we report a case series of 15 patients, including children and adults with hematological malignancy, wherein TLS was managed by a single dose of rasburicase.
| Materials and Methods|| |
The study included 15 patients, out of which 10 were pediatric (8 male:2 female) and five were adults (5 male:0 female). The patients were admitted to the Gujarat Cancer and Research Institute between January 2013 and December 2014. Patients with hematologic malignancies having Eastern Cooperative Oncology Group performance status 0–2 and at high risk for TLS were selected depending on the clinical and laboratory criteria. Among the adults, two patients had diffuse, large B-cell lymphoma, two had Burkitt lymphoma, and one patient was suffering from acute lymphoblastic leukemia (ALL). In the pediatric patients, four patients had Burkitt lymphoma, four had ALL, and two were suffering from T-cell lymphoblastic lymphoma. The median ages in pediatric and adult groups were 7.7 years and 32 years, respectively. The presence of hyperuricemia (plasma UA levels ≥7.5 mg/dl) or a diagnosis of very aggressive lymphoma or leukemia based on the basis of World Health Organization classification of hematopoietic and lymphoid neoplasms in patients was classified as high-risk. Rasburicase was administered in a single dose of 0.15 mg/kg intravenously over 30 min. All patients were screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency before the administration of rasburicase.
Response and Toxicity
Patients were evaluated by clinical examination and blood biochemical tests at frequent intervals. Plasma samples for UA were collected at baseline before rasburicase, 6–24 h post-rasburicase, 48 h post-rasburicase, and daily during treatment. The blood samples for UA during the course of treatment were collected in prechilled tubes containing heparin and immediately immersed and transported on ice. The blood samples were analyzed within 6 h of collection. Serum electrolytes, blood urea nitrogen, creatinine, calcium, and phosphorous were monitored daily till the parameters returned to normal levels.
| Results|| |
All the 15 patients received single dose of rasburicase and were assessed for clinical safety and response by measuring the renal parameters. The plasma UA levels rapidly declined approximately by 40% in all patients within 6 h, reaching a mean value of 10.5 mg/dl in adults and 11.3 mg/dl in children. The UA levels normalized in all patients within 24 h after the first dose with a mean value of 5.88 mg/dl in adults and 6.1 mg/dl in children. The falling trend of plasma UA continued further with the mean levels reaching 3.06 mg/dl in adults and 2.8 mg/dl in children at the end of 48 h. Plasma UA remained low thereafter during the course of hospital stay, and no patient required a second dose of rasburicase.
The serum creatinine levels followed a similar trend and declined slowly in all patients, reaching a mean value of 2.66 mg/dl in adults and 3.49 mg/dl in children within 6 h of administration. The reduction in serum creatinine levels continued within 24 h after the first dose with a mean value of 1.9 mg/dl in adults and 1.92 mg/dl in children, and further reaching 0.98 mg/dl in adults and 0.91 mg/dl in children at the end of 48 h [Table 1]. The treatment with rasburicase was well tolerated, and none of the patients analyzed had any serious side effects.
After the UA and creatinine levels declined within normal limits, ALL and lymphoblastic lymphoma patients were given preinduction steroids. Cytoreductive cyclophosphamide, vincristine, and steroids were administered to patients having Burkitt lymphoma. None of the treated patients had a subsequent rise in their creatinine and UA levels.
| Discussion|| |
TLS and hyperuricemia are life-threatening complications with significant morbidity and potential mortality in patients with hematological malignancies undergoing anticancer therapy.,,, Allopurinol, a xanthine oxidase inhibitor, has been used over the years for the management of TLS-related hyperuricemia. Allopurinol acts by decreasing the new production of UA by inhibiting enzyme xanthine oxidase and blocking oxidation of xanthine and hypoxanthine into UA. The slow onset of action requires the drug to be administered for more than 3 days for the achievement of significant reduction in UA levels.
Rasburicase, a recombinant urate oxidase enzyme, offers a distinct advantage over allopurinol by its rapid onset of action, reducing the pre-existing pool of UA within few hours and thereby declining the UA levels and improving the renal function. It is important to highlight the fact that urate oxidase is an endogenous enzyme commonly found in many mammalian species but not in humans because of nonsense mutation I, the coding region in the gene during evolution process.
Rasburicase is considered for the treatment and prophylactic management of high plasma UA levels (>7.5 mg/dl) in pediatric and adult patients with leukemia, lymphoma, and other hematological malignancies, which have the highest propensity to cause tumor lysis such as the tumors with a high proliferative rate (ALL and Burkitt lymphoma), tumors with high sensitivity to cytotoxic therapy, patients with large tumor masses, and those with pre-existing renal insufficiency and high serum Lactate Dehydrogenase (LDH) levels.
Goldman et al. and Pui et al. in the year 2001 confirmed the efficacy and safety of rasburicase over allopurinol in children with hematologic malignancies. Rasburicase was administered at a dose of 0.2 mg/kg intra-venous (IV) over 30 min for 5–7 days in this study population. Despite the proven clinical efficacy of rasburicase, the product could not be availed by majority of the patients in need largely because of the costs involved. In addition, the 5-day schedule approved by FDA increased significantly the financial burden. With single-dose rasburicase (SDR), the cost of treatment could be reduced by around 80%, as a single vial of 1.5 mg of rasburicase costs around Indian National Rupees (INR) 7500.
FDA initially approved rasburicase for the management of TLS in the pediatric setting on the basis of a randomized, controlled phase III clinical trial, wherein rasburicase (0.15 or 0.2 mg/kg) was administered for five consecutive days., In the adult patients, the drug was used in an “off label” manner for several years basically to meet the unmet medical needs for the management of adults with TLS.
Recently, FDA approved rasburicase at a dose of 0.2 mg/kg for up to 5 days in adult patients on the basis of a phase III study involving multiple-day dosing., However, several smaller noncontrolled studies involving retrospective case series have suggested shorter duration of treatment to minimize the cost.,,,,,,,, Some studies have questioned the overuse of rasburicase because of its very high cost in comparison to usual therapy with allopurinol and intravenous fluids. Similarly, our study emphasized the importance and effectiveness of only a single dose of rasburicase in majority of the patients with hematological malignancies and TLS. The drug was effective in rapidly decreasing the UA levels in the vast majority of patients, and none of the treated patients required a repeat dose, thus providing evidence that SDR could be a suitable alternative in resource-limited countries such as India.
Vadhan-Raj et al. evaluated the efficacy of a SDR at 0.15 mg/kg followed by as-needed dosing instead of the standard 5-day regimen with 0.2 mg/kg in adult patients at risk for TLS. The authors concluded that single dose was effective in most patients and only a subset of high-risk patients received a second dose. A study by McDonnell et al. depicted that a single dose of rasburicase at 6 mg was effective in the management of TLS in adults.
Similarly, a study by Feng et al. in adult cancer patients with hyperuricemia and at high risk for TLS demonstrated superior response rates and better control of UA levels with rasburicase compared to allopurinol. Standard SDR response rate was not inferior to that of daily-dose rasburicase, and the standard SDR was more cost-effective.
Lee et al. demonstrated the effectiveness of a single dose of rasburicase in three children with ALL and concluded that it was a feasible and cost-effective measure for pediatric patients.
All the patients in our study, including both children and adults, received a single dose of rasburicase (0.15 mg/kg over a 30 min infusion). The agent demonstrated excellent response rates, as the elevated UA and creatinine levels declined steadily over a period of 48 h to well below the normal range. None of the patients required dialysis for deranged renal profile. No second dose was required in any of the treated cases, thereby proving that it could be an alternative to the FDA-approved schedule of 5 days in resource-limiting countries such as India.
| Conclusion|| |
SDR is a highly cost-efficient and clinically effective strategy in the management of patients with TLS and could serve as an alternative to the 5-day treatment in a resource-limited country such as India.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med 1993;94:133-9.
Hochberg J, Cairo MS. Tumor lysis syndrome: Current perspective. Haematologica 2008;93:9-13.
Mughal TI, Ejaz AA, Foringer JR, Coifffier B. An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome. Cancer Treat Rev 2010;36:164-76.
Shimada M, Johnson RJ, May WS Jr, Lingegowda V, Sood P, Nakagawa T et al.
A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome. Nephrol Dial Transplant 2009;24:2960-4.
Cairo MS, Bishop M. Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol 2004;127:3-11.
Liu CY, Sims-McCallum RP, Schiffer CA. A single dose of rasburicase is sufficient for the treatment of hyperuricemia in patients receiving chemotherapy. Leuk Res 2005;29:463-5.
McDonnell AM, Lenz KL, Frei-Lahr DA, Hayslip J, Hall PD. Single-dose rasburicase 6 mg in the management of tumor lysis syndrome in adults. Pharmacotherapy 2006;26:806-12.
Reeves DJ, Bestul DJ. Evaluation of a single fixed dose of rasburicase 7.5 mg for the treatment of hyperuricemia in adults with cancer. Pharmacotherapy 2008;28:685-90.
Campara M, Shord SS, Haaf CM. Single-dose rasburicase for tumour lysis syndrome in adults: Weight-based approach. J Clin Pharm Ther 2009;34:207-13.
Trifillo S, Gordon L, Singhal S, Tallman M, Evens A, Rashid K et al.
Reduced-dose rasburicase (recombinant xanthine oxidase) in adult cancer patients with hyperuricemia. Bone Marrow Transplant 2006;37:997-1001.
Hummel M, Buchheidt D, Reiter S, Bergmann J, Adam K, Hehlmann R. Recurrent chemotherapy-induced tumor lysis syndrome (TLS) with renal failure in a patient with chronic lymphocytic leukemia − Successful treatment and prevention of TLS with low-dose rasburicase. Eur J Haematol 2005;75:518-21.
Lee AC, Li CH, So KT, Chan R. Treatment of impending lumor lysis with single-dose rasburicase. Ann Pharmacother 2003;37:1614-7.
Hummel M, Reiter S, Adam K, Hehlmann R, Buchheidt D. Effective treatment and prophylaxis of hyperuricemia and impaired renal function in tumor lysis syndrome with low doses of rasburicase. Eur J Haematol 2008;80:331-6.
Hutcherson DA, Gammon DC, Bhatt MS, Faneuf M. Reduced-dose rasburicase in the treatment of adults with hyperuricemia associated with malignancy. Pharmacotherapy 2006;26:242-7.
Legoux R, Delpech B, Dumont X, Guillemot JC, Ramond P, Shire D et al.
Cloning and expression in Escherichia coli
of the gene encoding Aspergillus flavus
urate oxidase. J Biol Chem 1992;267:8565-70.
Vadhan-Raj S, Fayad LE, Fanale MA, Pro B, Rodriguez A, Hagemeister FB et al.
A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome. Ann Oncol 2012;23:1640-5.
Goldman SC, Holcenberg JS, Finklestein JZ, Hutchinson R, Kreissman S, Johnson FL et al.
A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97:2998-3003.
Pui CH, Jeha S, Irwin D, Camitta B. Recombinant urate oxidase (rasburicase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: Results of a compassionate-use trial. Leukemia 2001;15:1505-9.
Smalley RV, Guaspari A, Haase-Statz S, Anderson SA, Cederberg D, Hohneker JA. Allopurinol: Intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol 2000;18:1758-63.
Cortes J, Moore JO, Maziarz RT, Wetzler M, Craig M, Matous J et al.
Control of plasma uric acid in adults at risk for tumor lysis syndrome: Efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone − Results of a multicenter phase III study. J Clin Oncol 2010;28:4207-13.
(Rasburicase) [Package Insert]. Bridgewater, NJ: Sanofi-Aventis; 2008.
Zaidi SZ, Aljurf M. Is rasburicase needed for prevention of tumor lysis syndrome during treatment of less aggressive hematolymphoid malignancies? J Clin Oncol 2004;22:3430-1.
Feng X, Dong K, Pence S, Inciardi J, Bhutada NS. Efficacy and cost of single-dose rasburicase in prevention and treatment of adult tumour lysis syndrome: A meta-analysis. J Clin Pharm Ther 2013;38:301-8.
Lee AC, Li CH, So KT, Chan R. Treatment of impending tumor lysis with single-dose rasburicase. Ann Pharmacother 2003;37:1614-7.