Original Study
A Clinical and Economic Comparison of Rasburicase and Allopurinol in the Treatment of Patients With Clinical or Laboratory Tumor Lysis Syndrome

Presented in part at the 54th Annual Meeting of the American Society of Hematology, Atlanta, Georgia December 8-11, 2012.
https://doi.org/10.1016/j.clml.2016.11.003Get rights and content

Abstract

Background

The aim of the study was to compare reductions in uric acid (UA), length of stay (LOS), and hospitalization costs in patients with tumor lysis syndrome (TLS) treated with rasburicase or allopurinol.

Patients and Methods

This retrospective study of administrative data included hospitalized pediatric and adult patients who had clinical or laboratory TLS and received rasburicase or allopurinol. Each rasburicase-treated patient was propensity score-matched with 4 allopurinol-treated patients. Mean changes in UA within ≤ 2 days of treatment initiation were determined. Economic outcomes included mean number of days in the intensive care unit (ICU), total LOS, costs/hospitalization, and costs/percentage change in UA.

Results

Twenty-six rasburicase-treated patients were matched with 104 allopurinol-treated patients. Reduction in plasma UA was 5.3 mg/dL greater for patients treated with rasburicase than for patients treated with allopurinol (P < .0001). Length of ICU stay was 2.5 days less for patients treated with rasburicase than for patients treated with allopurinol (P < .0001), and total LOS was 5 days less for patients treated with rasburicase than for patients treated with allopurinol (P = .02). Total costs per patient were $20,038 lower for patients treated with rasburicase than for patients treated with allopurinol (P < .02). Cost per percentage UA reduction was also lower for patients treated with rasburicase versus patients treated with allopurinol ($3899 vs. $16,894; P < .001).

Conclusion

In this analysis of TLS patients who received care in real-world settings, rasburicase versus allopurinol was significantly more effective in treating hyperuricemia and was associated with significantly shorter ICU and overall hospital stays and lower total inpatient costs.

Introduction

Tumor lysis syndrome (TLS) is a potentially fatal oncologic complication characterized by metabolic disturbances consequent to rapid release of nucleotides, proteins, and other contents of tumor cells that have undergone lysis.1 Most often, TLS follows initiation of chemotherapy or other cytotoxic treatment, but it can occur spontaneously before treatment.2 It most commonly occurs in certain hematological cancers, particularly non-Hodgkin lymphomas (NHLs) and acute leukemias, but it can also develop in other tumor types, particularly where there is a high proliferative rate, large tumor burden, or high sensitivity to cytotoxic therapy.3, 4

Tumor lysis syndrome has been defined in terms of laboratory abnormalities and clinical manifestations. Using the definition developed by Cairo and Bishop,2 a diagnosis of laboratory TLS requires the presence of ≥ 2 characteristic laboratory abnormalities—hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia—within 3 days before or 7 days after initiation of chemotherapy. Hyperphosphatemia and hyperkalemia consequent to tumor lysis might be exacerbated by renal insufficiency. A review of published case reports and series found that 42 of 105 patients (40%) have received renal replacement therapy, including hemodialysis and peritoneal dialysis.5 Even when not life-threatening, TLS might require delay administration of chemotherapy or necessitate dose reductions.6

Management of TLS has a considerable economic effect. In the United States, among patients with hematologic cancers, renal dialysis has been associated with a more than doubling of inpatient length of stay (LOS) and a tripling of costs.7 In a European analysis, costs in patients with TLS were 11 times higher than in patients with hyperuricemia but no TLS, with increased costs attributable mainly to intensive care unit (ICU) stays.8 Current management of patients at risk for TLS depends on the individual patient's level of risk defined according to type of malignancy, white blood cell counts, and type of therapy.1, 3 Allopurinol and its main metabolite reduce uric acid (UA) formation by inhibiting xanthine oxidase, the enzyme catalyzing oxidation of hypoxanthine to xanthine and xanthine to UA.3, 9 Because allopurinol does not reduce levels of preexisting UA, it might take several days to improve hyperuricemia.3 Additional limitations of allopurinol include risk of allergic reactions and possible clinically significant interactions with common chemotherapeutic agents. Finally, allopurinol can cause accumulation of xanthine, which can crystallize in the renal tubule, potentially resulting in acute obstructive uropathy.3

Rasburicase is a recombinant form of urate oxidase, an enzyme endogenous in many nonhuman mammalian species that catalyzes enzymatic oxidation of UA to allantoin.2, 10 Allantoin is more readily excreted than UA and is 5 to 10 times more soluble.11, 12 The recombinant molecule carries reduced liability for allergic reactions, including anaphylaxis, that have been associated with nonrecombinant urate oxidase.10 Unlike allopurinol, rasburicase reduces plasma UA concentrations in patients at high risk of TLS within 4 hours of administration.13, 14 Rasburicase has also shown superiority to allopurinol in overall antihyperuricemic efficacy, measured according to change in plasma UA concentrations14 or plasma UA response rates.13 Reduced need for dialysis with use of rasburicase has been suggested because of lower rates of dialysis in studies of rasburicase-treated patients than in studies of patients not receiving the agent,15 although no comparative trials designed to evaluate this outcome have been reported.

The clinical efficacy of rasburicase notwithstanding, estimated drug acquisition costs (in children, approximately $1575 per day, and in adults, approximately $7690 per day) have led to questions about cost-effectiveness.16, 17, 18 To address the cost-effectiveness of rasburicase in TLS, we conducted a hospital database analysis of pediatric and adult patients treated for documented TLS. We included in our study a comparison of changes in UA levels and comparisons of duration of ICU care, overall hospital LOS, and costs between patients who were treated with allopurinol and those treated with rasburicase.

Section snippets

Study Design and Data Source

This was a retrospective cohort study of administrative data. No institutional board approval was required. For the analysis we used the Cerner Health Facts database.19 This database captures and stores deidentified, longitudinal electronic health record patient data and then aggregates and organizes these data into data sets to facilitate analysis and reporting.19 Patient data are obtained from more than 400 US hospital facilities. The database is comprised of patient demographic

Demographic and Clinical Characteristics

A total of 26 rasburicase-treated patients met inclusion criteria and were matched with 104 allopurinol-treated patients. The 2 groups were comparable in mean age, gender, race, payer type, previous ICU admission, and baseline UA concentration (Table 1). In both groups, for a plurality of patients, tumor type was unknown. Distribution of tumor types did not differ significantly between the allopurinol and rasburicase groups: however, in allopurinol-treated patients, more tumors were designated

Discussion

We conducted an analysis of matched patients across all age ranges who received rasburicase or allopurinol for treatment of TLS. In our study we found that patients treated with rasburicase exhibited significantly greater reduction in serum UA relative to patients who received allopurinol and that these patients had significantly reduced ICU duration, overall LOS, and total inpatient costs. Cost per percentage of UA reduction was significantly lower for patients treated with rasburicase than

Conclusion

In this retrospective study of hospital administrative data from pediatric and adult patients with laboratory or clinical TLS we found that patients treated with rasburicase, compared with those who received allopurinol, had significantly greater mean reduction in UA levels and significantly shorter ICU and overall hospital LOS, and lower total hospitalization costs. Our analysis indicates that higher drug acquisition costs for rasburicase relative to allopurinol were outweighed by reductions

Disclosure

M.S.C. is on the Sanofi Speaker's Bureau, S.T. is an employee of Sanofi, US, and K.T. was an employee of Sanofi, US at the time of the study. The remaining authors have stated that they have no conflicts of interest.

Acknowledgments

This study was funded by Sanofi US, LLC.

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      The specimen should be analyzed within 4 hours for accuracy because rasburicase will continue to lower uric acid if the specimen is left at room temperature.27 Data from a retrospective study suggest that patients treated with rasburicase had a statistically significant greater reduction in serum uric acid levels, decreased length of stay in the ICU and hospital, and sustained lower hospital costs than patients who were treated with allopurinol.28 Prior to the initiation of treatment, patient and family education should be focused on the reasons the patient may be at risk for TLS, early identification of the signs and symptoms, and notifying the health care provider immediately, especially in the outpatient setting.

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      Proper agent selection not only optimizes clinical outcomes, but also minimizes healthcare-related costs. Optimal utilization including indication, timing, and dosing of rasburicase for prophylaxis and management of TLS remains controversial due to lack of evidence supporting clinical efficacy and high drug acquisition costs [5,6]. Though several randomized control trials have shown superiority of rasburicase in rapidly correcting hyperuricemia [7,8], no comparative trials have evaluated clinically meaningful outcomes such as improvement of AKI or need for renal replacement therapy [6].

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