Single 4.5 mg fixed-dose of rasburicase for hyperuricemia associated with tumor lysis syndrome

Introduction

Tumor lysis syndrome (TLS) is considered an oncologic emergency resulting from rapidly proliferating and therapy-sensitive malignancies exposed to cytotoxic therapy; spontaneous TLS may also occur. ¹ The risk of TLS depends on the tumor type, tumor burden, baseline renal function, baseline uric acid (UA) level, and specific therapeutic intervention. Potential metabolic derangements and end-organ damage include hyperuricemia leading to renal failure; hyperkalemia leading to cardiac dysrhythmias; hyperphosphatemia leading to tetany, seizures, or renal failure; and hypocalcaemia (secondary to hyperphosphatemia) leading to cardiac dysrhythmias. Hyperuricemia develops from rapid lysis of malignant cells and subsequent catabolism of nucleic acids. Crystallization and deposition of UA in renal tubules during hyperuricemic conditions often cause the acute renal insufficiency seen with TLS.

Guideline recommendations for management of hyperuricemia associated with TLS involve a combination of aggressive hydration, allopurinol, rasburicase, and possibly dialysis. ¹ Alkalinization is not routinely recommended due to lack of evidence of benefit and because it may increase the risk of precipitation of calcium phosphate crystals. Adequate hydration should be provided to maintain a urine output of 80–100 mL/m²/h. Allopurinol (xanthine oxidase inhibitor) is commonly used to prevent hyperuricemia by inhibiting production of UA, however it will not affect existing UA stores within the body. It may be started one to two days before the start of induction chemotherapy and continued for up to three to seven days afterwards, depending on the ongoing risk of TLS development. Rasburicase is a recombinant urate-oxidase enzyme that converts UA to allantoin, an inactive metabolite of UA that is 5–10x more soluble in the urine and more easily excreted from the body. ² Unlike allopurinol, rasburicase effectively depletes existing UA stores. Rasburicase is FDA-approved for the initial management of UA levels in patients who are expected to develop TLS after receiving chemotherapy. The approved FDA dose is 0.2 mg/kg intravenous (IV) once daily for up to five days. The average wholesale price for a 1.5 mg vial is US$815.20. ³ Since dialysis is effective at removing UA from the serum, rasburicase is not needed when patients are planned to undergo renal replacement therapy (RRT).

Due to the significant cost associated with rasburicase use, several publications have evaluated a single fixed-dose strategy (Table 1).^4–8 The doses of rasburicase in these studies ranged from 1.5 mg to 7.5 mg or a single weight-based dose (mean dose of 0.16 mg/kg). These evaluations are limited by their variable sample sizes, analyses including patients who received rasburicase for TLS prophylaxis, and inconsistent reporting of patients who received additional doses or RRT.

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Table 1.

Evidence for single fixed-dose rasburicase.

Study	Dose	Baseline UA (mg/dL)	Results
Herrington and Dinh 4 (n = 45)	1.5 mg (n = 6) 3 mg (n = 26) 4.5 mg (n = 1) 6 mg (n = 12)	11	• UA <8 mg/dL in 79.5% • 5 (11.1%) received additional doses • 6 (13.3%) received RRT
Mcbride et al. 5 (n = 373)	3 mg (n = 38) 6 mg (n = 99) 7.5 mg (n = 43) Wt-based a (n = 193)	6.85 8.8 8.0 9.2	• UA <7.5 mg/dL in 92.9% vs. 97.6% vs. 100.0% vs. 98.0% (NS) • 0 received RRT
Trifilio et al. 6 (287 episodes in 247 adults)	3 mg	9.3	• UA ≤7 mg/dL in 72% episodes • 51 (17.8%) episodes involving >1 dose
Vines et al. 7 (n = 34)	6 mg	9.2	• UA <4 mg/dL in 85% • 2 (5.9%) received additional doses
Reeves and Bestul 8 (n = 17)	7.5 mg	10	• UA ≤8 mg/dL in all patients • 1 (5.9%) received an additional dose

Based on clinical experience and a cost-savings initiative, Cleveland Clinic Main Campus adopted a single 4.5 mg IV fixed-dose of rasburicase as its standard of care for adult oncology patients with a serum UA ≥15 mg/dL or UA ≥12 mg/dL and acute kidney injury (AKI) related to TLS (defined as a 50–100% increase in serum creatinine from baseline). Hematology/oncology clinical pharmacists are involved in the clinical decision of rasburicase administration. Our dosing practice has not been evaluated with regard to normalization of serum UA levels. The goal of this study was to describe the effect of a single 4.5 mg fixed-dose of rasburicase in adult oncology patients at Cleveland Clinic Main Campus.

Methods

The Institutional Review Board at Cleveland Clinic approved this single-center, non-interventional, retrospective medical chart review (IRB # 14-1333). A pharmacy database report was utilized to identify patients who received rasburicase at Cleveland Clinic Main Campus between 1 January 2007 and 30 April 2014. Inclusion criteria consisted of adult oncology patients (greater than or equal to 18 years of age) who received an initial 4.5 mg IV fixed-dose of rasburicase. Patients were required to have at least one serum UA level documented prior to initial rasburicase dose. Patients were excluded if they received a different dosing regimen or if they required chronic RRT at baseline. The electronic medical record was utilized to collect data points including demographics, cancer diagnosis, concomitant TLS therapy, rasburicase administration times, serum UA levels, serum creatinine, and RRT requirements.

The primary outcome was the proportion of patients with normalization of serum UA level after a single 4.5 mg fixed-dose of rasburicase. Normalization of UA was defined as a serum level less than 8 mg/dL within 24 h of rasburicase administration (without receiving additional doses or RRT within the 24 h time period). If a follow-up UA level was not available, the missing data was omitted from the evaluation. Secondary outcomes were the incidence of initial treatment failure and the normalization of serum UA level in overweight versus non-overweight patients. Initial treatment failure was defined as the need for additional doses or progression to RRT within one week of the initial rasburicase dose. Overweight patients included those with a body mass index (BMI) of 25 kg/m² or greater. Descriptive statistics were used to report baseline characteristics and study outcomes. Continuous variables are displayed as mean ± standard deviation values. Nominal data are presented as numbers and percentages.

Results

One-hundred fifty-one patients were initially identified from the pharmacy database report as having a rasburicase order during the study period. Twenty-three patients were excluded from the evaluation for the following reasons: 10 had incomplete electronic medical data available for evaluation, six received a different initial dose, five were pediatric patients, and two did not have a documented baseline serum UA level prior to rasburicase administration. The remaining 128 patients were included in the evaluation.

Baseline characteristics of the study population are described in Table 2. A majority of the population (69.5%) was male and of white race (81.7%). The mean BMI, 29.8 kg/m², was within the overweight category. The most common cancer diagnosis was acute leukemia followed by Burkitt’s lymphoma/diffuse large B-cell lymphoma and multiple myeloma. Approximately 77% of the population received concomitant allopurinol for management of TLS. While 36.7% received IV hydration without sodium bicarbonate, 57% received IV hydration with sodium bicarbonate. The mean serum UA level and serum creatinine prior to rasburicase administration were 14.84 mg/dL and 2.73 mg/dL, respectively.

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Table 2.

Baseline characteristics.

Characteristic	Value
Total patients (n)	128
Male, n (%)	89 (69.5)
Age (years)	62 ± 14.89
Race (n = 126), n (%)
White	103 (81.7)
Black	19 (15.1)
Other	4 (3.2)
BMI (n = 125) (kg/m2)	29.8 ± 6.65
Cancer diagnosis, n (%)
Acute leukemia	39 (30.5)
Burkitt’s lymphoma/DLBCL	34 (26.6)
Multiple myeloma	16 (12.5)
Chronic leukemia	13 (10.2)
Solid malignancy	12 (9.4)
Other lymphoma	8 (6.3)
MDS/myeloproliferative disorder	6 (4.7)
Concomitant TLS therapy, n (%)
Allopurinol	99 (77.3)
IV hydration without sodium bicarbonate	47 (36.7)
IV hydration with sodium bicarbonate	73 (57)
Serum UA level (mg/dL)	14.84 ± 4.56
Serum creatinine (mg/dL)	2.73 ± 1.63

For the primary outcome, of the 112 patients with a follow-up serum UA level within 24 hours of initial rasburicase administration, 67.9% achieved normalization per study definition. The mean serum UA level at 24 h was 4.2 mg/dL. Normalization of UA in overweight versus non-overweight patients was not clinically different (65.9% versus 73.1%, respectively). When further dividing the overweight group, normalization of UA in overweight (BMI of 25–29.9 kg/m²) and obese (BMI of 30 kg/m² or greater) patients was also similar (63.2% and 68.1%, respectively).

For the secondary outcome, a total of 38 (29.7%) patients from the total population received additional treatment and therefore met the definition for initial treatment failure (Table 3). The mean baseline serum UA level and serum creatinine in these patients were higher than those in the overall population (17.41 mg/dL versus 14.84 mg/dL and 3.21 mg/dL versus 2.73 mg/dL, respectively). Ten (7.8%) patients received additional rasburicase doses; the mean serum UA level prior to the second additional dose was 13.8 mg/dL. Eight patients had normalization of their UA level within 48 h after the second dose, while one did not normalize and one did not have a follow-up serum UA level. Of note, two patients received a total of three doses and one patient received four doses.

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Table 3.

Patients receiving additional treatment.

Characteristic	Value
Patients receiving additional treatment, n (%)	38 (29.7)
Baseline serum UA Level (mg/dL)	17.41 ± 4.93
Baseline serum creatinine (mg/dL)	3.21 ± 1.78
Patients receiving additional rasburicase dose(s), n	10
One additional dose	7
Two additional doses	2
Three additional doses	1
Patients receiving RRT, n	28
RRT within 24 h of rasburicase  administration, n (%)	18 (64.3)
RRT indication, n (%)
TLS	18 (64.3)
Non-TLS	10 (35.7)

A total of 28 (21.9%) patients received RRT within one week of the initial rasburicase dose, and seven of these patients also received additional dose(s) (Table 3). Eighteen (64.3%) of these patients received dialysis treatment within 24 h of rasburicase administration; furthermore, 10 (35.7%) patients received RRT for a documented non-TLS indication (e.g. myeloma kidney). A majority of patients did not have documented chronic kidney disease at baseline (20/24, 83.3%). However, many patients presented with significant AKI as the mean serum creatinine prior to RRT was 4.44 mg/dL, while the mean serum UA level was 13.2 mg/dL (n = 27).

Discussion

Several studies have evaluated the use of single fixed-dose rasburicase in adult oncology patients.^4–8 The dosing strategy of a single 4.5 mg IV fixed-dose of rasburicase used at Cleveland Clinic Main Campus has not been previously studied in a large population. This dosing strategy allowed normalization of serum UA level in 68% of the population within 24 h of administration. When stratifying the population based on BMI, there was no clinically significant difference between overweight and non-overweight patients. However, almost 30% of patients received additional treatment with subsequent rasburicase dose(s), RRT, or both.

The baseline serum UA level in our study was 14.84 mg/dL, which is higher than that reported in previous evaluations of 6.85–11 mg/dL.^4–8 Some studies included patients receiving rasburicase for TLS prophylaxis. McBride et al. compared a single fixed dosing strategy (3 mg, 6 mg, or 7.5 mg) to a weight-based dosing regimen (mean dose = 0.16 mg/kg) in a retrospective study. ⁵ The median baseline serum UA level ranged from 6.85 mg/dL to 9.2 mg/dL. The authors did not find a statistically significant difference between the two dosing strategies in normalization of serum UA level (<7.5 mg/dL) within 24 h of rasburicase administration. Success rates ranged from 92.9% to 100%. The lower baseline serum UA level likely elevated the success rate in this population, as compared to our study population. These differences in rasburicase dose and baseline serum UA levels make it difficult to directly compare results among studies.

In addition, previous publications either lack or include minimal information regarding additional treatment provided to patients.^4–8 The patients in our study who received additional treatment had higher baseline serum UA and serum creatinine levels compared to the overall population. It is possible that these patients represented the most severe cases within the study population. Additional rasburicase doses provided to our study population ranged from 1.5 mg to 6 mg with a majority of patients receiving 4.5 mg; none of the patients received a weight-based dose. Additionally, we found that about 36% of patients underwent RRT for documented indications other than TLS, and 64% of patients received RRT within 24  h of rasburicase administration. This resulted in a falsely increased incidence of initial failure of rasburicase based on our study definition. Providing more education to clinicians regarding the place in therapy for rasburicase, including its lack of benefit in patients receiving RRT, may help improve appropriate use of the medication.

There is limited evidence for the use of single fixed-doses of rasburicase in overweight patients.^4,5 Our study did not find a clinically significant difference between overweight and non-overweight patients. Similarly, McBride et al. did not find a significant difference in UA level normalization between obese (BMI of 29.9 kg/m² or greater) and non-obese patients at 24, 48, or 72 h after rasburicase administration. A limitation of this study is that the sample size may have been too small to detect a difference, and the authors did not provide the actual number of patients normalizing in each group to determine any clinically significant difference. It is also unclear if there was any difference in the rasburicase dose administered to obese versus non-obese patients. In another retrospective study, Herrington et al. did not find a clinically significant difference in median UA level reduction in obese (BMI of 30 kg/m² or greater) and non-obese patients, 5.5 mg/dL and 7 mg/dL, respectively. The most common dose utilized in this study was 3 mg in 57% of the population.

With rising healthcare costs and need for cost-saving initiatives, judicious use of rasburicase is warranted given its average wholesale price of US$815.20/1.5 mg vial. ³ Based on the mean baseline weight of 88.6 kg in our study population, the initial dose of rasburicase would have been 17.7 mg per patient using the FDA approved weight-based dosing strategy of 0.2 mg/kg. This results in an estimated absolute cost difference of US$7,336.80 (average wholesale price) per dose per patient. ³ This does not account for additional doses that patients would likely receive under the FDA dosing recommendations. Our results further emphasize the potential cost-savings with the use of single fixed-dose rasburicase.

Our evaluation is not without limitations. We did not assess adequacy or appropriateness of other TLS therapies including hydration and allopurinol use. Additionally, there was increased use of sodium bicarbonate in our study population, likely due to previous standard of care followed by treating physicians; this practice may have confounded our results. Although alkalization with sodium bicarbonate increases the solubility of UA in the urine, it is not routinely recommended due to the concurrent increased risk of AKI. ¹ We could not compare our dosing strategy to a control group (or another fixed-dose) since our standard of care was 4.5 mg during the entire study period. The results of our study are indeed hypothesis-generating, and further studies are needed to determine the optimal single fixed-dose necessary for treatment response across all populations, including overweight patients.

Management of TLS requires a combination of therapeutic interventions including hydration, allopurinol, and potentially rasburicase. A single 4.5 mg fixed-dose of rasburicase appears effective in normalizing UA levels and potentially minimizing the need for RRT. However, the optimal single fixed-dose required to achieve treatment response across all patient populations requires further investigation.