Original Article
Fixed, low-dose rasburicase for the treatment or prevention of hyperuricemia in adult oncology patients
J Oncol Pharm Practice 2015, Vol. 21(2) 111–117 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214520821 opp.sagepub.com
Jon D Herrington1 and Brian C Dinh2
Abstract Purpose: Rasburicase is a recombinant urate oxidase enzyme administered to high risk patients or to those with preexisting hyperuricemia from tumor lysis syndrome (TLS). The objective of this retrospective review is to evaluate and characterize the use of fixed, low-dose rasburicase for the treatment of hyperuricemia in adult patients. Patients/Methods: A retrospective chart review from 1 October 2005 to 31 December 2011 was conducted in adult oncology patients who received fixed, low-dose rasburicase. Patients who met the inclusion criteria were evaluated for the uric acid level change from baseline and the achievement of uric acid level less than 8 mg/dL. Results: Forty-five patients were included in the analysis in which 26 (58%) patients received 3 mg rasburicase. For the 39 patients with baseline uric acid levels 8 mg/dL or higher, 80% achieved a uric acid level lower than 8 mg/dL with a single rasburicase dose. Six patients (13%) required renal replacement therapy despite rasburicase. The median uric acid level reduction 24 h post rasburicase dose 1.5 mg, 3 mg, 4.5 mg, and 6 mg were 5.5, 5.8, 3.8, and 10.05 mg/dL, respectively. There was no clinical difference between obese and non-obese patients in terms of their median uric acid reduction, 5.5 vs. 7 mg/dL, respectively. Conclusion: Fixed, low dose rasburicase produced a consistent lowering of uric acid levels and may be utilized in the management of hyperuricemia in TLS. Further study is necessary to determine if a larger fixed dose would be required in those patients with a higher baseline uric acid level.
Keywords Rasburicase, hyperuricemia, tumor lysis syndrome, fixed dose, low dose
Introduction Tumor lysis syndrome (TLS) is a life-threatening and one of the most common disease-related emergencies encountered in patients with rapidly dividing malignancies such as Burkitt’s lymphoma or acute lymphoblastic leukemia. When these cells die either spontaneously or in response to therapy, the release of intracellular contents lead to the characteristic findings of hyperuricemia, hyperkalemia, and hyperphosphatemia with subsequent hypocalcemia. The progression of electrolyte imbalances if not corrected can lead to life threatening complications such as renal failure, cardiac arrhythmias, and seizures.1 Prevention and optimal management of TLS requires careful monitoring for early signs and preservation of renal function. Pre-existing renal dysfunction
and elevated uric acid, lactate dehydrogenase (LDH), and white blood cell (WBC) count are risk factors for TLS.1 Patients at TLS risk should receive aggressive intravenous hydration to rapidly improve the flow rate through the renal tubules thereby decreasing the solute level and minimizing its precipitation that cause nephrotoxicity.1 Alkalinization of the urine is not recommended for TLS prevention or treatment since it may increase the risk of metabolic alkalosis and 1
Scott & White Memorial Hospital, Temple, TX, USA Memorial Hermann Cancer Center, Texas Medical Center, Houston, TX, USA 2
Corresponding author: Jon D Herrington, Scott & White Memorial Hospital, 2401 South 31st, Temple, TX 76502, USA. Email: [email protected]
112 increase nephrotoxicity from calcium and phosphate precipitation and/or xanthine or hypoxanthine precipitation in the renal tubules.2 Allopurinol traditionally has been used in patients with or at risk of hyperuricemia from TLS. Allopurinol, an analog of the purine base hypoxanthine, can be used to inhibit xanthine oxidase preventing the formation of downstream uric acid. However, allopurinol does not affect existing uric acid levels and it still needs to be renally eliminated.1 Despite the use of preventative measures the accumulation of uric acid can still occur. In such cases, the targeting of urate oxidase can aid in the elimination and rapid lowering of uric acid levels. This enzyme is present in most mammals, except humans and certain other primates.3 Rasburicase, a recombinant urate oxidase, rapidly catalyzes uric acid to allantoin.4 Allantoin is approximately 5–10 times more soluble than uric acid in urine and therefore does not contribute to the development of uric acid nephropathy.5 Rasburicase is Food and Drug Administration approved for the initial management of elevated uric acid levels in pediatric and adult patients with leukemia, lymphoma, or solid tumor malignancies who are receiving chemotherapy.4 The manufacturer’s adult rasburicase dosage is 0.2 mg/ kg daily to be given for up to five days.4 The costly nature of rasburicase has lead investigators at alternative dosing strategies to lower the overall expense. Studies have been conducted with the use of single fixed dose rasburicase resulting in significant lowering of uric acid concentrations (Table 1).3,5–12 These studies have led to the adaptation of optimized rasburicase dosing protocols at numerous institutions. The largest retrospective trial in 247 patients with rasburicase 3 mg fixed dose discovered a median uric acid reduction of 4.1 mg/dL and it dropped to 7 mg/dL or less in 72% of the patients.12 Our institutional guidelines recommend a single rasburicase 3 mg dose in adult patients who exhibit TLS risk factors or hyperuricemia from malignancy. The objective of this retrospective review is to evaluate and characterized the use of low, fixed-dose rasburicase at our institution for the treatment of hyperuricemia caused by TLS in adult patients.
Patients and methods This Institutional Review Board approved study is a retrospective electronic chart review at a large tertiary care academic medical center. The primary objective of this study was to evaluate and characterize the outcomes of adult patients who received a low-dose of rasburicase for treatment of hyperuricemia in TLS. In addition, we sought to evaluate the potential cost savings of the low dose regimen when compared to the
Journal of Oncology Pharmacy Practice 21(2) manufacturer’s recommendation of 0.2 mg/kg/day for five days. Adult patients (18 years of age) who received rasburicase during 1 October 2005 to 31 December 2011 were included. The institution’s recommended rasburicase dose for the treatment of TLS is a 3 mg fixed-dose. Even though a protocol was in place, physicians adjusted the rasburicase dose based on patient assessment (e.g. obesity, underlying renal dysfunction) and physician clinical judgment. High-risk factors for TLS were defined as an elevated WBC count (50,000/ mm3), elevated uric acid (10 mg/dL), elevated LDH (500 IU/L), and presenting renal dysfunction with an elevated serum creatinine (1.5 mg/dL). Determination to administer rasburicase was based on laboratory data gathered no greater than 24 h prior to the patient receiving a dose of rasburicase. Patients were excluded if they developed acute nephrotoxicity within 72 h of receiving nephrotoxic agents (e.g. NSAIDs, IV contrast, and cisplatin) or those requiring renal replacement therapy at baseline. Standard prophylaxis therapy for TLS with allopurinol and hydration was continued in all patients. Data collected using the institution’s electronic medical record databases included demographics, laboratory data, renal replacement therapy, concurrent supportive TLS therapy, dose of rasburicase, and diagnosis of malignancy. Patients who met the inclusion criteria were grouped into the dose of rasburicase used. Each group was evaluated for the total reduction of uric acid from baseline and achievement of uric acid level less than 8 mg/ dL. Reduction in uric acid levels of each low-dose group was also evaluated in the subset of the population that was obese (body mass index 30) and nonobese. In those patients with a baseline uric acid level 8 mg/dL or higher, achievement of uric acid level less than 8 mg/dL post dose of rasburicase was defined as a responder. The cost analysis was calculated based on the cost of rasburicase used in the study population compared to the potential cost using the manufacturer’s dosage for five days of treatment. The standard practice for handling laboratory draws as recommended by the manufacturer is for the blood sample to be drawn in pre-chilled tubes containing heparin, placed on ice, and assayed within 4 h from laboratory draw. This recommendation is the standard of practice at our institution, which limits the continued degradation of uric acid and potentially leading to falsely low levels.
Statistical analysis All variables including patient baseline demographics, laboratory characteristics, and change in uric acid level
11
42
11
180 fixed dose 193 weight-based
11
17
43
247
34
Chiang et al.5
Coutsouvelis et al.6
Hutcherson et al.7
McBride et al.8
McDonnell et al.9 Reeves et al.10
Trifilio et al.3
Trifilio et al.11
Vines et al.12 13 AML, 5 ALL, 6 NHL, 4 MM, 2 HD, 4 nonhematologic malignancies
20 plasma cell dyscrasias, 10 NHL, 7 AML, 3 CLL, 3 MDS 129 MM, 71 NHL, 63 AML, 14 CLL, 10 other
4 NHL, 3 AML, 1 CML, 1 MDS 14 NHL, 3 AML
4 AML, 2 MM, 2 NHL, 1 MDS, 1 CUP, 1 lung 133 AML, 86 lymphoma, 40 MM
13 ALL, 13 NHL, 12 AML, 4 other
NHL
Malignancy type
6 mg
3 mg
3 mg
7.5 mg
6 mg
3 mg (n ¼ 38), 6 mg (n ¼ 99), 7.5 mg (n ¼ 43), weight-based (n ¼ 193)
6 mg
6 mg (n ¼ 10) 4.5 mg (n ¼ 1) 3 mg
Rasburicase dose
1, except 6 patients (2 patients, 1.5 mg; 4 patients, 3 mg) 1, except 51 patients (42 patients, 2 doses; 5 patients, 3 doses; 4 patients, 4 doses) 1, except for 5 additional doses
1
1
N/A
1, except 8 patients (3 patients, 2 doses; 2 patients, 3 doses; 2 patients, 2 doses; 1 patient, 6 doses 1, except 1 patient, 2 doses
1
Number of doses
9.2 mg/dL (8.1–10.4) on day 1 declined to 1.8 mg/dL (1.0–3.8) on day 3 and 3.8 mg/dL (2.1–4.4) on day 7 (p < 0.0001); no response difference with patient weight
4.1 mg/dL (12 to +1) and 45% at 24 h; No difference in response with patient weight
6.85 mg/dL (5.7–8.4), 8.8 mg/dL (7.8–10.8), 8 mg/dL (5.15–10.4), 9.2 mg/dL (6.7–11.9) baseline in 3 mg, 6 mg, 7.5 mg, weight based groups, respectively, declined to 3.69 mg/dL (
Fixed, low-dose rasburicase for the treatment or prevention of hyperuricemia in adult oncology patients
J Oncol Pharm Practice 2015, Vol. 21(2) 111–117 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214520821 opp.sagepub.com
Jon D Herrington1 and Brian C Dinh2
Abstract Purpose: Rasburicase is a recombinant urate oxidase enzyme administered to high risk patients or to those with preexisting hyperuricemia from tumor lysis syndrome (TLS). The objective of this retrospective review is to evaluate and characterize the use of fixed, low-dose rasburicase for the treatment of hyperuricemia in adult patients. Patients/Methods: A retrospective chart review from 1 October 2005 to 31 December 2011 was conducted in adult oncology patients who received fixed, low-dose rasburicase. Patients who met the inclusion criteria were evaluated for the uric acid level change from baseline and the achievement of uric acid level less than 8 mg/dL. Results: Forty-five patients were included in the analysis in which 26 (58%) patients received 3 mg rasburicase. For the 39 patients with baseline uric acid levels 8 mg/dL or higher, 80% achieved a uric acid level lower than 8 mg/dL with a single rasburicase dose. Six patients (13%) required renal replacement therapy despite rasburicase. The median uric acid level reduction 24 h post rasburicase dose 1.5 mg, 3 mg, 4.5 mg, and 6 mg were 5.5, 5.8, 3.8, and 10.05 mg/dL, respectively. There was no clinical difference between obese and non-obese patients in terms of their median uric acid reduction, 5.5 vs. 7 mg/dL, respectively. Conclusion: Fixed, low dose rasburicase produced a consistent lowering of uric acid levels and may be utilized in the management of hyperuricemia in TLS. Further study is necessary to determine if a larger fixed dose would be required in those patients with a higher baseline uric acid level.
Keywords Rasburicase, hyperuricemia, tumor lysis syndrome, fixed dose, low dose
Introduction Tumor lysis syndrome (TLS) is a life-threatening and one of the most common disease-related emergencies encountered in patients with rapidly dividing malignancies such as Burkitt’s lymphoma or acute lymphoblastic leukemia. When these cells die either spontaneously or in response to therapy, the release of intracellular contents lead to the characteristic findings of hyperuricemia, hyperkalemia, and hyperphosphatemia with subsequent hypocalcemia. The progression of electrolyte imbalances if not corrected can lead to life threatening complications such as renal failure, cardiac arrhythmias, and seizures.1 Prevention and optimal management of TLS requires careful monitoring for early signs and preservation of renal function. Pre-existing renal dysfunction
and elevated uric acid, lactate dehydrogenase (LDH), and white blood cell (WBC) count are risk factors for TLS.1 Patients at TLS risk should receive aggressive intravenous hydration to rapidly improve the flow rate through the renal tubules thereby decreasing the solute level and minimizing its precipitation that cause nephrotoxicity.1 Alkalinization of the urine is not recommended for TLS prevention or treatment since it may increase the risk of metabolic alkalosis and 1
Scott & White Memorial Hospital, Temple, TX, USA Memorial Hermann Cancer Center, Texas Medical Center, Houston, TX, USA 2
Corresponding author: Jon D Herrington, Scott & White Memorial Hospital, 2401 South 31st, Temple, TX 76502, USA. Email: [email protected]
112 increase nephrotoxicity from calcium and phosphate precipitation and/or xanthine or hypoxanthine precipitation in the renal tubules.2 Allopurinol traditionally has been used in patients with or at risk of hyperuricemia from TLS. Allopurinol, an analog of the purine base hypoxanthine, can be used to inhibit xanthine oxidase preventing the formation of downstream uric acid. However, allopurinol does not affect existing uric acid levels and it still needs to be renally eliminated.1 Despite the use of preventative measures the accumulation of uric acid can still occur. In such cases, the targeting of urate oxidase can aid in the elimination and rapid lowering of uric acid levels. This enzyme is present in most mammals, except humans and certain other primates.3 Rasburicase, a recombinant urate oxidase, rapidly catalyzes uric acid to allantoin.4 Allantoin is approximately 5–10 times more soluble than uric acid in urine and therefore does not contribute to the development of uric acid nephropathy.5 Rasburicase is Food and Drug Administration approved for the initial management of elevated uric acid levels in pediatric and adult patients with leukemia, lymphoma, or solid tumor malignancies who are receiving chemotherapy.4 The manufacturer’s adult rasburicase dosage is 0.2 mg/ kg daily to be given for up to five days.4 The costly nature of rasburicase has lead investigators at alternative dosing strategies to lower the overall expense. Studies have been conducted with the use of single fixed dose rasburicase resulting in significant lowering of uric acid concentrations (Table 1).3,5–12 These studies have led to the adaptation of optimized rasburicase dosing protocols at numerous institutions. The largest retrospective trial in 247 patients with rasburicase 3 mg fixed dose discovered a median uric acid reduction of 4.1 mg/dL and it dropped to 7 mg/dL or less in 72% of the patients.12 Our institutional guidelines recommend a single rasburicase 3 mg dose in adult patients who exhibit TLS risk factors or hyperuricemia from malignancy. The objective of this retrospective review is to evaluate and characterized the use of low, fixed-dose rasburicase at our institution for the treatment of hyperuricemia caused by TLS in adult patients.
Patients and methods This Institutional Review Board approved study is a retrospective electronic chart review at a large tertiary care academic medical center. The primary objective of this study was to evaluate and characterize the outcomes of adult patients who received a low-dose of rasburicase for treatment of hyperuricemia in TLS. In addition, we sought to evaluate the potential cost savings of the low dose regimen when compared to the
Journal of Oncology Pharmacy Practice 21(2) manufacturer’s recommendation of 0.2 mg/kg/day for five days. Adult patients (18 years of age) who received rasburicase during 1 October 2005 to 31 December 2011 were included. The institution’s recommended rasburicase dose for the treatment of TLS is a 3 mg fixed-dose. Even though a protocol was in place, physicians adjusted the rasburicase dose based on patient assessment (e.g. obesity, underlying renal dysfunction) and physician clinical judgment. High-risk factors for TLS were defined as an elevated WBC count (50,000/ mm3), elevated uric acid (10 mg/dL), elevated LDH (500 IU/L), and presenting renal dysfunction with an elevated serum creatinine (1.5 mg/dL). Determination to administer rasburicase was based on laboratory data gathered no greater than 24 h prior to the patient receiving a dose of rasburicase. Patients were excluded if they developed acute nephrotoxicity within 72 h of receiving nephrotoxic agents (e.g. NSAIDs, IV contrast, and cisplatin) or those requiring renal replacement therapy at baseline. Standard prophylaxis therapy for TLS with allopurinol and hydration was continued in all patients. Data collected using the institution’s electronic medical record databases included demographics, laboratory data, renal replacement therapy, concurrent supportive TLS therapy, dose of rasburicase, and diagnosis of malignancy. Patients who met the inclusion criteria were grouped into the dose of rasburicase used. Each group was evaluated for the total reduction of uric acid from baseline and achievement of uric acid level less than 8 mg/ dL. Reduction in uric acid levels of each low-dose group was also evaluated in the subset of the population that was obese (body mass index 30) and nonobese. In those patients with a baseline uric acid level 8 mg/dL or higher, achievement of uric acid level less than 8 mg/dL post dose of rasburicase was defined as a responder. The cost analysis was calculated based on the cost of rasburicase used in the study population compared to the potential cost using the manufacturer’s dosage for five days of treatment. The standard practice for handling laboratory draws as recommended by the manufacturer is for the blood sample to be drawn in pre-chilled tubes containing heparin, placed on ice, and assayed within 4 h from laboratory draw. This recommendation is the standard of practice at our institution, which limits the continued degradation of uric acid and potentially leading to falsely low levels.
Statistical analysis All variables including patient baseline demographics, laboratory characteristics, and change in uric acid level
11
42
11
180 fixed dose 193 weight-based
11
17
43
247
34
Chiang et al.5
Coutsouvelis et al.6
Hutcherson et al.7
McBride et al.8
McDonnell et al.9 Reeves et al.10
Trifilio et al.3
Trifilio et al.11
Vines et al.12 13 AML, 5 ALL, 6 NHL, 4 MM, 2 HD, 4 nonhematologic malignancies
20 plasma cell dyscrasias, 10 NHL, 7 AML, 3 CLL, 3 MDS 129 MM, 71 NHL, 63 AML, 14 CLL, 10 other
4 NHL, 3 AML, 1 CML, 1 MDS 14 NHL, 3 AML
4 AML, 2 MM, 2 NHL, 1 MDS, 1 CUP, 1 lung 133 AML, 86 lymphoma, 40 MM
13 ALL, 13 NHL, 12 AML, 4 other
NHL
Malignancy type
6 mg
3 mg
3 mg
7.5 mg
6 mg
3 mg (n ¼ 38), 6 mg (n ¼ 99), 7.5 mg (n ¼ 43), weight-based (n ¼ 193)
6 mg
6 mg (n ¼ 10) 4.5 mg (n ¼ 1) 3 mg
Rasburicase dose
1, except 6 patients (2 patients, 1.5 mg; 4 patients, 3 mg) 1, except 51 patients (42 patients, 2 doses; 5 patients, 3 doses; 4 patients, 4 doses) 1, except for 5 additional doses
1
1
N/A
1, except 8 patients (3 patients, 2 doses; 2 patients, 3 doses; 2 patients, 2 doses; 1 patient, 6 doses 1, except 1 patient, 2 doses
1
Number of doses
9.2 mg/dL (8.1–10.4) on day 1 declined to 1.8 mg/dL (1.0–3.8) on day 3 and 3.8 mg/dL (2.1–4.4) on day 7 (p < 0.0001); no response difference with patient weight
4.1 mg/dL (12 to +1) and 45% at 24 h; No difference in response with patient weight
6.85 mg/dL (5.7–8.4), 8.8 mg/dL (7.8–10.8), 8 mg/dL (5.15–10.4), 9.2 mg/dL (6.7–11.9) baseline in 3 mg, 6 mg, 7.5 mg, weight based groups, respectively, declined to 3.69 mg/dL (
