1How Much is Too Much? The Use of Rasburicase in the Treatment of Tumor Lysis Syndrome Allison Weddington, PharmDPGY1 Pharmacy ResidentSt. Louis Children’s HospitalNovember 14, 2011My name is Allison Weddington and I am the current PGY1 resident at St. Louis Children’s Hospital. Today I am going to be discussing rasburicase in the treatment of tumor lysis syndrome and the controversy surrounding its dosing regimen. .
2Goals & ObjectivesDescribe the clinical background of tumor lysis syndrome, including risk factors and disease presentation.Compare and contrast rasburicase versus allopurinol in the treatment of tumor lysis syndrome.Assess the cost effectiveness of rasburicase compared to allopurinol.Critique the current dosage regimen for rasburicase and formulate possible alternative dosing regimens.
3Tumor Lysis Syndrome (TLS) Definition Group of metabolic disturbances as a result of intracellular constituents being released into the blood due to lysis of malignant cells
4Etiology and Incidence Non-Hodgkin’s lymphomas (NHL)Acute lymphoblastic leukemia (ALL)Overall incidence42% of Non-Hodgkin’s lymphoma patients16.1% of Burkitt’s lymphoma and leukemia pediatric patientsHande KR, et al. Am J Med. 1993;94:133-9.Wossman W, et al. Ann Hematol. 2003;82:160.
5Other Associated Malignancies Anaplastic large cell lymphomaT-cell and B-cell precursor ALLAcute myeloid leukemiaChronic lymphocytic leukemiaMultiple myeloma
6Hematologic Malignancy Related Factors Patient Related Factors Risk Factors for TLSHematologic Malignancy Related FactorsPatient Related FactorsRapid tumor cell proliferationHigh tumor burdenIncreased sensitivity to cytotoxic therapyRenal dysfunctionHyperuricemiaHyperphosphatemiaAcidic urineDehydration
7Risk of TLS Based on Tumor Type Coiffier B, et al. J Clin Oncol. 2008;26(16):
8Pathophysiology of TLS Hochberg J, et al. Expert Opin Biol Ther. 2008;8(10):
9Clinical Presentation of TLS Representative of metabolic abnormalitiesHyperkalemiaHyperphosphatemiaHypocalcemiaHyperuricemia
10Consequences of TLSHochberg J, et al . Expert Opin Biol Ther. 2008;8(10):
11Laboratory vs. Clinical TLS Laboratory TLSClinical TLSLaboratory TLS plus 1 of the followingSerum creatinine > 1.5 times upper limit of normalArrhythmiasSeizuresCoiffier B, et al. J Clin Oncol. 2008;26(16):Cairo MS, et al. Br J Haematol. 2004;127:3-11.
12Treatment Overview Hydration and diuresis Urinary alkalinization Agents acting on uric acidAllopurinolRasburicase.
13Hydration and Diuresis Initiate 1 – 2 days prior to chemotherapyAdminister D5 ½ NS or D5 ¼ NS + Sodium BicarbonateRate: 2 – 3L/m2/dayMonitorSpecific gravityUrine output parameters
14Urinary Alkalinization Previous recommendation: Addition of 40 – 80 mEq/L of sodium bicarbonateCurrent recommendation: No addition of sodium bicarbonate to fluids
20Allopurinol Monitoring Liver enzyme tests and bilirubinRenal functionSerum uric acid
21Allopurinol Drug Interactions Increase Levels/Effects of AllopurinolIncrease Levels/Effects of Other MedicationsLoop DiureticsThiazide DiureticsACE InhibitorsAzathioprine6-MercaptopurineCyclophosphamideAmoxicillinAmpicillin
26Rasburicase Warnings Black box warnings and contraindications Anaphylactic reactionsHemolytic reactions with glucose-6-phosphate dehydrogenase (G6PD) deficiencyMethemoglobinemiaInterference with uric acid laboratory values
27Rasburicase Warnings Precautions Maintain adequate hydration Urinary alkalinization is not recommendedAntibody response risk increases with each dose
31Treatment Based on Risk Low RiskHydration + Monitoring of TLS labsIntermediate RiskHydration + AllopurinolMay consider initial management with a single dose of rasburicase in the pediatric populationHigh RiskHydration + Rasburicase
33Cost for Pediatric Patient 7 year old– weight 23kg and height 111.7cm; BSA: 0.84m2Allopurinol dose: 300mg/m2/dayPatient’s dose: 252mg daily x 7 daysAllopurinol cost: $4.90Rasburicase dose: 0.2mg/kg daily x 5 daysPatient’s dose: 4.5mg daily x 5 daysRasburicase cost: $10,560.75Rasburicase cost/day: $2,112.15
34Cost for Pediatric Patient 16 year old– weight 100kg and height 170cm; BSA 2.17m2Allopurinol dose: 300mg/m2/dayPatient’s dose: 650mg daily x 7 daysAllopurinol cost: $11.62Rasburicase dose: 0.2mg/kg daily x 5 daysPatient’s dose: 20mg daily x 5 daysRasburicase cost: $49,284.10Rasburicase cost/day: $9,856.82
35Economic Comparison of Rasburicase and Allopurinol for Treatment of Tumor Lysis Syndrome in Pediatric PatientsEaddy M, Seal B, Tangirala M, Davies E, O’Day K Am J Health-Sys Pharm. 67(24): December 2010
36ObjectiveCompare the economic outcomes, including hospitalization costs, length of stay, and duration of critical care, of pediatric patients receiving rasburicase or allopurinol for tumor lysis syndrome
37Design Retrospective study Premier Perspective Database to collect dataRasburicase and allopurinol treated patients were propensity score matched
38Primary Endpoints Costs per hospitalization Length of stay Duration of critical care
39Methods Inclusion criteria Exclusion criteria Pediatric patients Diagnosis of lymphoma or leukemiaReceived allopurinol or rasburicase within 2 days of hospital admissionExclusion criteriaAge > 18 yearsReceived hemodialysis on hospital admission
40Statistics Primary outcome differences Baseline demographics Assessed using the γ-distributed generalized linear models with a log-link functionBaseline demographicsCategorical variablesChi-SquareContinuous variablesT-testSignificance level set at 0.05
41Results 126 patients were included in analysis Patient demographics 63 rasburicase treated patients matched with 63 allopurinol treated patientsPatient demographicsGroups were not similar in regards to provider type, admission source, and critical care admission on day 1Average age: 7.4 years old27% females and 73% males
42ResultsEaddy M, et al. Am J Health-Sys Pharm Dec 15;67(24):
43Authors’ Conclusions“Examination of claims from a large hospital database showed that treatment with rasburicase, compared with allopurinol, was associated with a significant reduction in critical care days but not with a significant difference in mean LOS or total cost.”
44Limitations Lack of randomization Possible confounding factors No account for patient acuityGreater percent of patients in the rasburicase treated group considered critical care admissionsClinical outcomes not assessed between groupsSmall sample size
45StrengthsOne of the first studies to look at cost effectiveness of allopurinol and rasburicase in the pediatric populationPrimary endpoints were appropriate
46Applicable Conclusions Statistically significant resultsMean duration of critical care daysStandard of practice should not be altered based on this study
47Weight Based Dosing vs. Single-Fixed Dosing in Adults
48Single-Dose Rasburicase 6mg in the Management of Tumor Lysis Syndrome in Adults 6 mg rasburicase x 1 doseBaseline median uric acid: 11.7mg/dLDecreased to 2 mg/dL82.9% decrease within 24 hours1 patient redosed8 patients presented with secondary renal dysfunction7 returned to baselineMcDonnell AM, et al. Pharmacother. 2006;26(6):
49Evaluation of a Single Fixed Dose of Rasburicase 7 Evaluation of a Single Fixed Dose of Rasburicase 7.5mg for the Treatment of Hyperuricemia in Adults with Cancer0.15 mg/kg vs. 7.5 mg doseAverage dose in control group = 12 mgUric acid measured at 12 and 24 hours5 patients redosed in control group1 patient redosed in 7.5 mg groupNo changes in serum creatinineReeves DJ, et al.. Pharmacother. 2008;28(6):
50Single-Dose Rasburicase for Tumor Lysis Syndrome in Adults: Weight-Based Approach Dose based on ideal or adjusted body weightAverage dose = 11 mgBaseline mean uric acid: 11.4 mg/dLDecreased to 1.4 mg/dL89.7% decrease in 24 hoursNo patients required second doseMean serum creatinine at baseline: 2.3 mg/dLDecreased in 13 patients1 increased > 0.5 mg/dL2 increased > 0.1 mg/dL but < 0.5 mg/dLCampara M, et al. J Clin Pharm Ther. 2009;34:
51Evaluation of a Low, Weight-Based Dose of Rasburicase in Adult Patients for the Treatment or Prophylaxis of Tumor Lysis Syndrome0.05 mg/kg rasburicase x 1 doseMedian dose = 4.5 mgTreatment groupBaseline median uric acid: 9.35 mg/dLDecreased to 3.3 mg/dL – 64.7% decreaseProphylaxis groupBaseline median uric acid: 6.5 mg/dLDecreased to 1.45 mg/dL – 77% decrease8 patients redosedNo changes in serum creatinineKnoebel R, et al. J Oncol Pharm Pract. 2010;17(3):
52Fixed-Dose Rasburicase 6mg for Hyperuricemia and Tumor Lysis Syndrome in High Risk Cancer Patients 6mg rasburicase x 1 doseBaseline median uric acid: 9.2mg/dLDecreased to 1.8mg/dL on day 3 & 3.8mg/dL on day 780.4% decrease in 24 hours2 patients redosed1 received 2 additional doses1 received 3 additional dosesBaseline median serum creatinine: 1.9mg/dLDecreased to 1.1mg/dL on day 7Vines AN, et al. Ann Pharmacother. 2010;44:
53Effectiveness of a Single 3mg Rasburicase Dose for the Management of Hyperuricemia in Patients with Hematological Malignancies3mg rasburicase x 1 doseBaseline median uric acid: 9.3 mg/dLDecreased to 5.3 mg/dL – 45%decrease51 episodes needed redosed42 episodes required 1 additional dose5 episodes required 2 additional doses4 episodes required 3 additional dosesBaseline serum creatinine : 1.7 mg/dL28% of patients had renal failure (2.5 mg/dL) at baselineDecreased to 1.6 mg/dL at 24 hoursTrifilio SM, et al. Bone Marrow Transplant. 2011;46:800-5.
54Weight Based Dosing vs. Single-Fixed Dosing in Pediatrics Flat dosing shown to be effective in adultsSame dose and possibly even lower dose should be effective in pediatric patientsLiterature is lacking in pediatric population
55Treatment of Impending Tumor Lysis with Single Dose Rasburicase 3 case summaries in pediatric patientsAll diagnosed with acute lymphoblastic leukemia2 cases given standard dose of rasburicaseCaseWhite blood count: 198,000/mm3Uric acid: 11.4mg/dLSerum creatinine: 0.6mg/dLAllopurinol and hydration initiatedRasburicase 4.5 mg (0.08mg/kg) was givenNo additional rasburicase doses were neededLee A, et al. Ann Pharmacother. 2003;37:
56SummaryTLS: Oncologic emergency characterized by metabolic disturbancesIdentify patient risk and initiate appropriate therapyTreatment consists of fluids and allopurinol or rasburicaseStudies have shown that a maximum doses of 6mg and 7.5mg is effective in adults
57RecommendationsBased on the published literature, single-fixed dosing shows to be effective in the adult populationA single-fixed dose of rasburicase 6mg should be administered in adult patientsDosing in the pediatric population should remain weight-based but with a max dose of 6mg
58How Much is Too Much? The Use of Rasburicase in the Treatment of Tumor Lysis Syndrome Allison Weddington, PharmDPGY1 Pharmacy ResidentSt. Louis Children’s HospitalNovember 14, 201158