Dose Of Rasburicase Research Articles

The optimal single-dose regimen of rasburicase for management of tumour lysis syndrome in children and adults: a systematic review and meta-analysis.

To perform a meta-analysis exploring the optimal single-dose regimen for managing tumour lysis syndrome (TLS) in children and adults with haematological malignancies. We systematically searched PubMed, MEDLINE, Web of Science, the Cochrane Library and the ClinicalTrials.gov website for studies regarding single-dose rasburicase in paediatric and adult patients with TLS. Data were analysed using Open MetaAnalyst statistical software. Fifteen adult studies (fourteen retrospective studies and one randomized controlled trial) and four observational studies using children were extracted, with a total of 906 and 92 subjects, respectively. Single doses of 1·5, 3, 4·5, 6, 7·5 mg and weight-based single doses of 0·05 and 0·15 mg/kg were compared. The response rate for 6, 7·5 mg and 0·15 mg/kg single doses was 90% (95% CI: 0·825-0·974), 98·6% (95% CI: 0·957-1·015) and 93·6% (95% CI: 0·864-1·007), respectively, and higher than other dosing regimens tested. The single doses of 6 mg and 0·15 mg/kg rasburicase decreased uric acid levels more than the other regimens, and the mean uric acid reduction was 8·45 mg/dL (95% CI, 7·51-9·38) and 10 mg/dL (95% CI, 8·58-11·42), respectively. Our meta-analysis revealed that, for adult patients, a single 6 mg rasburicase dose is sufficient to normalize and sustain lower uric acid and creatinine levels in adults with TLS. This dose, therefore, balances cost and efficacy of treatment. The 3- and 4·5-mg single dose can be considered if the baseline uric acid level <12 mg/dL, with close monitoring of clinical and biochemical parameters, and repeat dosing if required. The 1·5 mg and 0·15 mg/kg single dose were sufficient to manage TLS in children.

Efficacy of single-dose rasburicase in the management of tumor lysis syndrome: a case series from a regional cancer center in western India

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.

A Comparison of Single Dose Rasburicase 3 Mg Versus 6 Mg for the Management of Tumor Lysis Syndrome

Introduction: Rasburicase, a recombinant form of urate oxidase, is a highly effective treatment for tumor lysis syndrome (TLS). Although the FDA-approved dose for rasburicase is 0.2 mg/kg/day for up to five days, many centers have adopted alternative dosing strategies to decrease cost, the most common being a single 6 mg dose. We hypothesized that further reducing the dose to 3 mg would result in similar efficacy and yield significant cost savings compared to the 6 mg dose strategy.Methods: We conducted a retrospective cohort study to examine the comparative effectiveness of a single 3 mg dose of rasburicase versus a single 6 mg dose in 108 adults with hematological malignancies presenting with a baseline uric acid (UA) ≤ 12 mg/dL between June 2009 and February 2015. Prior to January 2012, our institutional policy recommended a single 6 mg dose for all patients who met criteria for rasburicase for TLS. In January 2012, the policy was amended to recommend a single 3 mg dose for patients with a baseline UA ≤ 12 mg/dL. Thus, the study included 56 patients with UA ≤ 12 who received a single 6 mg dose prior to the policy modification and 52 patients with UA ≤ 12 given the 3 mg dose after the amendment. The primary endpoint was the percentage of patients who achieved a UA ≤ 8 mg/dL (the upper limit of normal at our institution) 24 hours after a single dose of rasburicase. Fisher's exact test was used to analyze categorical variables and t-tests were used to analyze continuous variables. The a priori level of significance was set at α < 0.05.Results: The mean baseline UA was 9.3 mg/dL and 9.8 mg/dL in the 3 mg arm and 6 mg arm, respectively (P = .19). At 24 hours there was no difference in the percentage of patients who achieved a UA ≤ 8 mg/dL (92% vs. 98%; P = 0.36). In addition, there was no difference in the percentage of patients who achieved a UA ≤ 8 mg/dL at 48 hours (98% vs. 100%; P = 0.48). Six (11.5%) patients in the 3 mg arm and one (1.8%) patient in the 6 mg arm required a second dose of rasburicase to achieve a UA <8 mg/dL (P = 0.1). Of note, the 6 mg group had a greater percent reduction in UA from baseline compared to the 3 mg group at both 24 hours (-68.1% vs. -48.6%; P < .01) and 48 hours (-69.3% vs. -51.3%; P = 0.02) after rasburicase administration. There was no difference in the percent change of serum creatinine between the two dosing strategies at 24 hours (-6.5% vs. 0.1%; P = 0.11) or 48 hours (-4.5% vs. -2.5%; P = 0.22). In addition, no difference was observed with respect to the percent of patients who required renal replacement therapy within 7 days of rasburicase administration (8.9% vs. 9.6% P = 1.0). Based on the average wholesale price of $815 for one 1.5 mg vial of rasburicase, the single 3 mg dose was associated with approximately $1,500 cost savings per encounter compared to the 6 mg dose.Conclusion: A single 3 mg dose of rasburicase was as effective as 6 mg in normalizing UA within 24 hours. Our findings demonstrate that administering a single 3 mg dose of rasburicase is a cost-effective alternative for TLS management in patients with hematological malignancies presenting with a UA ≤ 12 mg/dL. DisclosuresSvoboda:Immunomedics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding. Ganetsky:Onyx: Speakers Bureau.

Efficacy of Fixed Low Dose Rasburicase in the Prevention and Treatment of Tumor Lysis Syndrome

Tumour Lysis Syndrome (TLS) is a serious complication of malignancies and can result in renal failure or death. Hyperuricaemia is one of the prominent features of TLS which if not adequately prevented or treated can lead to renal failure requiring dialysis. Rasburicase is the most recent agent indicated for treating TLS which is a recombinant urate oxidase enzyme that will oxidize uric acid to allantoin, a metabolite with 5-10 fold greater solubility than uric acid and reduces serum uric acid (SUA) levels within four hours of administration. The recommended dose according to US Food and Drug Administration is 0.15 to 0.2 mg/kg/d for 5 days. This retrospective study was aimed to evaluate the clinical efficacy of fixed low dose Rasburicase (1.5mg) in hyperuricemic patients who was admitted under Medical Oncology, Department in Amrita Institute of Medical Sciences And Research Centre, Kochi. 55 patient received Rasburicase during the study period of approximately 3years (July 2012 - June2015). 52 patients (94.54%) showed reduction in serum uric acid level in day 1 and by day 3.All patients (100%) had significant reduction in SUA after administration. In this study we found that Rasburicase significantly lowered the serum uric acid level. Single dose of 1.5mg of rasburicase was found to be effective in rapidly correcting the hyperuricemia in all these patients. This can lead to considerable cost saving in the treatment and prevention of TLS occurring in patients with both solid tumors and hematological malignancies. The advantage of Rasburicase over Allopurinol is its rapid onset of action, efficacy in patients with renal dysfunction and is well tolerated with very few side effects.

Single dose rasburicase in the management of tumor lysis syndrome in childhood acute lymphoblastic leukemia: A case series.

Tumor lysis syndrome (TLS) occurs in malignancies with high proliferative potential and tumor burden, such as lymphomas and leukemias. TLS syndrome is an oncologic emergency, requiring prompt intervention. The metabolic derangements cause acute kidney failure and may lead to cardiac arrhythmias, seizures, and death. With the advent of rasburicase, a recombinant urate oxidase, there has been a decline in the TLS-mediated renal failure and the need for dialysis. The recommended regimen and doses pose a heavy financial burden for patients in developing countries like India. With data and studies proving a similar efficacy for the reduced dose and lesser number of rasburicase, we report here a case series of seven children with acute leukemias, whose TLS was managed by a single dose of rasburicase. A retrospective analysis of case records of seven children with acute lymphoblastic leukemia and TLS, admitted to our Pediatric Oncology Unit of our Hospital between the period 2011 and 2013, was done. All our patients responded to a single dose, indicating that in appropriately monitored patients, single dose followed by as-needed dosing can be cost-saving.

Restrospective Review of Incidence, Complications and Management of Tumor Lysis Syndrome in High Risk Patients with Hematologic Malignancies

Background: The tumor lysis syndrome (TLS) has been reported to be common in hematologic malignancies, particularly those associated with a high proliferative index, high tumor burden, and highly effective therapy. The classification proposed by Cairo and Bishop (Cairo MS, Bishop M. Br J Haematol 2004; 127:3-11) provides criteria that define laboratory TLS (hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia) and clinical TLS (e.g., cardiac dysrhythmias, neuromuscular irritability, signs or symptoms clearly associated with hypocalcemia, seizures, sudden death, oliguria, elevations of creatinine above baseline). Patients with laboratory manifestations of TLS are considered to be at high risk for developing clinical TLS. It has been recommended that these patients receive rasburicase as part of initial management. The purpose of this restrospective study was to survey the incidence of laboratory/clinical TLS and to attempt to evaluate the role of allopurinol vs rasburicase for TLS prophylaxis and treatment at our institution.Methods: We reviewed a series of consecutive patients presenting to our institution for initial inpatient therapy who were considered to be at high risk for tumor lysis by virtue of their hematologic diagnosis and need for aggressive chemotherapy. ICD9 codes were used to identify patients at 19 years of age or greater with Burkitt lymphoma, high tumor burden diffuse large B cell lymphoma (DLBCL)/mantle cell lymphoma (MCL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)/lymphoma receiving their initial inpatient chemotherapy between 2007 and 2011. Electronic medical records were used to document demographic data, laboratory and clinical course information, including TLS prophylaxis/treatment strategies, from 3 days prior to 10 days post chemotherapy. Exclusion criteria were hypersensitivity to allopurinol or rasburicase or known glucose-6-phosphate dehydrogenase (G6PD) deficiency. Clinical and laboratory TLS was defined according to the method described by Cairo and Bishop.Results: A total of 149 patients met the inclusion criteria. One hundred thirty seven (92%) patients had no presenting clinical or laboratory manifestations of TLS (“prophylaxis group”) and 12 (8%) patients with manifestations of TLS at presentation were considered as the “treatment group”. In the prophylaxis group, 128 (93%) patients received allopurinol alone, 3 (2%) received rasburicase alone and 6 (5%) received both allopurinol and rasburicase. In the treatment group, all 12 patients received both rasburicase and allopurinol. Four patients in the prophylaxis group that received allopurinol alone (4/128, 3%) eventually developed TLS which was managed successfully without the addition of rasburicase. The median total dose of rasburicase in the treatment group was 12 mg (range 6-18) and repeated doses were administered on only 3 occasions. In this group, arrhythmias due to TLS were observed in 1 (8%), acute kidney injury in 8 (67%) and hyperkalemia in 3 (25%) patients. Two patients (17%) required nephrology consult and 1 (8%) received hemodialysis. Three patients (25%) in this group died - 2 from acute respiratory distress syndrome and 1 from acute subdural hematoma with herniation and pneumonia. The highest incidence of TLS was in patients with AML, in whom 11 out of 81 (13.5%) patients developed TLS.Conclusions: The incidence of TLS was approximately 11% in this high risk patient population. This study suggests that allopurinol as monotherapy can be effective as a prophylaxis strategy against TLS in a high risk patient population receiving initial chemotherapy. With appropriate monitoring, rasburicase may be added quickly in patients who develop progressive hyperuricemia during induction chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Low-dose rasburicase in hematologic malignancies.

To define the efficacy and safety of low-dose rasburicase in children from south India with hematologic malignancies. This study is a retrospective analysis of data on 41 children with hematologic malignacies with laboratory evidence of tumor lysis syndrome (TLS) or clinical features indicating high risk for developing TLS. Patients were treated with rasburicase in doses of 0.1-0.15 mg/kg dose, repeated when necessary. Male : Female ratio was 32:9. Thirty-six children had laboratory evidence of TLS and 5 were at risk for TLS. Diagnoses were T-cell acute lymphoblastic leukemia (ALL), 19; Pre-B ALL, 17; B-non-Hodgkin lymphoma (NHL), 2; T-NHL, 2; and acute myeloid leukemia (AML), 1. Initial plasma uric acid (PUA): median, 8.5 mg/dl (range, 4.3 to 45.5). Six had creatinine levels of >2 mg/dl on admission; and 10 had peak PO4 levels of >10 mg/dl. Dose of rasburicase used: median, 0.12 mg/kg (range, 0.08-0.24). Median reduction of PUA at 6 h: 80 % (range 40 to 98 %). Twenty-seven needed only one dose; 12 needed 2 or 3 doses; and two needed 5 doses each. One child required dialysis. None of the children developed anaphylaxis or hemolysis and there were no deaths from TLS. Low-dose rasburicase (0.1-0.15 mg/kg) is safe and effective in reducing PUA in Indian children with lymphoid malignancies, and thus it may reduce the risk of renal failure from TLS.

O2-1-1 - Efficacy of Rasburicase for the Prophylaxis of Tumor Lysis Syndrome in Non-Hodgkin Lymphoma Patients

Background: Tumor lysis syndrome (TLS) is a severe complication associated with anticancer chemotherapy and may become fatal. Serum uric acid (sUA) is known to play an important role in the pathology of TLS. Rasburicase, which catalyzes the oxidation of sUA to its soluble metabolite, has often been used for the prophylaxis and management of TLS. However, the optimal dose has not yet been established.Methods: We retrospectively collected data on 23 patients with non-Hodgkin lymphoma who received rasburicase at single institution between May 2012 and December 2013 for the prophylaxis of TLS before first-line chemotherapy, and we assessed clinical background, response to the drug, and occurrence of TLS.Results: The median age of the patients was 59 years (range, 28–85 years), and 14 patients were male. With regard to patients' TLS disease risk, 2 cases were designated as low risk, 6 were designated as intermediate risk, and 6 were designated as high risk. All patients had elevated serum lactate dehydrogenase levels with a high tumor burden and/or aggressive disease. The median level of sUA was 7.8 mg/dL (range, 1.3–16.4 mg/dL) and was considered elevated in 12 patients. The mean total dose of rasburicase per body weight was 0.24 mg/kg (range, 0.10–0.66 mg/kg). Patients with low or intermediate risk disease were all well managed with only 1 day of drug administration. Among the high-risk disease patients, 6 required longer duration of administration, up to 3 days, but none of the patients developed clinical TLS.Conclusions: A reduced dose of rasburicase may be effective for prophylactic TLS treatment in Japanese lymphoma patients.

Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer.

Tumour lysis syndrome (TLS) is a serious complication of malignancies and can result in renal failure or death. Preliminary reports suggest that urate oxidase is effective in reducing serum uric acid, the build-up of which causes TLS. It is uncertain whether high-quality evidence exists to support its routine use in children with malignancies. To assess the effects and safety of urate oxidase for the prevention and treatment of TLS in children with malignancies. This is an update of the original review. We performed a comprehensive search of the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library issue 1, 2013), MEDLINE (1966 to February 2013), Embase (1980 to February 2013), and CINAHL (1982 to February 2013). In addition, we searched the reference lists of all identified relevant papers. We also explored other internet sources (updated search on 26 February 2013): the NHS' National Research Register, the US National Institutes of Health Ongoing Trials Register, the metaRegister of Controlled Trials, and ProQuest Dissertations & Theses Database. We also screened conference proceedings of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the International Society of Paediatric Oncology meetings from 1993 to 2012. Finally, we contacted experts in the field and the manufacturer of rasburicase, Sanofi-aventis. Randomised controlled trials (RCT) and controlled clinical trials (CCT) of urate oxidase for the prevention or treatment of TLS in children under 18 years with any malignancy. Two review authors independently extracted trial data and assessed individual trial quality. We used risk ratios (RR) for dichotomous data and mean difference (MD) for continuous data. We included seven trials, involving 471 participants in the treatment groups and 603 participants in the control groups. One RCT and five CCTs compared urate oxidase and allopurinol. Three trials tested Uricozyme, and three trials tested rasburicase for the prevention of TLS.The RCT showed no significant difference in mortality (both all-cause mortality and mortality due to TLS), renal failure, and adverse effects between the treatment and the control groups. The frequency of normalisation of uric acid at four hours (Fisher's exact test P < 0.001) and area under curve of uric acid at four days (MD -201.00 mg/dLhr, 95% confidence interval (CI) -258.05 mg/dLhr to -143.95 mg/dLhr; P < 0.00001) were significantly better in the treatment group. The trial did not evaluate the primary outcome (incidence of clinical TLS).Pooled results of three CCTs showed significantly lower mortality due to TLS in the treatment group (RR 0.05, 95% CI 0.00 to 0.89; P = 0.04); all-cause mortality was not significantly different between the groups. Pooled results from five CCTs showed significantly lower incidence of renal failure in the treatment group (RR 0.26, 95% CI 0.08 to 0.89; P = 0.03). Results of CCTs also showed significantly lower uric acid in the treatment group at two days (three CCTs), three days (two CCTs), four days (two CCTs), and seven days (one CCT) after therapy, but not one day (three CCTs), five days (one CCT), and 12 days (one CCT) after therapy. Pooled results from three CCTs showed higher frequency of adverse effects in participants who received urate oxidase (RR 9.10, 95% CI 1.29 to 64.00; P = 0.03). One CCT evaluated the primary outcome; no significant difference was identified.Another included RCT, with 30 participants, compared different doses of rasburicase (0.2 mg/kg versus 0.15 mg/kg), which demonstrated no significant difference in uric acid normalisation and uric acid level at four hours). Common adverse events of urate oxidase included hypersensitivity, haemolysis, and anaemia, but no significant difference between treatment groups was identified. No significant difference in mortality (all-cause mortality and mortality due to TLS) and renal failure was identified. The primary outcome was not evaluated.All included trials were highly susceptible to biases. Although urate oxidase might be effective in reducing serum uric acid, it is unclear whether it reduces clinical tumour lysis syndrome, renal failure, or mortality. Adverse effects might be more common for urate oxidase compared with allopurinol. Clinicians should weigh the potential benefits of reducing uric acid and uncertain benefits of preventing mortality or renal failure from TLS against the potential risk of adverse effects.

Fixed-Dose Rasburicase in Overweight and Obese Patients Versus Normal-Weight Patients.

Fixed-dose rasburicase (FDR) is common practice in treating hyperuricemia associated with tumor lysis syndrome in adults; however, there is a lack of data regarding the effectiveness of this dosing strategy specifically in the overweight and obese patient populations. To determine if patient weight per body mass index (BMI) category is associated with failure of initial FDR as defined by the need for additional dose(s) based on a uric acid level (UAL) ≥7.5 mg/dL within 10 days of previous rasburicase administration. Adults who received FDR per institutional guidelines from October 2008 to August 2013 were reviewed. Patients had either a baseline UAL ≥7.5 mg/dL or were considered high risk (leukemia or lymphoma diagnosis with white blood cell count >50 000/mm3 or lactate dehydrogenase level greater than 2 times the upper limit of normal). Patients were stratified by BMI as underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), or obese (30+). Overall, 12 out of 151 patients who received FDR required a repeat dose of rasburicase. The percentage of patients requiring a repeat rasburicase dose was not different between obese/overweight versus normal/underweight patients (8.7% vs 6.4%, P = 0.75). Similarly, there was no difference between obese alone versus normal/underweight patients (12.3% vs 6.4%; P = 0.51). In this retrospective analysis, patient BMI did not correlate with failure of FDR in adults, suggesting that this dosing strategy is efficacious in the adult population.

Fixed, low-dose rasburicase for the treatment or prevention of hyperuricemia in adult oncology patients

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. 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. 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. 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.

Outcomes Of Repeated Administration Of Rasburicase In Recurrent Cycles For Patients With Leukemia

IntroductionRasburicase, a recombinant urate oxidase, is effective at reducing plasma uric acid levels in patients who are at risk for tumor lysis syndrome. Since rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain using the cDNA from an Aspergillus flavus strain, it may cause anti-rasburicase antibodies to develop. Anti-rasburicase antibodies pose a major safety and efficacy concern in that they can contribute to hypersensitivity reaction and/or the loss of uricolytic activity in patients who receive more than one cycle of rasburicase. We sought to evaluate the efficacy and rate of adverse reactions in those patients who received more than one cycle of rasburicase. MethodsPharmacy records were used to identify patients treated on the adult leukemia service who received more than one cycle of rasburicase therapy during the time period of January 2003 to May 2013. To be classified as a new cycle, a break in rasburicase therapy of at least 21 days needed to occur. Electronic medical records were used to document demographic, laboratory and clinical course information for the first 3 cycles of rasburicase administered. Uric acid levels as well as adverse events possibly attributable to rasburicase were collected for up to 3 days following the first dose of a cycle. Tumor lysis risk was determined using the method described by Cairo, et al (Cairo MS, et al on behalf of the TLS expert panel. Br J Haematol 2010; 149: 578-586.). ResultsTwo hundred and forty-two patients were identified that received at least 2 cycles of rasburicase therapy. Fifty-two of the patients received a third cycle of rasburicase therapy. Median patient age was 61 years for those patients receiving a second cycle and 56 years for those receiving a third cycle. The majority of the patients had AML (45%), ALL (20%) or CLL (16%). The second and third cycles of rasburicase were administered a median of 86.5 (range: 22-3736) and 52.5 (range: 21-690) days, respectively, from the previous cycle. The median uric acid level measured the day following the first dose of rasburicase therapy was below the laboratory normal range (2.6 – 7.1 mg/dL) on all cycles: 1.5 mg/dL on Cycle 1, 2.4 mg/dL on Cycle 2 and 2.15 mg/dL on Cycle 3. Seventeen patients (7%) experienced adverse events that could possibly be attributed to rasburicase therapy, including shortness of breath, chills, nausea, itching and rash. In 11 of the 17 patients, concomitantly administered agents, such as monoclonal antibodies, were more likely to be causative of the adverse events based on temporal or clinical findings. Only 1 patient (0.4%), who experienced shortness of breath and rash approximately 30 minutes following the rasburicase dose, had symptoms that would be consistent with a hypersensitivity reaction due to rasburicase. Despite the reaction, the patient's uric acid level following rasburicase decreased into the normal range. ConclusionsThis study indicates that, in our population of adult patients with leukemia, subsequent cycles of rasburicase therapy remain safe and effective. Rasburicase was able to lower baseline uric acid levels to below the normal range following the first dose. Additionally, only 1 patient experienced a hypersensitivity reaction that was clearly attributable to rasburicase administration. Prospective studies evaluating antibody production in those patients who develop hypersensitivity reactions, or fail to have a clinical response, to rasburicase therapy would help validate our observations. Disclosures:Off Label Use: Rasburicase is not approved for the administration of repeated courses of therapy. Ravandi:Sanofi: Research Funding. Cortes:Sanofi: Research Funding.

Mortality Following Rasburicase-Induced Methemoglobinemia

To report a case of mortality following rasburicase-induced methemoglobinemia. A 62-year-old African American male with chronic lymphocytic leukemia and small lymphocytic lymphoma was admitted for tumor lysis syndrome and renal failure. He was treated with 2 doses of rasburicase, subsequently developed methemoglobinemia, and required intubation, multiple packed red blood cell (PRBC) transfusions, and 2 doses of methylene blue. A screen for glucose-6 phosphate dehydrogenase (G6PD) deficiency was negative. His course was complicated by hemolytic anemia, nosocomial pneumonia, Clostridium difficile infection, and septic shock. His methemoglobin concentrations normalized over several days; however, the patient eventually died on hospital day 16. An objective causality assessment revealed that the adverse drug reaction was probable. Our case was similar to previously published cases, except that our patient died and his G6PD screen was negative. Although it was negative, it is likely that this was a false negative result because this blood was drawn shortly after PRBC transfusions and during active hemolysis. Both these are likely to cause false-negative results. Methemoglobinemia is a rare adverse effect associated with the use of rasburicase and occurs most often in patients with G6PD deficiency. G6PD testing should not be ordered during active hemolysis or after blood transfusion because this may lead to false-negative results. Methylene blue should not be used as an antidote because it may worsen hemolytic anemia in patients with G6PD deficiency.

Cyanosis in a male Nigerian infant with acute kidney injury: Questions

and fractional excretion of sodium (0.29 %) indicated predominantly prerenal acute kidney injury. Ultrasound showed normal-sized kidneys with medullary hyperechogenicity. Abdominal lymphadenopathy and organomegaly were absent. A chest X-ray was normal. Isotonic fluid replacement [20 ml/kg body weight (BW) intravenously] was started, and a single dose of rasburicase (0.2 mg/kg BW iv) was given. Urine output subsequently increased to >2 ml/kg/h within 1 h. Two and ahalf hours later routine monitoring by pulse oximetry demonstrated a gradual and continuous decrease in oxygen saturation leveling at a blood oxygen saturation (SpO2) of approximately 80 %. Chest auscultation was normal, and the patient did not present any signs of respiratory distress. Echocardiography showed normal cardiac filling and biventricular function. Nasal application of oxygen up to 4 L/min had no effect on cyanosis.

Comparative Evaluation of Single Fixed Dosing and Weight‐Based Dosing of Rasburicase for Tumor Lysis Syndrome

To evaluate single fixed dosing versus weight-based dosing strategies for rasburicase to determine the minimum dose required to mitigate hyperuricemia in the treatment or prevention of tumor lysis syndrome. Retrospective medical record review Academic medical center A total of 373 patients with a diagnosis of a hematologic malignancy or solid tumor and who received at least one dose of rasburicase over a 6-year period between January 1, 2005, and February 18, 2011; 180 patients received single doses of 3mg (38 patients), 6mg (99 patients), or 7.5mg (43 patients), and 193 patients received weight-based dosing. Tumor lysis syndrome laboratory data were recorded at baseline and monitored up to 72hours after initial rasburicase administration. Median baseline plasma uric acid levels were 6.85mg/dl, 8.80mg/dl, 8.00mg/dl, and 9.20mg/dl, respectively, in the 3-mg, 6-mg, 7.5-mg, and weight-based dosing groups. Treatment success was defined as a normalized plasma uric acid level (<7.5 mg/dl) within 24hours after receiving rasburicase. The mean weight-based dose was 0.16mg/kg. Six rasburicase treatment failures occurred; two were in the 3-mg group, one was in the 6-mg group, and three were in the weight-based dosing group. At 24hours after rasburicase administration, no statistically significant differences in treatment success were noted among groups (92.9% vs 97.6% vs 100.0% vs 98.0% in the 3-mg, 6-mg, 7.5-mg, and weight-based dosing groups, respectively, p=0.1238). The efficacy of all single fixed doses and weight-based dosing strategies evaluated in this study appear to be comparable in normalizing plasma uric acid levels within 24hours of rasburicase administration. Although use of a 3-mg rasburicase dose may be the most cost-effective treatment strategy in managing hyperuricemia secondary to tumor lysis syndrome, the 6-mg dose resulted in lower sustained uric acid levels after rasburicase administration. Further analysis of patient specific factors contributing to the need for repeat rasburicase administration should be conducted in larger, prospective clinical trials.

Effectiveness of a single fixed dose of rasburicase 3 mg in the management of tumour lysis syndrome

Effectiveness of a single fixed dose of rasburicase 3 <scp>mg</scp> in the management of tumour lysis syndrome

Lethal Effect of a Single Dose of Rasburicase in a Preterm Newborn Infant

This case report describes a preterm newborn infant who was treated with a single dose of rasburicase for an increase in uric acid level. He died on the third day as a result of complications of hemolysis, which appeared to be precipitated by rasburicase. The patient's death was preceded by progressive respiratory insufficiency, lactic acidosis, and hyperbilirubinemia, culminating in refractory hypoxia and hypotension. A postmortem assay for glucose-6-phosphate dehydrogenase showed deficiency and the glucose-6-phosphate dehydrogenase Mediterranean genotype.

Urate Oxidase (Rasburicase) to Inhibit Graft Versus Host Disease (GVHD) After Myeloablative HLA-Matched Allogeneic Hematopoietic Cell Transplantation (HCT).

Abstract 3063 Background:Dying mammalian cells release danger signals that stimulate antigen presenting cells (APCs) to promote an immune response. It has been demonstrated that uric acid released from injured cells alerts the immune system to cell death, acts as a danger signal to stimulate cytotoxic T cell responses and that elimination of uric acid in mouse models reduces this immune response (Ref: Nature 2003; 425:516–521). Rasburicase is a recombinant urate-oxidase enzyme that catalyzes oxidation of uric acid into an inactive soluble metabolite and is currently used to prevent tumor lysis syndrome. We hypothesized that rasburicase administered during myeloablative conditioning prior to allogeneic HCT will reduce the serum levels of uric acid and thereby may decrease the incidence of acute GVHD via inhibition of danger signal-mediated activation of host APCs. Methods:In this pilot trial at the Massachusetts General Hospital, between 2007 and 2010, 23 patients (median age: 41 years, range: 19–59) with hematologic malignancies in complete remission (AML, n=13; ALL, n=8; MDS, n=1; MPD, n=1;) received myeloablative preparative regimens (Bu/Cy, n=14; Cy/TBI, n=7; Bu/Flu, n=2) followed by GCSF-mobilized HLA-matched (MRD, n=18; MUD, n=5) peripheral blood HCT. GVHD prophylaxis consisted of cyclosporine or tacrolimus and methotrexate for MRD transplants and tacrolimus/MTX and anti-thymocyte globulin (Thymoglobulin) for MUD transplants. Rasburicase was administered beginning on the first day of conditioning therapy, at a dose of 0.20 mg/kg intravenously daily for 5 consecutive days. Outcomes were compared to 44 controls at this institution from the same time period identified using retrospective chart review. Patients in the control group received allopurinol during the conditioning as a part of the institutional guidelines. Associations between categorical variables were evaluated using Fisher’s exact test. Overall and disease-free survival (OS and DFS) were estimated using the method of Kaplan and Meier. Results:The mean serum uric acid concentration was 0.2 mg/dl (range, 0–1.7) on 6 consecutive days, beginning the day after the first dose of rasburicase. Engraftment was achieved in all patients, and the median times to neutrophil (at least 0.5 × 109/ul) and platelet engraftment (at least 20 × 109/ul) were 18 days (range, 7–26 × 109/ul) and 16 days (range, 8–57 × 109/ul), respectively. The only serious toxicity caused by rasburicase was intravascular hemolysis in one patient who was found to have G6PD deficiency; this patient received only 2 doses of rasburicase. Greater than or equal to grade II-IV acute GVHD occurred in 5 out of 23 patients (22%), 4/18 in MRD and 1/5 in MUD recipients: grade II, n=1; grade III, n=2; and grade IV, n=2. When compared with 44 patients (AML 28, ALL 5, MDS 4, NHL 5, MPD 1, CML 1), comparable to rasburicase-treated patients with respect to age, gender, disease status, donor sources, conditioning and GVHD prophylaxis, who received myeloablative HCT (MRD, n=32; MUD, n=12) at the MGH during the same time period as the patients in the rasburicase-treated group, there was significantly less grade II or higher aGVHD in the rasburicase group (rasburicase: 22% vs. institutional control: 48% [total 21/44, 13/32 in MRD and 8/12 MUD recipients], Fisher’s exact test, p=0.033). There was no significant difference in the incidence and severity of chronic GVHD between the two groups (rasburicase, 61%, control 48%; Fisher’s exact test, p=0.721). At 3 years, there was no significant difference in disease-free survival (DFS) or overall survival (OS) between the rasburicase-treated and control groups (DFS: rasburicase vs. control 51.2% vs. 40.4%, p=0.97; OS: rasburicase vs. control 55.3% vs. 44.9%, p=0.88). Conclusion:Rasburicase can be safely administered during myeloablative conditioning, results in a profound lowering of serum uric acid levels and has the potential to reduce the incidence of acute GVHD. Based on these data a prospective randomized phase II trial is planned in order to verify whether rasburicase inhibits acute GVHD after myeloablative HCT and to study the possible mechanisms of protection from GVHD. Disclosures:Off Label Use: Rasburicase for GVHD prevention in allo-HSCT.

Anaphylaxis Associated with Administration of Repeated Courses of Rasburicase: A Research On Adverse Drug Events and Reports (RADAR) Project

AbstractAbstract 1351 PurposeRasburicase (recombinant urate oxidase) is used to rapidly metabolize uric acid in patients with hyperuricemia. Rasburicase is considered immunogenic given that it is produced by a genetically modified Saccharomyces cerevisiae. Rasburicase labeling indicates that anaphylaxis rarely occurs (<1% of patients) after a single course of therapy, yet has been shown to elicit an antibody response in 64% of healthy volunteers within one to six weeks after the initial course, and with persistent antibodies for well over one year. Currently there are no data available on the incidence of anaphylaxis in patients receiving a subsequent rasburicase course after an interval of at least three weeks. We sought to determine the incidence of anaphylaxis after repeated courses of rasburicase during subsequent episodes of hyperuricemia. MethodsElectronic medical records were used to identify patients with hematological malignancies who were treated with rasburicase for separate episodes of hyperuricemia. All evaluable patients received subsequent identical low doses of rasburicase (3mg or 6mg) for separate hyperuricemia episodes with at least 21 day intervals. Anaphylaxis included diagnostic coding and documentation in the record of angioedema and airway compromise. ResultsNinety-seven patients met criteria for inclusion in the study. No patients experienced anaphylaxis during the first treatment course of rasburicase, however six patients (6.2%) experienced anaphylaxis after a subsequent course (p=0.03), three of which required intubation, and two resulted in cardiac arrest with one death (see Table 1). The subsequent course of rasburicase associated with anaphylaxis was administered an average of 8.5 months after the first course and anaphylaxis occurred, on average, 93 minutes after rasburicase was administered. Notably, two of the six patients met laboratory criteria for tumor lysis syndrome at the time of the anaphylactic reaction. There was no evidence of hemolysis in the six patients, and they were not tested for G6PD deficiency or methemoglobinemia. The calculated number needed to harm after administration of a subsequent course of rasburicase is 17 (95% CI 9.1 – 71.9). ConclusionThis study indicates that, in our population, the incidence of anaphylaxis after the administration of subsequent treatment courses of rasburicase for hyperuricemic episodes may be greater than that described in the FDA-approved package insert for initial treatment courses. Caution is advised given the serious nature of the events (i.e. anaphylaxis, cardiac arrest, death) when administering repeated courses of rasburicase, and as with other agents that may predispose to immediate hypersensitivity reactions, premedication with antihistamines and corticosteroids should be considered.Table 1Anaphylaxis (n=6) associated with administration of repeated courses of rasburicase (n=97)Pt #Number of coursesTotal rasburicase exposure (mg)Time between courses (days)Time between dose and reaction (min)Diagnosed as AnaphylaxisLaboratory Tumor Lysis SyndromeICU admitIntubationCardiac ArrestDeath12622112YYYYYN22621337YNYYYY32969540YYNNNN421231910YNNNNN526150< 10YNNNNN641833559YNYNNN Disclosures:Off Label Use: Rasburicase is not approved for the administration of repeated courses of therapy.

Letter to the editor

Letter to the editor Vito D’Alessandro,1 Mario Greco21Respiratory Oncology Section – Internal Medicine Department, 2Hematopoietic Stem Cell Transplantation Unit Hematology-Oncology Department, of Scientific Institute, “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (FG), ItalyWe particularly appreciated the recent successful attempt at review of management of tumor lysis syndrome, entitled “Emerging role of rasburicase in the management of increased plasma uric acid levels in patients with hematologic malignancies”1 which reported some practical management considerations and financial implications of a complex subject. The praiseworthy aim was to give clear and easily applicable indications for clinical practice from recently published off-label treatment studies, using lower and fewer doses of rasburicase than recommended.View original paper by Kennedy and colleagues.