Dose Of Rasburicase Research Articles

Abstracts of the 17th International Symposium on Bioluminescence and Chemiluminescence ‐ (ISBC 2012)

WARNING : The light-emitting molecular structures responsible for the chemiluminescence and fluorescence phenomena are not necessarily the same!

Methemoglobinemia induced by rasburicase in a pediatric patient: A case report and literature review

Rasburicase is a recombinant urate oxidase enzyme indicated for tumor lysis syndrome (TLS), a potential life-threatening oncologic emergency that occurs most commonly during chemotherapy for hematological malignancies. As a result of the defects in the physiological antioxidant pathway, erythrocytes of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are not protected against the oxidating stress exerted by hydrogen peroxide generated with the administration of rasburicase. Therefore, rasburicase is contraindicated in patients with known G6PD deficiency and the manufacturer recommends screening all patients with high risk for G6PD deficiency before initiating rasburicase therapy. However, it is logistically difficult in clinical settings because of the high risk of morbidity and mortality associated with TLS if treatment is delayed and the long turnaround time of the G6PD deficiency screening. Therefore, administering rasburicase to patients developing TLS before confirming a patient's G6PD status is practically inevitable. Methemoglobinemia, and/or hemolysis, may result from the oxidative stress. Descriptions of the clinical course should it happen are limited in the literature. There are eight reported cases of rasburicase-related methemoglobinemia, with or without hemolytic anemia, in the literature of which five are pediatric patients. Six reports (including three pediatric patients) had detailed descriptions of the event and management. The recent reports of methemoglobinemia observed in patients with probable G6PD activity further complicated the picture. We are reporting a 16-year-old patient diagnosed with Burkitt's lymphoma who developed methemoglobinemia after receiving one dose of rasburicase. He was managed by transfusion and oxygen support. The patient recovered well and the observed methemoglobinemia was reversible.

Management of tumor lysis syndrome with a single fixed dose of rasburicase in Asian lymphoma patients: A case series and literature review

Recently, a number of studies have demonstrated the effectiveness of a single reduced dose of rasburicase for the management of tumor lysis syndrome (TLS) in adults. Whether Asian lymphoma patients similarly respond to a single dose of rasburicase is currently unknown. We aim to assess the efficacy of a single dose rasburicase in preventing TLS in Asian lymphoma patients. This was a single-center case series of adult lymphoma patients at high risk of TLS who received a single fixed dose of rasburicase. Patients had to have their uric acid, serum creatinine, lactate dehydrogenase and electrolytes monitored for at least 24-48 h post-administration. Eleven patients were identified. Majority were Chinese (91%), male (64%) and with a median age of 61 years (range 41-84). All had at least two risk factors for developing TLS. Ten patients received a 6-mg dose and one received 4.5 mg. Prior to rasburicase administration, the mean uric acid level was 835 µmol/L (range 318-1237 µmol/L) and the level 24-h post-administration was 186 µmol/L (range 30-653 µmol/L) (P < 0.001). Eight patients (73%) experienced an improvement of renal function 72-h post-rasburicase. Normalization of serum electrolytes was achieved within 96 h. Among Asian lymphoma patients who manifested at least two risk factors for developing TLS, a single fixed dose of rasburicase at 6 mg is deemed to be effective for rapidly lowering uric acid levels as well as sustaining reduced levels for up to 72 h.

The Efficacy of Rasburicase and Rituximab Combined with FAB Chemotherapy in Children and Adolescents with Newly Diagnosed Stage III/IV, BM+ and CNS+ Mature B-NHL: A Children's Oncology Group Report

Abstract 2702 Introduction/BackgroundTumor Lysis Syndrome (TLS) is a potentially life-threatening metabolic syndrome that frequently complicates the management of newly diagnosed mature B-NHL in children and adults (Cairo et al., BJH 2010). We have demonstrated rasburicase to be superior to allopurinol in the rapid reduction of uric acid (UA). (Goldman/Cairo et al, Blood 2001) In the previous FAB/LMB/96 international mature B-NHL trial, variables associated with a significant inferior EFS included advanced stage, elevated LDH, primary mediastinal involvement (PMBL) and combined BM/CNS disease (Cairo et al, JCO, 2011). We have previously reported the pharmacokinetics and safety of the addition of rituximab to a modified FAB/LMB/96 backbone in children and adolescents with advanced stage mature de-novo B-NHL. (Cairo et al., ASCO, 2010) Here we focus on outcome in those specific high-risk sub-categories of advanced childhood mature B-NHL following the incorporation of a recombinant urate oxidase (Rasburicase) and targeted immunotherapy (Rituximab) to the FAB/LMB/96 chemotherapy backbones. Material and MethodsChildren with newly diagnosed stage III/IV or high-risk (BM+±CNS+) de-novo mature B-NHL were prospectively treated with cyclophosphamide, vincristine, and prednisone (COP) reduction therapy preceded by 4–24 hours of non-alkaline hydration and rasburicase (0.2mg/kg) (generously supplied by Sanofi-Aventis). Laboratory and clinical TLS (LTLS and CTLS) was prospectively monitored as previously defined (Cairo & Bishop, BJH, 2004). Immunochemotherapy consisted of FAB B4 or C1 therapy (adriamycin 1 hr infusion) as we have previously described (Patte et al and Cairo et al, Blood, 2007) with the addition of rituximab 375 mg/m2/dose (generously supplied by Genentech) with 2 doses administered in each induction cycle and 1 dose in each consolidation cycle. ResultsWith respect to LTLS and CTLS, 78 patients were evaluable: group B (stage III/IV) with NL-LDH (<2X ULN, n=23), Group B with HI-LDH (≥ 2X ULN, n=18), and Group C (n=37). The mean initial UA levels (mg/dl +/− SD) were 4.7±2, 8.7±4.6, and 7.1±4.6, respectively. At presentation, 31% of patients (all groups) had an elevated (> 8mg/dl) UA, and 47% received elective doses of rasburicase in the days prior to the first day of chemotherapy. The incidence of LTLS prior to rasburicase in Group B NL-LDH, Group B HI-LDH, and Group C, was 4.3%, 5.5%, and 16.6%, respectively. The incidence of CTLS prior to rasburicase was 0%, 11%, and 8.6%, respectively. Following the administration of rasburicase, the incidence of new onset LTLS and CTLS for the entire cohort was 13% (2.6% with hyperuricemia) and 4% (1% with hyperuricemia), respectively. Furthermore, there was a significant improvement in the estimated GFR in those with renal impairment from day -1 prior to rasbursicase to day+7 post R-COP (55 ± 29 ml/min1.73 m2 to 136 ± 29 respectively; p<0.0007; Figure 1). Following combined FAB 96 chemotherapy (with 1 hour Adriamycin) and rituximab, the 3- year EFS (95% CI) for pilot patients (6 doses of rituximab) with Stage III/IV and Group C BM/CNS patients were 95% (80–99%) (Figure 2) and 89% (73–98%), respectively. Interestingly, two of four patients with centrally reviewed mediastinal primaries developed recurrent disease, while none of the 19 stage III/IV patients with LDH < 2X ULN developed recurrent disease or toxic deaths. [Display omitted] ConclusionsRasburicase and non-alkaline hydration largely prevented (94% of the time) new onset TLS with hyperuricemia safely during COP reduction therapy in children with advanced stages of de-novo mature B-NHL. For patients with mediastinal primaries, the high failure rate with group B4 therapy + rituximab suggests it would be appropriate to investigate new treatment strategies. Excluding this histology, combined modified FAB/LMB 96 chemotherapy and rituximab resulted in only 5 deaths (2 toxic deaths, 3 disease related deaths) among our cohort of 62 with advanced mature B-NHL. In comparing these current results from the previous FAB/LMB 96 trial without rituximab, the stage III/IV patients had a 95% vs. 84% and patients with CNS+ disease a 93% vs. 72% 3 year EFS. (Patte et al., Cairo et al. Blood, 2007) Future efforts to intensify chemotherapy in patients with CNS involvement should proceed only with careful toxicity monitoring, as preliminarily these patients seem to have excellent outcome with this immunochemotherapy approach. Disclosures:Gross:Pfizer Oncology: Consultancy; Roche/Genentech: Consultancy; Eli Lilly: Consultancy.

Rasburicase for hyperuricemia in hemolytic uremic syndrome

Acute kidney injury (AKI) with elevated serum uric acid (UA) levels has been reported in patients with hemolytic uremic syndrome (HUS). AKI is thought to result from tubular obstruction by UA crystals. Inducing a diuresis may ameliorate the oligoanuria in such patients. We describe a child with HUS in whom reducing UA with fluids and rasburicase appeared to accelerate the recovery of renal function. A 9-month-old Caucasian male infant presented with 6 days of diarrhea, 3 days of vomiting, and 24 h of oliguria. On admission, hemoglobin was 8.3 g/dL, platelet count 36,000/L, blood urea nitrogen 73 mg/dL, and serum creatinine (SCr) 2.7 mg/dL. Diarrhea-associated HUS was diagnosed. The day after admission, SCr was 2.9 mg/dL and UA 12.3 mg/dL. On hospital day 2, he received a dose of intravenous rasburicase 0.18 mg/kg, and less than 12 h later, the UA had fallen to 0.3 mg/dL. The SCr level also started to fall, and urine output progressively increased without the use of diuretics. Renal function continued to improve, and the UA level remained normal despite ongoing hemolysis requiring a second red blood cell transfusion on hospital day 5. The patient was discharged on hospital day 7 in good physical condition. Two months later, he was in good health, with a SCr level of 0.2 mg/dL and UA of 4.2 mg/dL. We postulate that aggressive management of the high serum UA level with rasburicase and fluid hydration accelerated the recovery of our patient. Further studies are needed to determine the role of rasburicase in the treatment of hyperuricemia in patients with HUS.

Rasburicase improves hyperuricemia in patients with acute kidney injury secondary to rhabdomyolysis caused by ecstasy intoxication and exertional heat stroke

To report the successful use of rasburicase in two children with hyperuricemia secondary to severe rhabdomyolysis. : Case report. Pediatric intensive care unit in a freestanding quaternary hospital. Two pediatric patients with severe rhabdomyolysis and hyperuricemia caused by ecstasy intoxication and exertional heat stroke. Use of a single low dose (6 mg) of rasburicase, a urate oxidase enzyme. Rasburicase was administered on the first and second hospital days with a single low dose of 6 mg (0.086 mg/kg in patient A and 0.092 mg/kg in patient B). Within 24 hrs, the levels of serum uric acid in both patients decreased dramatically, and their creatinine levels decreased and urine output increased concurrently. Continuous improvements in the uric acid levels, creatinine levels, and urine output were noted during hospitalization. Rasburicase seems to be a safe and effective drug for improving hyperuricemia in patients with rhabdomyolysis and renal failure.

The Tumor Lysis Syndrome

TO THE EDITOR: We recently admitted a patient to our intensive care unit with methemoglobinemia and severe hemolytic anemia after he received a single dose of rasburicase. The patient was 55-year-old black man with chronic lymphocytic leukemia in whom the tumor lysis syndrome developed after rituximab and bendamustine treatment despite saline and allopurinol prophylaxis. Within 6 hours after receiving rasburicase at dose of 0.2 mg per kilogram of body weight, he became hypoxic, with a methemoglobin concentration of 12.2% (Table 1). He subsequently had acute intravascular hemolysis, with the hemoglobin level decreasing from 13.1 to 4.5 g per deciliter, the lactate dehydrogenase level increasing from 158 to 1229 U per liter, and the haptoglobin level decreasing from 130 to 10 mg per deciliter. An elevated plasma oxyhemoglobin level (30.9 mg per deciliter [4.8 μmol per liter]; reference range, 0.0 to 12.4 mg per deciliter [0.0 to 1.9 μmol per liter]) was accompanied by acute pulmonary hypertension (tricuspid regurgitant jet velocity of 3.5 m per second; reference range, 1.7 to 2.8).1,2 He was found to have a glucose-6-phosphate dehydrogenase (G6PD) deficiency. Rasburicase causes oxidative stress by releasing hydrogen peroxide during the conversion of uric acid to allantoin.3 Although not specifically mentioned in the review by Howard et al. (May 12 issue),4 the Food and Drug Administration recommends that patients from populations where G6PD deficiency is common undergo testing before treatment with rasburicase.5 Table 1 Biochemical Evidence of Methemoglobinemia and Intravascular Hemolysis after Rasburicase Administration.*

Rasburicase in cancer-related hyperuricemia

Tumor lysis syndrome (TLS) is an oncological emergency consisting of several metabolic derangements: hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. The rupture of tumor cells in cancer patients can be spontaneous or caused by anticancer therapy. Clinical manifestations of TLS include nausea, anorexia, arrhythmias or renal failure. Prevention and treatment measures include aggressive hydration and concomitant antihyperuricemic therapy. Allopurinol has historically been the only available pharmacological option. Rasburicase was subsequently approved for the management of elevated plasma uric acid levels in adults. This recombinant urate oxidase converts uric acid to allantoin, a more soluble byproduct that is safely eliminated by the kidneys. Manufacturer-labeled dosing for rasburicase in the pediatric and adult populations is 0.2 mg/kg as a daily intravenous (i.v.) infusion for up to 5 days. This review summarizes several studies suggesting that flat, single rasburicase dosing regimens may be just as effective as weight-based dosing. The optimal, most cost-effective adult dose and schedule have yet to be determined.

Single 4.5mg Dose of Rasburicase for Tumor Lysis Syndrome In Adults

AbstractAbstract 1779 Introduction:Tumor Lysis Syndrome (TLS) is an oncologic emergency that leads to a host of metabolic disturbances which can ultimately result in acute renal failure and death.Currently rasburicase, Elitek™, is FDA approved for the treatment of TLS in patients with leukemia, lymphoma, and solid tumor malignancies which have risk factors for TLS. The approved adult dose is 0.2mg/kg/day over 30 minutes for up to 5 days. Chemotherapy should be initiated within 24 hours of rasburicase administration. Since rasburicase's introduction to the market, various studies have examined single dose use (3mg and 6mg) in the adult population, trying to resolve the dilemma of determining a dosing regimen for adults that is as effective as the FDA approved dosing regimen, while minimizing cost.This study was aimed at determining if a single 4.5mg dose of rasburicase would be adequate in reducing uric acid levels (UAL) as compared to the FDA approved conventional weight based approach; it also sought to determine the cost-effectiveness of this approach. Method:This is a retrospective study of the John H. Stroger Jr. Hospital of Cook County (JHS) patients who were administered a single dose of 4.5 mg rasburicase for TLS from 12/2007 to 06/2010. We included patients ≥ 18 years old, with a hematologic malignancy and on chemotherapy or about to start receiving chemotherapy within 24 hours of rasburicase administration. Patients with low risk for TLS or an indication other than prevention and management of TLS were excluded. Result:Demographics:Total number of patients:25Male 18(72%)Female7 (28%)Average age (years)54Average weight (kg)78.1RaceAfrican American15 (60%)White6 (24%)Hispanic3 (12%)Asian1 (4%)Characteristics:Responders are defined as patients that achieved more than 50% reduction in the UAL at 24 hours, 48 hours or 96 hours or a decrease of UAL to normal levels. Two patients required a second dose to achieve response. The non-responders did not receive any additional doses for unclear reasons. No adverse events were noted. Conclusion:This retrospective study provides evidence that a single 4.5mg dose of rasburicase effectively reduced plasma UAL to within normal limits. In addition, decrease in plasma UAL was observed within 24 hours after administration. No effect on electrolytes and serum creatinine was noted. [Display omitted] The cost-effectiveness of a single 4.5mg dose of rasburicase was evaluated based on dose and drug cost. The potential cost saving was substantial when compared with the FDA approved dose.In our opinion, this study validates the use of a single dose of 4.5mg rasburicase in the treatment and prophylaxis of TLS. This dose can be considered as a possible alternative to the FDA approved adult dosing regimen. Disclosures:No relevant conflicts of interest to declare.

Evaluation of Low Dose Rasburicase In the Prevention of Renal Insufficiency and Dialysis After Chemotherapy

AbstractAbstract 2574Rasburicase is a recombinant urate oxidase approved for the prevention of tumor lysis syndrome (TLS). In adults, the recommended dose is 0.2 mg/kg intravenously daily up to 5 days. For a 75 kg person, the cost is over $5100. Given the vast reduction of uric acid seen with this dose, it may be possible to use a reduce dose. The aim of this study is to evaluate the effectiveness of 0.1 mg/kg dose vs the recommended dose in the prevention of TLS. Between October of 2003 and February of 2009, all patients with a hematologic or oncologic diagnosis who received rasburicase were reviewed. Rasburicase had been dosed at either 0.1 mg/kg (low dose) or 0.2 mg/kg (standard dose) due to variations in practice among the practitioners. Rasburicase was given on the first day of chemotherapy and repeated as necessary. Renal insufficiency was defined by 0.5 mg/dl rise in serum creatinine (Scr) within 7 days of chemotherapy initiation. The need for dialysis was recorded separately. Labs were performed pretreatment and usually daily after chemotherapy until electrolytes stabilized. A multivariate analysis using pretreatment labs was performed to determine risk factors for renal insufficiency or failure. During the study period, 125 patients received rasburicase. Fifty-five patients received low dose rasburicase and 70 received the standard dose. The diagnoses are listed in Table 1. Lactate dehydrogenase (LDH) was similar between the two groups (604 U/l in low dose vs 665 U/l in standard dose, p = 0.69). Additional doses were required in 14.5% of the low dose patients vs 21.4% of the standard dose patients, p = 0.36. Renal insufficiency was noted only in the standard dose patients 7.4% vs 0%, p = 0.04. Rates of dialysis were similar between low dose patients 7.3% vs 17.4% in the standard dose patients, p = 0.10. Dialysis was often initiated for hyperkalemia and hyperphosphatemia. Only 12.5% were started for elevation in Scr. Uric acid reduction was higher in the standard dose patients (90.4 ± 15.8%) as compared with low dose patients (82.0 ± 19.0%, p = 0.01). Pretreatment Scr, uric acid and phosphorus levels were found to be significant variable for dialysis but only uric acid was found to be significant in the multivariate analysis. Pretreatment uric acid was a risk factor for dialysis (p < 0.001) but not for renal insufficiency (p = 0.24). Our results suggest that low dose rasburicase may be as effective as 0.2 mg/kg. While high dose rasburicase was more effective at reducing uric acid, it did not reduce the need for dialysis because dialysis was often needed for hyperkalemia and hyperphosphatemia which rasburicase did not affect. Despite bias, our results suggest low dose rasburicase may be a viable alternative and definitely support further study into its use. The potential savings could be enormous given that it would be $2550 per patient.Table 1Baseline diagnosis of 125 patients with TLSDiagnosisLow doseStandard dose doseDiffuse large B-cell lymphoma1317Chronic lymphocytic leukemia312Multiple myeloma75Non-Hodgkin's lymphoma47Acute myeloid leukemia47Burkitt's lymphoma34T-cell lymphoma43B-cell lymphoma51Solid Tumor15Myelofibrosis32Mantle cell lymphoma31Amyloidosis02Blast crisis in acute leukemia11B-cell lymphoproliferative disorder01Chronic myeloproliferative disorder01Follicular mixed lymphoma01Hodgkin's lymphoma10undifferentiated10Lymphoreticular myeloid malignancy10Post-transplant lymphoproliferative disorder01Splenic marginal cell lymphoma10Waldenstrom macroglobulinemia10Total5570 Disclosure:No relevant conflicts of interest to declare.

Is Rasburicase Effective In Reversing Acute Renal Failure In Patients with Tumor Lyses Syndrome?

AbstractAbstract 4939Tumor lysis syndrome (TLS) is a potentially life-threatening complication that can occur spontaneously or following treatment of malignant neoplasms, particularly leukemias and lymphomas. TLS can cause acute renal failure (ARF) by precipitation of uric acid (UA) and phosphate crystals in renal tubules. Rasburicase, a recombinant urate oxidase, was proven to be effective in the treatment of TLS and is known to cause an improvement in renal function in a subset of patients with TLS. For the purposes of our analysis ARF was defined as more than 50% increase in creatinine from baseline value or presenting with creatinine more or equal to 2 mg/dl with no previous history of chronic renal failure. To assess the efficacy of Rasburicase in adult patients with documented TLS and ARF in improving or normalizing the creatinine clearance (CrCl), we conducted a retrospective analysis of 53 patients that received Rasburicase for documented TLS. 41 patients fit the inclusion criteria. The median age was 54 yr (26-90), 13 were female. The majority of patients had hematological malignancies (acute leukemia, 11; chronic leukemia, 5; myeloproliferative/myelodysplastic syndromes, 4; lymphoma or myeloma, 10; solid tumor; 11).Results: On the first day of rasburicase infusion (day 0), median UA, creatinine and CrCl were 11.5 mg/dl (5.1 - 23.7mg/dl), 3.26 mg/dl and 32.5 ml/min (8.0 - 97.8 ml/min) calculated using Cockcroft-Gault equation, respectively. Patients received an average total dose of 0.17 mg/kg (0.06-0.51 mg/kg) of rasburicase in one or two doses. UA levels normalized in 97.3% and 100% of patients by day 2 and 7 respectively. Creatinine levels normalized in 19% and 59.4% by day 2 and 7 respectively. CrCl improved form a median of 32.5 ml/min to 40.5 ml/min and 58 ml/min by day 2 and 7 respectively. A sub analysis for patients with baseline CrCl <30 ml/min (n=17) on day 0 of Rasburicase infusion revealed a similar benefit to those with baseline CrCl >30 ml/min. CrCl improved in this subset of patients from a median of 17 ml/min (8-28.2 ml/min) to 24.5 and 47.4 ml/min on days 2 and 7 respectively. Patients who received a total dose of <0.1mg/kg of rasburicase (n=8) derived similar benefits to those who received 0.2mg/kg or more (n=11).Conclusion: Rasburicase infusion is effective in improving the creatinine clearance even in patients with advanced renal failure (CrCl<30 ml). Lower doses of Rasburicase are as effective as higher doses, even in patients with advanced renal failure, making the lower dose advisable and cost effective. Disclosures:No relevant conflicts of interest to declare.

Oncology: Fixed-Dose Rasburicase 6 mg for Hyperuricemia and Tumor Lysis Syndrome in High-Risk Cancer Patients

Rasburicase is indicated for the initial management of plasma uric acid levels in adults receiving anticancer therapy who are at risk for acute tumor lysis syndrome (TLS) and subsequent hyperuricemia. The labeled dose is 0.2 mg/kg/day administered intravenously over 30 minutes for up to 5 days. Our institutional adult guidelines recommend rasburicase 6 mg for uric acid levels >8 mg/dL in most adults with TLS, or 4-8 mg/dL in high-risk patients. Repeat dosing is indicated for uric acid levels >4 mg/dL determined ≥12 hours following the initial dose. To determine the efficacy of a single dose of rasburicase 6 mg per institutional adult TLS guidelines to decrease uric acid levels to <4 mg/dL by day 3, as well as to determine the effect on serum creatinine and phosphorus concentrations. The secondary objectives were to evaluate the appropriateness of our institutional guidelines and identify TLS risk factors. The study was approved by the University of Maryland Medical Center Institutional Review Board. A retrospective review of all adults between July 2008 and February 2009 who received at least one 6-mg dose of rasburicase, with redosing, if indicated, before day 3, was conducted. Subsequent TLS monitoring over 7 days after initial dosing was recorded. Patients were excluded if dosing did not adhere to institutional guidelines. We observed a decline in median uric acid levels from 9.2 mg/dL (interquartile range 8.1-10.4) on day 1 to between 1.8 (1.0-3.8) on day 3 and 3.8 mg/dL (2.1-4.4) on day 7 (p < 0.0001) with 2 patients requiring repeat dosing before day 3 (n = 34). The majority of the population was hyperuricemic (>8 mg/dL; 76%) or at high risk for TLS (85%). A 6-mg dose of rasburicase effectively decreased uric acid to <4 mg/dL by day 3, rarely requiring repeat dosing, in a high-risk population.

Effectiveness of a single 3-mg rasburicase dose for the management of hyperuricemia in patients with hematological malignancies

Rasburicase was administered at a fixed dose of 3 mg to treat 287 episodes of elevated serum uric acid levels (>7 mg/dL) in 247 adult patients with hematological malignancies. The median total dose of 36 μg/kg (range: 18-65) was a fraction of the recommended total pediatric dose of 0.75-1.0 mg/kg. The median change in uric acid levels at 24 h was -4.1 mg/dL (range: -12 to +1) and -45% (range: -95 to +9). Uric acid levels normalized at 24 h in 72% of patients. There was no relationship between the weight-based dose and uric acid decline. The only predictor of success was the baseline uric acid; the failure rate was 84% with baseline level >12 mg/dL and 18% if it was ≤ 12. Uric acid levels continued to decline beyond 24 h in most patients without additional treatment. Serum creatinine remained stable over 24 h, and declined over 48 h and 7 days. There was no relationship between the extent of reduction in uric acid levels and serum creatinine. We conclude that a single 3-mg dose of rasburicase, used with close monitoring, is sufficient to treat most adults with uric acid levels up to 12 mg/dL.

A single, fixed dose of rasburicase (6 mg maximum) for treatment of tumor lysis syndrome in adults

A single, fixed dose of rasburicase (6 mg maximum) for treatment of tumor lysis syndrome in adults

Rasburicase in the treatment of hyperuricemia of newborns

Sirs,The article by Hobbs and coworkers [1] provides scientificevidence for what we believe is a common clinical practice:the use of rasburicase in hyperuricemic newborns withacute kidney injury (AKI).These authors retrospectively reviewed the charts of 7hyperuricemic infants with AKI, successfully treated with asingle dose of rasburicase (0.17±0.04 mg/kg).Duringthelastfewyearswealsoexperiencedtheefficacyand safety of rasburicase in 10 AKI newborns (7 boys, 3girls), with a mean (± SD) body weight of 1,226 g (± 644.4),born at 29.4 weeks (± 30 days) and with a mean age atadministration of therapy of 20.2 days (± 11.5). Six of themwere of very low birth weight (VLBW) and 9 werepremature (data not published).After a single intravenous dose of rasburicase (0.2 mg/kgin 30 min) we also observed a statistically significantdecrease in serum uric acid concentration of a mean levelranging from 14.5±3.6 mg/dl to 6.6±7.5 mg/dl (p<0.002).No side effects were recorded.Hobbs and coworkers reported a significant improvementin serum creatinine and urine output on day 1 followingrasburicase [1]. The authors seem to attribute these results tothe reduction in serum uric acid as described in oncologicalpatients with tumor lysis syndrome (TLS) [2–4]. These dataare not confirmed by our study. We believe that uric acidplays a pathogenetic role in AKI secondary to TLS, while, asin the series by Hobbs et al., our patient’s uric acid increasedas a consequence of a reduction in urinary excretion, ratherthan overproduction. In fact, if we analyze each patientseparately it can be speculated that the specific therapy of theunderlying diseases, such as rehydration, is the main factorexplaining the improvement in serum creatinine and urineoutput, as evidenced by the sharp decrease in blood ureanitrogen and the improvement in urine output (in patients 1,3, and 7) after rehydration and/or resuscitation. Moreover, in2 cases (patients 2 and 4) serum creatinine remainedsignificantly high during the first week after treatment.At present, various studies have confirmed that rasburi-case is effective in reducing uric acid concentration and iswell tolerated [1, 4, 5], even in the neonatal period [3] andin premature newborns, as shown by our experience.References

Evaluation of a low, weight-based dose of rasburicase in adult patients for the treatment or prophylaxis of tumor lysis syndrome

Rasburicase is a recombinant urate oxidase enzyme generally reserved for the treatment or prevention of hyperuricemia in patients that are at high risk of developing tumor lysis syndrome (TLS). The primary objective of this study is to evaluate and characterize the outcomes of patients receiving low dose rasburicase for treatment or prophylaxis of hyperuricemia secondary to TLS. A retrospective chart review between April 1, 2007 and September 31, 2008 was completed. All adult patients who received a dose of 0.05mg/kg with either a leukemia or lymphoma diagnosis in addition to at least two TLS risk factors: WBC ≥ 50 × 109/L, LDH 2 × ULN, uric acid ≥ 8 mg/dl, SCr ≥ 1.5 mg/dl were included. Forty-eight patients received rasburicase for prophylaxis (n = 18) or treatment (n = 30) of TLS. Forty patients achieved and maintained a uric acid less than 8 mg/dL, 24 h after receipt of a single dose of rasburicase without the requirement for renal replacement therapy. A statistically significant decrease in UA was achieved in all patients when compared to baseline (p < 0.001). Cost analysis revealed a $ 1.96 million (96%) direct cost savings for the 48 patients in this study when compared to the cost of manufacturer's dosing recommendation. Low dose rasburicase was efficacious and cost effective for both prophylaxis and treatment of TLS. Administration of a single dose of 0.05mg/kg of rasburicase was sufficient in correcting uric acid levels for most patients.

Randomized Clinical Trial of Rasburicase Administered as a Standard Fixed Five Days Dosing Vs a Single Dose Followed by as Needed Dosing in Adult Patients with Hematologic Malignancies at Risk for Developing Tumor Lysis Syndrome.

Abstract 105Tumor lysis syndrome (TLS) is a potentially life threatening complication resulting from massive lysis of malignant cells and most frequently observed in patients with rapidly proliferating, bulky, and chemo-sensitive malignancies. The prevention and management of TLS includes hydration and reduction in the levels of serum uric acid by drugs that decrease production or increase excretion of uric acid. Rasburicase is a recombinant urate oxidase that rapidly reduces the levels of uric acid by enhancing the conversion of existing uric acid into allantoin which is more soluble in urine than uric acid. Rasburicase is approved in the USA for the treatment of pediatric patients at high risk for developing TLS, to be administered at a dose of 0.15 to 0.2 mg/kg once daily for 5 days. Although, activity has been seen with lower doses and shorter duration of treatment, the optimal dosing of rasburicase has not been established for adults. The purpose of this study was to evaluate the efficacy of rasburicase (0.15 mg/kg) administered as a single dose followed by as needed (max 5 doses over 5 days) as compared to standard fixed 5-days dosing in patients with hematologic malignancies at risk for TLS. The patients were stratified based on their risk for TLS and randomized 1:1 to rasburicase administered as a single dose followed by as needed (Arm A) or fixed daily dose x 5 days (Arm B). Sixty six patients were enrolled; 20 had > 2-fold LDH levels and 9 had above-normal serum creatinine. 64 patients received at least one dose of rasburicase and were evaluable for response [24 high risk with mean baseline uric acid levels, 9.8 (7.6–16.1 mg/dL) and 40 potential risk with uric acid, 5.3 (2.4-7.4 mg/dL)]. All patients normalized their uric acid levels at 4 hours after the first dose; 83% to an undetectable level (<0.7 mg/dL). On Arm B (fixed 5-days dosing), all patients (n=34, 100%) had a sustained response, as defined by the normalization of uric acid levels in 48 hours and its maintenance within normal range for 6 days. On Arm A, all except for 4 patients (all 4 high risk for TLS) had a sustained response (26 of 30, 87%) to a single dose of rasburicase. Four of 11 patients from the high risk group required a second dose around day 4 for uric acid levels >7.5 mg/dL. Serum creatinine normalized in all patients by day 5. The treatment was well tolerated, except for one incident of methemoglobinema and hemolytic anemia in a patient found to have G6PD deficiency. Since high uric acid levels have been associated with elevated cytokine levels, we examined the effects of treatment on plasma cytokines. At baseline, high risk patients showed increased TNF-α and IL-6 plasma levels. There was a marked decrease in the plasma levels of TNF-α (from mean 14.2 to 6.4 pg/ml, p<0.0001), and IL-6 (from 11.2 to 8 pg/mL, p=0.05) during treatment.Conclusion: Rasburicase is a highly effective uricolytic agent for prevention and management of TLS. This study demonstrates that it is feasible to decrease the duration of administration of rasburicase at the approved dose of 0.15 mg/kg. The majority of patients responded to a single dose of the agent, and only a small subset at high risk for TLS required a second dose. Disclosures:Vadhan-Raj:Sanofi Aventis: Honoraria, Research Funding. Off Label Use: Rasburicase is indicated for the initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of uric acid. The approved administration dose, route, and schedule are 0.15-0.20 mg/kg IV infusion for 5 days, respectively.

Effectiveness of a Single 3 Mg Rasburicase Dose for the Management of Hyperuricemia in Patients with Hematologic Malignancies.

Abstract 2479Poster Board II-456Hyperuricemia(HU) is a frequent complication following therapy for hematologolical malignancies(HM). Conventional therpy with alkalinization, hydration and allopurinol may not be sufficient to lower pre-existingly high uric acid levels(UA). Rasburicase, recombinant urate oxidase, when given at pediatric doses(0.15-.2mg/kg/d x 3-5d)is very effective in lowering UA levels <2mg/dl. The high cost and questionable need to lower UA to near undectectable levels prompted a pre-emptive dose reduced strategy to lower UA. Rasburicase was administered at a single fixed dose of 3 mg to treat 287 episodes of elevated serum UA (>7 mg/dL) in 247 adult patients with hematologic malignancies. 28% had renal failure (serum creatinine >2.5 mg/dL) and 29% had tumor lysis syndrome. The median dose of 36 μg/kg (range 18-65) was a fraction of the recommended pediatric dose of 0.75-1.0 mg/kg over 5 days. The median change in the uric acid levels at 24 hours was -4.1 mg/dL (range -12 to +1) and -45% (range -95 to +9). The uric acid levels normalized at 24 hours in 78% of patients. There was no relationship between the weight-adjusted dose and uric acid decline. The only predictor of resolution of hyperuricemia was baseline uric acid; the failure rate was 84% with baseline uric acid of >12 mg/dL compared to 18% if the baseline level was '12. The level continued to decline beyond 24 hours in the majority of patients in the absence of additional doses. Serum creatinine remained stable over 24 hours and declined over 48 hours and 7 days. There was no relationship between the extent of reduction in uric acid levels and serum creatinine. The approach We conclude that a single 3 mg dose of rasburicase, used with close clinical and laboratory monitoring, is sufficient in most adults with elevated serum uric acid levels up to 12 mg/dL. The best approach to patients with higher levels remains unclear.Table 2:Serum uric acid and creatinine levels and changes (median, range)Serum uric acid (Median, range)Baseline level (mg/dL)9.3 (7.1–27.3)24-hour level (mg/dL)5.3 (0.5–23.0)24-hour direction of changeAny increase9 (3%)No change1 (<1%)Any decrease277 (97%)Increase or <10% decrease21 (7%)≥10% decrease266 (93%)24-hour absolute change (mg/dL)−4.1 (−12 to +1)24-hour per cent change (%)−45 (−95 to +9)24-hour level >7 mg/dL81 (28%)24-hour level >5 mg/dL150 (52%)Serum creatinine (Median, range)Baseline level (mg/dL)1.7 (0.6–9.7)24-hour level (mg/dL)1.6 (0.6–8.7)24-hour direction of changeAny increase88 (31%)No change54 (19%)Any decrease145 (50%)≥10% increase52 (18%)<10% change143 (50%)≥10% decrease92 (32%)24-hour absolute change (mg/dL)−0.1 (−3.3 to +1.4)24-hour per cent change (%)−3 (−80 to +70)Serum uric acid (mg/dL)24/7 failureP24/5 failureP≤1013%<0.000138%<0.0001>1064%85%≤1218%<0.000145%<0.0001>1284%93%≤1525%<0.000150%<0.0001>1579%89% Disclosures:No relevant conflicts of interest to declare.

Rasburicase for the prevention and treatment of hyperuricemia in tumor lysis syndrome

To review current knowledge about tumor lysis syndrome (TLS), a set of metabolic imbalances, including hyperuricemia, that often occur during chemotherapeutic or biotherapeutic treatment of patients with hematologic malignancies. English language journal articles indexed in PubMed. Recent reviews and original research articles related to TLS, hyperuricemia, and treatment of hyperuricemia were selected for inclusion. The incidence of TLS depends highly on the type of malignancy, its growth characteristics, and the total tumor burden. Patients are at heightened risk if they have hyperuricemia, hypovolemia, or poor renal function before anticancer therapy begins. Recently published guidelines make risk assessment and patient staging more systematic. Prophylactic measures should be used to reduce the risk for TLS in vulnerable patients. Such measures include hydration to facilitate urinary excretion and administration of allopurinol to prevent de novo production of uric acid. If hyperuricemia occurs despite preventative efforts, uric acid concentrations can be reduced with rasburicase, a recombinant, intravenously administered urate oxidase. The cost of rasburicase therapy is substantial but is considerably less than that of hemodialysis and extended hospitalization. Shorter courses or smaller doses of rasburicase than those recommended may be effective in reducing hyperuricemia in some patients, but it is important to recognize that the alternative dosing still awaits validation. Allopurinol and rasburicase are recommended for preventing hyperuricemia in patients at intermediate or high risk for TLS, respectively. If hyperuricemia develops despite preventative measures, rasburicase treatment is an effective method for lowering uric acid concentrations within normal limits.

A study of rasburicase for the management of hyperuricemia in pediatric patients with newly diagnosed hematologic malignancies at high risk for tumor lysis syndrome

Tumor lysis syndrome (TLS), including hyperuricemia, is a frequent serious complication in patients with hematologic malignancies. This study in Japanese patients evaluated the efficacy, safety, and pharmacokinetic profile of rasburicase in pediatric patients with hematologic malignancies. Patients aged <18 years at high risk for TLS, with newly diagnosed hematologic malignancies, were randomized to intravenous rasburicase 0.15 mg/kg/day (n = 15) or 0.20 mg/kg/day (n = 15) for 5 days. Chemotherapy was started 4-24 h after the first rasburicase dose. Response was defined as a reduction in plasma uric acid to < or = 6.5 mg/dL (patients <13 years) or < or = 7.5 mg/dL (patients > or = 13 years) by 48 h after the first administration, lasting until 24 h after the final administration. Response rates were 93.3 and 100% with rasburicase 0.15 and 0.20 mg/kg/day, respectively. Uric acid levels declined rapidly within 4 h of starting rasburicase administration in both groups. Most adverse events were related to the underlying chemotherapy regimens. Two hypersensitivity reactions, including grade 1/2 pruritus, were considered to be related to rasburicase. Rasburicase is effective and well tolerated for the management of hyperuricemia in Japanese pediatric patients at high risk of developing TLS.