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Rasburicase

Web Resources: Rasburicase
Recent Research Publications

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Recent Research Publications

Kimakura M, Abe T, Nagahara A, et al.
Metastatic testicular cancer presenting with liver and kidney dysfunction treated with modified BEP chemotherapy combined with continuous hemodiafiltration and rasburicase.
Anticancer Drugs. 2016; 27(4):364-8 [PubMed] Free Access to Full Article Related Publications
A 25-year-old man was admitted to our hospital complaining of right scrotal pain and upper abdominal pain. A computed tomographic scan indicated a right scrotal mass, a huge liver mass, and multiple lung masses, although there was no enlarged retroperitoneal lymph node swelling. Laboratory tests showed severe liver and kidney dysfunction and high levels of serum α-fetoprotein (11,997 ng/ml). Although needle biopsies of the testicular and liver masses were performed, the tissues were insufficient for a pathological diagnosis. As liver and kidney function worsened, we started chemotherapy with bleomycin, etoposide, and cisplatin (BEP chemotherapy), which was modified because of the liver and renal dysfunction. We also used continuous hemodiafiltration and rasburicase to prevent tumor lysis syndrome. After induction of chemotherapy, the liver and kidney dysfunction improved immediately and the high orchiectomy was performed on day 8 after chemotherapy. The pathological diagnosis was a yolk sac tumor. He underwent four courses of the BEP regimen and five courses of the TIN regimen (paclitaxel, ifosphamide, and nedaplatin), followed by the resection of liver metastases. There was no evidence of viable cells in the resected liver and no recurrence was evident at 1 year postoperatively.

Daly GF, Barnard EB, Thoreson L
Renal Calculi: An Unusual Presentation of T-Cell Acute Lymphoblastic Leukemia.
Pediatrics. 2016; 137(1) [PubMed] Related Publications
Spontaneous tumor lysis syndrome is a rare initial presentation of hematologic malignancy in children that typically presents with complications of electrolyte derangement, specifically hyperkalemia, hyperphosphatemia, and hyperuricemia. We report a case of a 5-year-old boy who presented to the emergency department with gross hematuria, abdominal pain, and vomiting and was ultimately diagnosed with uric acid nephrolithiasis and acute renal failure secondary to spontaneous tumor lysis syndrome in the setting of T-cell acute lymphoblastic leukemia. Tumor lysis syndrome is considered an oncologic emergency, and in this case, the child required urgent treatment with potassium-binding agents, rasburicase, and hemodialysis. This case demonstrates that occult hematologic malignancy should be suspected in cases of nephrolithiasis and acute renal failure when found in conjunction with hyperuricemia despite a normal complete blood count at the time of presentation.

Alessa MA, Craig AK, Cunningham JM
Rasburicase-Induced Methemoglobinemia in a Patient with Aggressive Non-Hodgkin's Lymphoma.
Am J Case Rep. 2015; 16:590-3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Rasburicase is a recombinant urate oxidase enzyme that converts uric acid to allantoin (an inactive and soluble metabolite that is readily excreted in urine). It is used for the management of tumor lysis syndrome (TLS) in cancer patients receiving chemotherapy. Although rasburicase is a generally safe and effective treatment, it can be associated with the rare and potentially severe complication of methemoglobinemia. Here, we report a case of rasburicase-induced methemoglobinemia in a patient who was diagnosed with aggressive non-Hodgkin's lymphoma.
CASE REPORT: A 74-year-old man with aggressive non-Hodgkin's lymphoma was admitted for initiation of chemotherapy. Upon admission, the patient was found to have hyperkalemia, hyperuricemia, hyperphosphatemia, elevated LDH levels, and acute renal failure. As a result, he was diagnosed with TLS. Rasburicase 6 mg was administered intravenously over a period of 30 min to treat TLS. Later, methemoglobinemia developed, with requirements for oxygen supplementation. Multiple units of packed red blood cells were transfused for recurrent significant anemia secondary to his cancer co-morbidity. The patient was tested for glucose-6 phosphate dehydrogenase (G6PD) deficiency, which returned negative; therefore, methylene blue was considered. After transfusion, the methemoglobin level normalized over the course of a few days, and the oxygen saturation improved without the use of methylene blue. However, during his hospitalization, the patient also developed a pulmonary embolism and had evidence of acute coronary syndrome. Later, the patient died of multiple complications related to his cancer co-morbidity on day 12 of admission.
CONCLUSIONS: Blood transfusion and supplemental oxygen, without the use of methylene blue, may be an appropriate therapeutic alternative in rasburicase-induced methemoglobinemia treatment.

Saleh RR, Rodrigues J, Lee TC
A tumour lysis syndrome in a chemotherapy naïve patient with metastatic pancreatic adenocarcinoma.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
A 56-year-old woman with a new diagnosis of metastatic pancreatic cancer presents to the emergency room with generalised fatigue. The patient is afebrile, however, hypotensive and tachycardic. Physical examination shows diffuse lymphadenopathy. Initial laboratory tests indicate that the patient has hyperkalaemia, hypocalcaemia, with a high lactate dehydrogenase and high uric acid. The patient was also in renal failure. On the basis of the clinical presentation, the patient was diagnosed with spontaneous tumour lysis syndrome, despite the syndrome never having been reported in metastatic pancreatic cancer. The patient was treated appropriately with intravenous hydration, allopurinol and rasburicase. All laboratory abnormalities were corrected by day 3 of treatment.

Cheuk DK, Chiang AK, Chan GC, Ha SY
Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer.
Cochrane Database Syst Rev. 2014; (8):CD006945 [PubMed] Related Publications
BACKGROUND: 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.
OBJECTIVES: To assess the effects and safety of urate oxidase for the prevention and treatment of TLS in children with malignancies.
SEARCH METHODS: 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.
SELECTION CRITERIA: 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.
DATA COLLECTION AND ANALYSIS: 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.
MAIN RESULTS: 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.
AUTHORS' CONCLUSIONS: 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.

Digumarti R, Sinha S, Nirni SS, et al.
Efficacy of rasburicase (recombinant urate oxidase) in the prevention and treatment of malignancy-associated hyperuricemia: an Indian experience.
Indian J Cancer. 2014 Apr-Jun; 51(2):180-3 [PubMed] Related Publications
BACKGROUND: Patients with hematological malignancies that are highly proliferative and have high tumor burden are at high risk of developing hyperuricemia and tumor lysis syndrome (TLS), spontaneously and while undergoing chemotherapy.
AIM: To assess the safety and efficacy of a new generic formulation of recombinant rasburicase in prevention and treatment of malignancy-associated hyperuricemia.
MATERIALS AND METHODS: An open-label, multicenter, phase-III study was conducted on 100 eligible patients with high risk for TLS. Rasburicase was administered 0.2 mg/kg intravenously over 30 min, daily, for 4 days. The outcome measures were percentage of reduction in plasma uric acid at 4 h after rasburicase, plasma uric acid area under the curve (AUC)(0-96 h) and incidence of adverse events.
RESULTS: Eighty eight patients completed the study period of 10 days. After rasburicase administration, there was a 75.3 ± 28.5% of reduction in plasma uric acid at 4 h as compared to baseline. The plasma uric acid AUC(0-96 h) was 259.9 ± 215.5 mg/dL h. Safety of rasburicase was assessed on the basis of changes in vitals, hematological, and biochemical parameters from baseline to termination. Except for the plasma uric acid level, there was no significant difference in any of the parameters. Mild to moderate adverse events were reported in 29 patients. Three patients had serious adverse events (SAEs) unrelated to rasburicase.
CONCLUSIONS: These results demonstrated that recombinant rasburicase that is indigenously developed is effective for prevention and management of hyperuricemia in patients who are at high risk of developing TLS.

Burns RA, Topoz I, Reynolds SL
Tumor lysis syndrome: risk factors, diagnosis, and management.
Pediatr Emerg Care. 2014; 30(8):571-6; quiz 577-9 [PubMed] Related Publications
Tumor lysis syndrome (TLS) is a potentially fatal complication of induction therapy for several types of malignancies. Electrolyte derangements and even downstream complications may also occur prior to the initial presentation to a medical provider, before an oncologic diagnosis has been established. It is therefore imperative that emergency physicians be familiar with the risk factors for TLS in children as well as the criteria for diagnosis and the strategies for prevention and management. Careful evaluation of serum electrolytes, uric acid, and renal function must occur. Patients at risk for TLS and those who already exhibit laboratory or clinical evidence of TLS require close monitoring, aggressive hydration, and appropriate medical treatment.

Yun S, Vincelette ND, Phan T, Anwer F
Spontaneous tumour lysis syndrome associated with contrast dye iohexol use in mantle cell lymphoma.
BMJ Case Rep. 2014; 2014 [PubMed] Related Publications
We describe a case of a 73-year-old man who presented with right-sided abdominal pain associated with palpable mass. Initial laboratory examination was normal except lactate dehydrogenase level. Subsequent CT image showed situs inversus and splenic mass with multiple lymph nodes enlargement. Biopsy taken from the splenic mass demonstrated mantle cell lymphoma. Staging CT examination was performed with intravenous contrast, and patient developed altered mental status, respiratory failure and acute kidney injury requiring intensive care unit care. Laboratory examination revealed hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia, which are consistent with spontaneous tumour lysis syndrome. The patient was successfully treated with rasburicase and haemodialysis, and completed the first course of chemotherapy without further complications.

Shely RN, Ratliff PD
Carfilzomib-associated tumor lysis syndrome.
Pharmacotherapy. 2014; 34(5):e34-7 [PubMed] Related Publications
Multiple myeloma is the second most common type of hematologic malignancy. It is a B-cell malignancy that affects the bone marrow and often results in thrombocytopenia as well as renal dysfunction. Treatment options range from oral and intravenous chemotherapy to bone marrow transplantation and supportive care. Carfilzomib was approved by the U.S. Food and Drug Administration in 2012 as a treatment option for patients with refractory multiple myeloma who have received at least two previous therapies and have demonstrated recent disease progression. According to the product labeling, the frequency of tumor lysis syndrome (TLS) is less than 1% in patients treated with carfilzomib. To our knowledge, no postmarketing events of TLS have been reported or published. We describe a 55-year-old man with relapsed multiple myeloma who developed a case of TLS that occurred after he received his first two doses of carfilzomib therapy on days 1 and 2; he also had chronic kidney disease secondary to his neoplastic disease. Beginning on day 4, his uric acid levels spiked to critical levels, prompting the use of rasburicase, which returned the levels to within normal limits. His phosphorus and creatinine levels increased during days 5 and 6. On day 8, the patient died, likely due to a combination of disease progression and the adverse effects of treatment. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the patient's development of TLS and carfilzomib therapy. The Hill criteria were used as a secondary measure to ensure causality, which also suggested a link between the patient's development of TLS and the administration of carfilzomib. This case report shows that even the most unlikely of adverse events may occur with medications, especially in the case of a new or recently approved medication. Caution must be taken when deciding to treat and when choosing hydration and premedications with regard to biologic and chemotherapeutic medications. In this case, additional hydration may have been considered. Although given the extent of the adverse reaction combined with the patient's underlying renal dysfunction, extra fluid may or may not have proven beneficial. The use of prophylactic rasburicase or allopurinol could have been considered, but these measures are not typically used with multiple myeloma due to the low incidence of TLS. All things considered, this unlikely adverse reaction may occur in certain patients. If other cases such as this occur, it may be advisable to use TLS prophylaxis in the future in certain patient populations, including those with renal dysfunction or worsening disease states.

Bakhshi S, Singh RB, Munot K, Pathania S
Complications of "very high" leukocytosis in pediatric acute leukemia patients managed without rasburicase and leukopheresis.
Indian J Pediatr. 2014; 81(8):817-20 [PubMed] Related Publications
The authors evaluated complications in pediatric acute leukemia with "very high" leukocytosis (VHL) prior to rasburicase availability and without leukopheresis. From Jun 2003 through Dec 2009, 45 out of 457 (10 %) pediatric acute leukemia patients had VHL. Median WBC for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients was 296,500/mm3 (200,000-615,220) and 206,300/mm3 (106,100-541,900) respectively. Laboratory and clinical tumor-lysis-syndrome was seen in 37.7 % and 13.3 % patients respectively; none required dialysis; 6.6 % died due to CNS/pulmonary bleed. Thrombocytopenia <31,000/mm3 was associated with hypocalcemia (p = 0.04) and mortality (p = 0.04), and hypoalbuminemia with kidney dysfunction (p = 0.04). In resource-limited setting, VHL patients with thrombocytopenia may warrant rasburicase with or without leukopheresis, and aggressive platelet support.

Galardy PJ, Hochberg J, Perkins SL, et al.
Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: a Children's Oncology Group Report.
Br J Haematol. 2013; 163(3):365-72 [PubMed] Free Access to Full Article Related Publications
Laboratory (LTLS) and clinical (CTLS) tumour lysis syndrome (TLS) are frequent complications in newly diagnosed children with advanced mature B cell non-Hodgkin lymphoma (B-NHL). Rasburicase, compared to allopurinol, results in more rapid reduction of uric acid in paediatric patients at risk for TLS. However, the safety and efficacy of rasburicase for the treatment or or prevention of TLS has not been prospectively evaluated. Children with newly diagnosed stage III-IV, bone marrow(+) and/or central nervous system(+) mature B-NHL received hydration and rasburicase prior to cytoreductive therapy. Rasburicase was safe and well-tolerated and there were no grade III-IV toxicities probably or directly related to rasburicase. Patients with an initial lactate dehydrogenase ≥2× upper limit of normal had a significantly elevated uric acid level (P = 0·005), increased incidence of TLS (P-0·005) and lower glomerular filtration rate (GFR; P < 0·001). Following rasburicase, there was only a 9% and 5% incidence of LTLS and CTLS, respectively. Furthermore, there was a significant improvement in estimated GFR from Day 0 to Day 7 following rasburicase (P = 0·0007) and only 1·3% of patients required new onset renal assisted support after rasburicase administration. A TLS strategy incorporating rasburicase prior to cytoreductive chemotherapy proved safe and effective in preventing new onset renal failure and was associated with a significant improvement in GFR.

Darmon M, Vincent F, Camous L, et al.
Tumour lysis syndrome and acute kidney injury in high-risk haematology patients in the rasburicase era. A prospective multicentre study from the Groupe de Recherche en Réanimation Respiratoire et Onco-Hématologique.
Br J Haematol. 2013; 162(4):489-97 [PubMed] Related Publications
In tumour lysis syndrome (TLS), metabolic alterations caused by the destruction of malignant cells manifest as laboratory abnormalities with (clinical TLS) or without (laboratory TLS) organ dysfunction. This prospective multicentre cohort study included 153 consecutive patients with malignancies at high risk for TLS (median age 54 years (interquartile range, 38-66). Underlying malignancies were acute leukaemia (58%), aggressive non-Hodgkin lymphoma (29.5%), and Burkitt leukaemia/lymphoma (12.5%). Laboratory TLS developed in 17 (11.1%) patients and clinical TLS with acute kidney injury (AKI) in 30 (19.6%) patients. After adjustment for confounders, admission phosphates level (odds ratio [OR] per mmol/l, 5.3; 95% confidence interval [95% CI], 1.5-18.3), lactic dehydrogenase (OR per x normal, 1.1; 95%CI, 1.005-1.25), and disseminated intravascular coagulation (OR, 4.1; 95%CI, 1.4-12.3) were associated with clinical TLS; and TLS was associated with day-90 mortality (OR, 2.45; 95%CI, 1.09-5.50; P = 0.03). In this study, TLS occurred in 30.7% of high-risk patients. One third of all patients experienced AKI, for which TLS was an independent risk factor. TLS was associated with increased mortality, indicating a need for interventional studies aimed at decreasing early TLS-related deaths in this setting.

Chao CT, Chiang CK
Rasburicase for huge hepatocellular carcinoma with tumor lysis syndrome: case report.
Med Princ Pract. 2012; 21(5):498-500 [PubMed] Related Publications
OBJECTIVE: To report a case of huge hepatocellular carcinoma associated with tumor lysis syndrome and its management.
CLINICAL PRESENTATION AND INTERVENTION: A 51-year-old hepatitis B carrier visited our clinic with progressive weight loss over recent months. Abdominal ultrasonography and magnetic resonance imaging revealed a huge hepatic mass in a cirrhotic liver, identified as hepatocellular carcinoma. A hepatologist and surgeon recommended transarterial chemoembolization followed by hepatectomy. The patient underwent the procedure, with the complication of tumor lysis syndrome. He was treated with a single high dose (9 mg) of rasburicase and his clinical condition improved dramatically, with acute kidney injury subsiding without emergent hemodialysis.
CONCLUSIONS: This was a case of hepatocellular carcinoma with tumor lysis syndrome and acute kidney injury, treated successfully with rasburicase.

McCurdy MT, Shanholtz CB
Oncologic emergencies.
Crit Care Med. 2012; 40(7):2212-22 [PubMed] Related Publications
OBJECTIVES: To provide an up-to-date review of current literature on the pathophysiology, diagnosis, and management of five key malignancy-related complications: superior vena cava syndrome, malignant pericardial effusion, malignant spinal cord compression, hypercalcemia, and acute tumor lysis syndrome.
DATA SOURCES: Database searches and review of relevant medical literature.
DATA SYNTHESIS: Malignancy-related complications demand increased attention from intensivists due to their frequency and increasing cancer prevalence. Although such complications portend a poor prognosis, proper acute management can improve short-term outcomes by facilitating either definitive care of the underlying malignancy or the institution of appropriate palliative measures.
CONCLUSIONS: Knowledge of malignancy-induced complications in critically ill patients expedites the ability of the intensivist to properly manage them. Five complications commonly requiring emergency management are addressed in this review. Specifically, superior vena cava syndrome may warrant radiation, chemotherapy, vascular stenting, or surgical resection. Malignant pericardial effusion may require emergency pericardiocentesis if cardiac tamponade develops. Malignant spinal cord compression demands immediate spinal imaging, glucocorticoids, and either surgery or radiation. Hypercalcemia requires aggressive intravenous hydration and a bisphosphonate. Acute tumor lysis syndrome necessitates intravenous hydration, rasburicase, and management of associated electrolyte abnormalities.

Malaguarnera G, Giordano M, Malaguarnera M
Rasburicase for the treatment of tumor lysis in hematological malignancies.
Expert Rev Hematol. 2012; 5(1):27-38 [PubMed] Related Publications
Tumor lysis syndrome (TLS) is a common oncologic emergency in patients with hematological malignancies sensitive to cytotoxic treatment that present a high proliferative rate. High proliferative cancer rate, high sensitivity of cytotoxic treatment and renal failure represent risk factors for development of TLS. TLS is also responsible for several electrolytic alterations, such as hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. There are different established therapeutic options for the treatment of TLS such as hydration, allopurinol and rasburicase. Rasburicase reduces uric acid levels within 4 h, both in pediatric and adult patients, catalyzing the oxidation of uric acid into allantoin, rapidly excreted by the kidneys. Rasburicase is well tolerated and was approved in the EU and in the USA for the management of acute hyperuricemia.

Chiang J, Chan A, Lian T, et al.
Management of tumor lysis syndrome with a single fixed dose of rasburicase in Asian lymphoma patients: a case series and literature review.
Asia Pac J Clin Oncol. 2011; 7(4):351-6 [PubMed] Related Publications
AIM: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.

Ahn YH, Kang HJ, Shin HY, et al.
Tumour lysis syndrome in children: experience of last decade.
Hematol Oncol. 2011; 29(4):196-201 [PubMed] Related Publications
The strategy against tumour lysis syndrome (TLS) had been hyperhydration, urine alkalinization, and allopurinol. Recently, rasburicase was added to the armament against this life-threatening condition. In Korea, rasburicase is used as a rescue therapy for cases with allopurinol-resistant hyperuricemia, because of the restriction by the National Health Insurance. We reviewed our experiences to re-assess the risk factors of TLS and the efficacy of rasburicase. Medical records were retrospectively reviewed for 396 children who were diagnosed as positive with acute leukemia and non-Hodgkin lymphoma between the years 2000 and 2009. The risk factors for TLS were analyzed statistically, and those before and after the availability of rasburicase were compared. Sixty eight patients (17.2%) had TLS. Multivariate analysis showed that pre-chemotherapy hypophosphatemia was a risk factor for TLS, in addition to the known risk factors of hyperuricemia and high lactate dehydrogenase concentration. The availability of rasburicase as a rescue therapy did not negate the importance of uric acid as a risk factor of TLS. Rasburicase as a second line treatment for intractable hyperuricemia was not effective in reducing the incidence of TLS. Pre-chemotherapy hypophosphatemia was a significant independent risk factor for TLS.

Will A, Tholouli E
The clinical management of tumour lysis syndrome in haematological malignancies.
Br J Haematol. 2011; 154(1):3-13 [PubMed] Related Publications
Tumour lysis syndrome (TLS) is caused by the disintegration of malignant cells, usually following the instigation of chemotherapy, although it may already be established at the time of initial presentation in a minority of cases. As a direct consequence of malignant cell breakdown, intracellular ions, proteins, nucleic acids and their metabolites are released into the plasma causing the characteristic metabolic abnormalities of TLS; hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia. In many cases the release of large amounts intracellular contents is so abrupt that the normal homeostatic mechanisms are rapidly overwhelmed and without prompt, effective management, the clinical effects of TLS soon become apparent.

Murray MJ, Metayer LE, Mallucci CL, et al.
Intra-abdominal metastasis of an intracranial germinoma via ventriculo-peritoneal shunt in a 13-year-old female.
Br J Neurosurg. 2011; 25(6):747-9 [PubMed] Related Publications
A 13-year-old patient presented with massive intra-abdominal metastasis and spontaneous acute tumour lysis syndrome, 17-months after VP shunt placement for metastatic pineal germinoma treated with cranio-spinal-irradiation. Hyperhydration/rasburicase improved renal function, allowing chemotherapy with subsequent surgery. The patient remains event-free 34-months later. Risk of intra-abdominal metastasis from VP shunts is discussed.

Bauters T, Mondelaers V, Robays H, et al.
Methemoglobinemia and hemolytic anemia after rasburicase administration in a child with leukemia.
Int J Clin Pharm. 2011; 33(1):58-60 [PubMed] Related Publications
CASE: We report a case of simultaneous methemoglobinemia and hemolytic anemia, probably related to the use of rasburicase, in a child starting treatment for acute lymphoblastic leukemia (ALL). In addition, the patient developed symptoms of pancreatitis. All complications resolved after 3 days of supportive therapy.
CONCLUSION: Although usually well tolerated in pediatrics, physicians prescribing rasburicase should be aware of these possible life-threatening adverse reactions.

Schuman S, Pearson JM, Lucci JA, Twiggs LB
Metastatic gestational trophoblastic neoplasia complicated by tumor lysis syndrome, heart failure, and thyrotoxicosis: a case report.
J Reprod Med. 2010 Sep-Oct; 55(9-10):441-4 [PubMed] Related Publications
BACKGROUND: Tumor lysis syndrome (TLS) is an extremely rare complication of solid tumors and is more frequently observed in patients with hematologic malignancies. This report describes a novel approach to the management of a rare case of TLS in metastatic gestational trophoblastic neoplasia (GTN).
CASE: A 17-year-old female presented 8 weeks postpartum with severe anemia, thyrotoxicosis, and elevated serum beta-human chorionic gonadotropin (beta-hCG). Imaging studies confirmed metastatic GTN to the lungs. The patient developed grade 4 TLS after the first cycle of etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMA-CO). She did not respond to standard treatment of aggressive hydration and allupurinol and continued to be in renal failure with elevated uric acid. A single dose of recombinant urate oxidase, rasburicase, rendered the uric acid level undetectable in 3 days and completely reversed the renal failure, avoiding hemodialysis. Three more cycles of EMA-CO were then administered. Subsequently, the patient developed congestive heart failure and was switched to single-agent actinomycin-D. Beta-hCG became negative after 5 cycles, and her ejection fraction returned to baseline.
CONCLUSION: This is a rare case of TLS in the setting of metastatic GTN. To our knowledge this is the first reported case of utilizing rasburicase for the management of TLS in GTN.

Vines AN, Shanholtz CB, Thompson JL
Fixed-dose rasburicase 6 mg for hyperuricemia and tumor lysis syndrome in high-risk cancer patients.
Ann Pharmacother. 2010; 44(10):1529-37 [PubMed] Related Publications
BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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%).
CONCLUSIONS: 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.

Trifilio SM, Pi J, Zook J, et al.
Effectiveness of a single 3-mg rasburicase dose for the management of hyperuricemia in patients with hematological malignancies.
Bone Marrow Transplant. 2011; 46(6):800-5 [PubMed] Related Publications
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.

Cortes J, Moore JO, Maziarz RT, et al.
Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study.
J Clin Oncol. 2010; 28(27):4207-13 [PubMed] Related Publications
PURPOSE: Rasburicase is effective in controlling plasma uric acid in pediatric patients with hematologic malignancies. This study in adults evaluated safety of and compared efficacy of rasburicase alone with rasburicase followed by oral allopurinol and with allopurinol alone in controlling plasma uric acid.
PATIENTS AND METHODS: Adults with hematologic malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomly assigned to rasburicase (0.20 mg/kg/d intravenously days 1-5), rasburicase plus allopurinol (rasburicase 0.20 mg/kg/d days 1 to 3 followed by oral allopurinol 300 mg/d days 3 to 5), or allopurinol (300 mg/d orally days 1 to 5). Primary efficacy variable was plasma uric acid response rate defined as percentage of patients achieving or maintaining plasma uric acid ≤ 7.5 mg/dL during days 3 to 7.
RESULTS: Ninety-two patients received rasburicase, 92 rasburicase plus allopurinol, and 91 allopurinol. Plasma uric acid response rate was 87% with rasburicase, 78% with rasburicase plus allopurinol, and 66% with allopurinol. It was significantly greater for rasburicase than for allopurinol (P = .001) in the overall study population, in patients at high risk for TLS (89% v 68%; P = .012), and in those with baseline hyperuricemia (90% v 53%; P = .015). Time to plasma uric acid control in hyperuricemic patients was 4 hours for rasburicase, 4 hours for rasburicase plus allopurinol, and 27 hours for allopurinol.
CONCLUSION: In adults with hyperuricemia or at high risk for TLS, rasburicase provided control of plasma uric acid more rapidly than allopurinol. Rasburicase was well tolerated as a single agent and in sequential combination with allopurinol.

Meinhardt A, Burkhardt B, Zimmermann M, et al.
Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin's lymphoma and Burkitt leukemia.
J Clin Oncol. 2010; 28(19):3115-21 [PubMed] Related Publications
PURPOSE: The activity of rituximab in pediatric B-cell non-Hodgkin's lymphoma (B-NHL) has not yet been determined. We conducted a phase II window study to examine activity and tolerability of rituximab in newly diagnosed pediatric B-NHL.
PATIENTS AND METHODS: Patients younger than age 19 years with CD20(+) B-NHL with at least one measurable site were eligible. Treatment consisted of rituximab at 375 mg/m(2) administered intravenously on day 1; concomitant therapy consisted of rasburicase, intrathecally (IT) triple drug (methotrexate, cytarabine, and prednisolone) on days 1 and 3 for CNS-positive patients and steroids only for anaphylaxis. Response criterion was the product of the two largest perpendicular diameters of one to three lesions and/or the percentage of blasts in bone marrow (BM) or peripheral blood (PB) within 24 hours before rituximab and on day 5. Responders had > or = 25% decrease of at least one lesion or BM or PB blasts and no disease progress at other sites. Response rate (RR) was set at 45% for unfavorable activity or at 65% for favorable activity.
RESULTS: From April 2004 to August 2008, 136 patients were enrolled. National Cancer Institute Common Toxicity Criteria 3/4 toxicities attributable to rituximab were general condition, 15%; fatigue, 13%; anaphylaxis, 7%; infection, 3%; glutamic-oxaloacetic transaminase/glutamic-pyruvic transaminase, 8%; no capillary leakage; and no toxic death. Forty-nine patients were not evaluable for response because of withdrawal from the study (n = 16), IT therapy in CNS-negative patients (n = 8), corticosteroid treatment (n = 3), technical inadequacy of response evaluation (n = 21), or no evaluable lesion (n = 1). Of 87 evaluable patients, 36 were responders (RR, 41.4%; 95% CI, 31% to 52%); among them, 27 of 67 with Burkitt lymphoma and seven of 15 with diffuse large B-cell lymphoma. A response was more frequently observed in BM (12 of 18) compared with solid tumor lesions (36 of 108; P = .007).
CONCLUSION: Rituximab is active as a single-agent in pediatric B-NHL even though the RR was lower than requested in the phase II plan.

Bercovitz RS, Greffe BS, Hunger SP
Acute tumor lysis syndrome in a 7-month-old with hepatoblastoma.
Curr Opin Pediatr. 2010; 22(1):113-6 [PubMed] Related Publications
Acute tumor lysis syndrome (TLS) is characterized by the triad of hyperuricemia, hyperkalemia, and hyperphosphatemia and is caused by the death of tumor cells and release of intracellular contents into the circulation. This syndrome is most frequently associated with hematopoietic malignancies with a high growth fraction, including acute leukemias and lymphomas, but can be encountered in patients with nonhematopoietic solid tumors. Acute tumor lysis is typically precipitated by chemotherapy leading to rapid cell death, but may also occur spontaneously prior to treatment. In severe cases, the metabolic abnormalities of TLS can cause renal failure, cardiac arrhythmias, and death. Standard therapies include intravenous hydration, alkalinization of the urine to increase the solubility of uric acid, and administration of allopurinol to block production of uric acid. Recombinant urate oxidase (rasburicase) is a newer agent that directly cleaves uric acid. It is important for the clinician to maintain a high level of clinical suspicion for TLS when initiating therapy in children newly diagnosed with cancer, including those with solid tumors, and to know how to prevent and treat this potentially deadly metabolic complication.

Kikuchi A, Kigasawa H, Tsurusawa M, et al.
A study of rasburicase for the management of hyperuricemia in pediatric patients with newly diagnosed hematologic malignancies at high risk for tumor lysis syndrome.
Int J Hematol. 2009; 90(4):492-500 [PubMed] Related Publications
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.

Ishizawa K, Ogura M, Hamaguchi M, et al.
Safety and efficacy of rasburicase (SR29142) in a Japanese phase II study.
Cancer Sci. 2009; 100(2):357-62 [PubMed] Related Publications
The purpose of this study was to investigate the safety profile of SR29142 when administered as a single agent both prior to chemotherapy and during treatment, and to compare the efficacy of SR29142 administered at two dose levels in adult Japanese patients with leukemia or lymphoma. During this open-label, multicenter, phase II study, patients received SR29142 for 5 days, administered at either 0.15 or 0.20 mg/kg per day. Chemotherapy was started 4–24 h after the first infusion of SR29142. The primary end-point was overall response rate, defined as the normalization of plasma uric acid to 7.5 mg/dL or less, from 48 h after the first infusion to 24 h after the last infusion of SR29142. SR29142-related adverse events including hypersensitivity (allergic) reactions were assessed. Overall, 50 patients received SR29142 at either 0.15 mg/kg per day (n = 25) or 0.20 mg/kg per day (n = 25) followed by chemotherapy. The overall response rate was 100.0% (95% confidence interval, 86.3–100.0%) with 0.15 mg/kg and 96.0% (95% confidence interval, 79.6–99.9%) with 0.20 mg/kg. Both dose levels of SR29142 were equally effective at reducing plasma uric acid levels. In six patients, seven drug-related adverse events of grade 1/2 occurred before chemotherapy. SR29142-related, hypersensitivity-associated reactions occurred in three patients, and rash, anorexia, application site pain and pyrexia occurred in one patient each; only five patients (10%) showed anti-SR29142 antibodies by day 29. In conclusion, SR29142 is effective at reducing plasma uric acid levels with a tolerable safety profile as a single agent both prior to chemotherapy and during treatment.

Calvo-Villas JM, Urcuyo BM, Umpierrez AM, Sicilia F
Acute tumor lysis syndrome during oral fludarabine treatment for chronic lymphocytic leukemia. Role of treatment with rasburicase.
Onkologie. 2008; 31(4):197-9 [PubMed] Related Publications
INTRODUCTION: Oral fludarabine is the first oral formulation of a purine analogue available for clinical use which has produced encouraging results in patients with B-cell chronic lymphocytic leukemia (CLL). It has a similar tolerability profile to that of the intravenous formulation. Acute tumor lysis syndrome (TLS) induced by fludarabine appears to be a fairly unusual complication during the treatment of CLL.
CASE REPORT: The present report describes the case of a 78-year-old man who developed acute renal failure associated with TLS following the first course of oral fludarabine. Laboratory investigations fulfilled the TLS typical criteria, including hyperkalemia, marked hyperuricemia, hyperphosphatemia, hypocalcemia, and acute renal failure. Despite the many documented side effects of oral fludarabine, there is only one similar case of oral fludarabine-induced TLS reported to date. Conventional therapy with short-term supportive hemodialysis and a short treatment of rasburicase for 2 days achieved a complete recovery of renal function and a decrease of the urate level to within the normal range.
CONCLUSIONS: Clinicians should be alert to this potentially life-threatening metabolic emergency among CLL patients treated with oral fludarabine.

Bertrand Y, Mechinaud F, Brethon B, et al.
SFCE (Société Française de Lutte contre les Cancers et Leucémies de l'Enfant et de l'Adolescent) recommendations for the management of tumor lysis syndrome (TLS) with rasburicase: an observational survey.
J Pediatr Hematol Oncol. 2008; 30(4):267-71 [PubMed] Related Publications
Rasburicase (Fasturtec), a recombinant urate oxidase, is highly effective in preventing and treating hyperuricemia in children with hematologic malignancies. We conducted a prospective, multicenter observational study in 174 patients at 8 pediatric hemato-oncology centers to establish whether the SFCE (Société Française de Lutte contre les Cancers et Leucémies de l'Enfant et de l'Adolescent) recommendations for the use of rasburicase in the management of pediatric patients at risk of tumor lysis syndrome (TLS) are valid in routine clinical practice. Patients were classified as being at high or low risk of TLS according to the Children's Oncology Group criteria and were treated in accordance with the SFCE recommendations. The primary end point was the number of patients requiring a higher dose of rasburicase or a longer duration of treatment than advised in the SFCE recommendations. Of the 135 patients at high risk of TLS, 27 patients received a higher dose and 35 patients received a longer duration of treatment. Some patients received treatment with rasburicase for less than the recommended duration (median 4 d for high-risk patients). One patient required hemodialysis. Only minor adjustments to the SFCE recommendations were required to ensure the optimal use of rasburicase in pediatric patients at risk of TLS.

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