Tumor lysis syndrome (TLS) is a group of PROCEEDINGS CURRENT AND EMERGING TREATMENT OPTIONS FOR PATIENTS WITH TUMOR LYSIS SYNDROME * Sima Jeha, MD

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1 CURRENT AND EMERGING TREATMENT OPTIONS FOR PATIENTS WITH TUMOR LYSIS SYNDROME * Sima Jeha, MD ABSTRACT Tumor lysis syndrome (TLS) is a life-threatening complication of cancer chemotherapy in which hyperuricemia is the principal characteristic. High serum uric acid levels can lead to uric acid precipitation in the renal tubules, which results in acute kidney failure. TLS is typically associated with rapidly dividing cell types observed with high-risk leukemia and lymphoma, which are more prone to rapid breakdown, triggering TLS. Although potentially fatal, TLS is a desired result of chemotherapy and complications can be prevented. Traditionally, the management of TLS includes hydration to force diuresis and alkalinization of the urine to promote uric acid excretion. Uric acid-lowering agents are used to control the serum levels of the final end product of the purine metabolism cascade in humans. Dialysis is reserved as a last resort treatment for uncontrolled hyperuricemia, hyperkalemia, hyperphosphatemia, or decreased urine output with fluid overload. Allopurinol, a xanthine oxidase inhibitor, has historically been the uric acid-lowering agent of choice and works by preventing the conversion of xanthine and hypoxanthine to uric acid. Although it inhibits the production of uric acid, allopurinol is ineffective *Based on a presentation given by Dr Jeha at a symposium held in conjunction with the ONS 6th Annual Institutes of Learning in Phoenix, Arizona, on November 12, Director, Leukemia and Lymphoma Developmental Therapeutics Program, Associate Member, Hematology/ Oncology Department, St. Jude Children s Research Hospital, Memphis, Tennessee. Address correspondence to: Sima Jeha, MD, Hematology/Oncology Department, St. Jude Children s Research Hospital, 332 North Lauderdale Street, Memphis, TN sima.jeha@stjude.org. in reducing existing uric acid pools. Rasburicase is a recombinant form of urate oxidase that interferes with the cascade at a later stage, allowing the conversion of all insoluble precursors to uric acid, then converting all existing uric acid to soluble allantoin. In clinical studies that enrolled patients at high risk of TLS, rasburicase was superior to allopurinol in controlling uric acid in adult and pediatric patients with lymphoma or leukemia. The agent is well tolerated and has resulted in minimal adverse events and no reported drug interactions. Unlike allopurinol, rasburicase has a rapid onset of action, and its effect can be measured within a few hours of administration. The drug can help avoid delays in chemotherapy because of electrolyte imbalances, has a good safety profile, and effectively reduces uric acid levels. By breaking down uric acid, rasburicase reduces the potential for uric acid crystallization, which leads to renal failure and the need for dialysis. (Adv Stud Nurs. 2006;4(3):49-57) Tumor lysis syndrome (TLS) is a group of metabolic complications that occurs in malignancies associated with a large tumor burden, rapid cell proliferation, and high sensitivity to chemotherapy, such as acute T-cell and B-cell leukemia and non- Hodgkin s lymphoma, notably Burkitt s and lymphoblastic lymphoma. 1 TLS also has been reported to occur in patients with certain solid tumors, such as carcinoma of the breast, small-cell lung cancer, and neuroblastoma. 2 Johns Hopkins Advanced Studies in Nursing 49

2 The hallmark metabolic abnormalities of TLS include hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia, which result from massive lysis of malignant cells. 3 These electrolyte disturbances occur when the kidneys cannot process and excrete the large amounts of intracellular ions and metabolic byproducts spilled into the general circulation. High levels of uric acid and calcium phosphate can precipitate in the renal tubules causing acute renal failure. Cardiac and neurological complications 4,5 may also ensue because of hyperkalemia and hypocalcemia. Although preventable in almost all patients, TLS is potentially fatal. PROGNOSTIC FACTORS ASSOCIATED WITH TLS Several risk factors have been clearly associated with TLS. 6 Most important among these is tumor cell type (Table 1). 7 Burkitt s and Burkitt s-like lymphoma have been classically associated with TLS because they are rapidly growing tumors with a high proliferative index and they are extremely responsive to chemotherapy. These are the cell types that are most prone to break down rapidly, which triggers TLS. Lymphoblastic lymphoma is also highly likely to result in TLS, especially in patients with bulky disease or bone marrow involvement. Another TLS risk factor is a high lactate dehydrogenase (LDH) level, usually twice the normal range (normal: units/l). Patients who have hyperuricemia or renal impairment at diagnosis are also at high risk. TLS typically occurs within 24 to 48 hours after the initiation of chemotherapy, and the greatest risk accompanies the initial course of therapy. 1 The development of TLS is linked to the use of a variety of drugs, including steroids, cyclophosphamide, cisplatin, cytarabine, etoposide, intrathecal methotrexate, and paclitaxel. 8 Biologic agents, such as interferons, interleukins, and tumor necrosis factors, are also associated with TLS. Surgery and radiation are also linked to the syndrome, although less frequently. As more effective cancer therapies evolve, the incidence of TLS will increase because of the lysis of malignant cells that result from these treatments, as witnessed in patients with chronic lymphocytic leukemia treated with fludarabine or rituximab. 9,10 MANAGEMENT OF TUMOR LYSIS SYNDROME An overview of the management of TLS is presented in Table 2. 11,12 Because hyperuricemia is the leading Table 1. Risk for Tumor Lysis Syndrome by Tumor Type Frequent cases Recognized complications but few occurrences Case reports only Burkitt s lymphoma; lymphoblastic lymphoma; acute leukemia Low-grade lymphoma treated with chemotherapy, radiotherapy, or steroids; breast carcinoma treated with chemotherapy or hormonal therapy; small-cell lung carcinoma; seminoma Low-grade lymphoma treated with interferon; Merkel s cell carcinoma; medulloblastoma; neuroblastoma; adenocarcinoma of the gastrointestinal tract Reprinted with permission from Chasty and Liu-Yin. Br J Hosp Med. 1993; 49: Table 2. Overview of Tumor Lysis Syndrome Management Hydration To maintain urine output at more than 100 ml/m2/hour. Maintain strict intake versus output balance and give diuretics as needed to prevent fluid overload. Alkalinization Isotonic intravenous sodium bicarbonate solutions to maintain urine ph between 7.0 and 7.5 to minimize intratubular precipitation of uric acid. Caution: alkaline urine favors precipitation of calcium phosphate, which complicates outcome. Correct electrolyte Aggressively treat and monitor hyperkalemia; abnormalities immediately restrict dietary potassium and remove potassium from intravenous fluids; use potassium-wasting diuretics with caution; may worsen renal precipitation in the volumecontracted patient; manage hyperphosphatemia with oral phosphate binders. Consider If the other methods fail, initiation of hemodialysis dialysis may avoid irreversible renal failure, as appropriate other life-threatening complications; indications include persistent hyperkalemia or hyperphosphatemia, volume overload, uremia, symptomatic hypocalcemia, and hyperuricemia; hemodialysis is preferred to peritoneal dialysis because of better phosphate and uric acid clearance rates. 12 Reprinted with permission from Jones et al. Pediatr Nephrol. 1995;9: Vol. 4, No. 3 April 2006

3 factor responsible for TLS and its sequelae, uric acidlowering therapy is pivotal in the prevention and management of TLS. Historically, allopurinol has been used to interrupt the production of xanthine oxidase, a dehydrogenase involved in the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the final catabolite of purines. More recently, rasburicase, a recombinant form of urate oxidase, has been shown to be superior to allopurinol in controlling uric acid in adult and pediatric patients with high-grade lymphoma or leukemia. 13,14 Urate oxidase is an endogenous enzyme found in most mammals, but not in humans because of a nonsense mutation in the gene-coding region. 15 Urate oxidase catalyzes the enzymatic oxidation of uric acid into allantoin, a metabolite that is 5 to 10 times more soluble in the urine than uric acid. The recombinant form has been cloned from Aspergillus flavus and is expressed in the Saccharomyces cerevisiae yeast strain. 16 Recombinant rasburicase has a higher purity and greater specificity than the nonrecombinant form, which has resulted in a 4.5% incidence of hypersensitivity reactions. 17 Although allopurinol prevents the formation of uric acid, it can result in upstream accumulation of xanthine and hypoxanthine. Whereas hypoxanthine is more soluble than uric acid, xanthine is actually less soluble than uric acid. As a result, uric acid levels could be measured and found to be within normal limits, but xanthine nephropathy and renal failure may still occur despite normal uric acid levels. However, rasburicase allows the cascade to proceed all the way to uric acid and dissolves all the uric acid while preventing excessive accumulation of upstream metabolites. STUDIES OF RASBURICASE OR ALLOPURINOL In a series of pediatric studies, patients diagnosed with stage IV B-cell non-hodgkin s lymphoma or acute B-cell lymphoid leukemia were administered intense cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or light cyclophosphamide, vincristine, and prednisone (COP) cytoreductive chemotherapy Despite the use of hydration and allopurinol, 23% of children treated with CHOP required dialysis. 18 Light COP decreased this percentage to 16% in children treated with allopurinol, whereas the studies using nonrecombinant urate oxidase and the recombinant urate oxidase rasburicase reported a 2.6% and 0% incidence of hemodialysis, respectively Studies in which adults with leukemia or lymphoma were administered urate-lowering agents showed a similar trend. In trials in which allopurinol was used, the incidence of acute renal failure was 6% and 23% compared to 0.9% and 0% in patients treated with rasburicase. 3,13,22,23 In a study by Pui et al, the safety and efficacy of rasburicase was assessed in 131 children with newly diagnosed leukemia or lymphoma who were at high risk for TLS. 20 At study entry, 50% of the patients were hyperuricemic, and 21% had impaired renal function. The dose of rasburicase was 0.15 to 0.2 mg/kg daily administered intravenously over 30 minutes for as many as 5 to 7 days; every 12-hours dosing was allowed during the first 48 hours. As a result, plasma urate levels were reduced by 82% within the first 4 hours of rasburicase administration. Large amounts of allantoin were present in the urine, which confirmed the ability of rasburicase to prevent hyperuricemia. The main adverse events were nausea and vomiting in 1 patient and bronchospasm and hypoxemia in 1 patient. 20 Thus, the study demonstrated that rasburicase is safe and effective for the prophylaxis and treatment of hyperuricemia in children with leukemia or lymphoma. 20 Seventeen patients (13%) developed antibodies to rasburicase. 20 However, this finding was not associated with an allergic reaction or a blunted response to the drug. Another study is now focusing on the clinical significance of the formation of antibodies to rasburicase, in addition to the timing of antibody formation, the washout period, and the effect of antibody formation on response. The first analysis of the safety and efficacy of rasburicase in adults was presented in a phase II, singlearm, open-label study by Coiffier et al. 13 Although only 11% of the 100 patients with aggressive non- Hodgkin s lymphoma were hyperuricemic at presentation, patients were at risk for TLS during the first cycle of chemotherapy because of large tumor size ( 5 cm) or elevated LDH. 13 Rasburicase 0.2 mg/kg/day was administered intravenously for 3 to 7 days, starting on day 1 of chemotherapy in 87 patients or 1 day before chemotherapy initiation in another 12 patients. 13 Most patients (81%) received 3 days of treatment, and another 14% received 4 to 6 days of treatment. 13 In all patients, uric acid concentrations decreased within 4 hours of rasburicase administration and Johns Hopkins Advanced Studies in Nursing 51

4 remained low throughout treatment. 13 Mean uric acid levels in 11 patients with hyperuricemia decreased from 9.6 to 1.3 mg/dl 4 hours after rasburicase treatment. 13 No patient had a significant increase in serum creatinine (Cr) or required dialysis. 13 Serum potassium, phosphorus, and calcium levels were well controlled. Four patients discontinued therapy during the first 2 days of treatment because of an increase in liver enzyme level; discontinuation may have resulted from rasburicase administration, anthracycline-based chemotherapy, gastrointestinal hemorrhage, or some combination thereof. 13 No safety issues were observed in 20% of patients who also received rituximab, which has been associated with TLS. 24 Thus, this study documented that rasburicase is a highly effective, fast-acting, and reliable uricolytic agent for adults with aggressive lymphoma. COMPASSIONATE USE STUDIES IN CHILDREN AND ADULTS A compassionate use trial published by Jeha et al enrolled 682 children and 387 adults. 25 Most patients had a hematologic malignancy; 5% of children and 1% of adults had solid tumors. Sixty-one percent of patients were hyperuricemic at study entry, and the remaining 39% were at high risk for hyperuricemia. 25 Both age groups had median LDH levels that surpassed 1500 U/L, which put them at high risk for hyperuricemia. 25 Rasburicase 0.2 mg/kg/day was administered intravenously for 1 to 7 days at a maximum frequency of once every 12 hours during the first 72 hours of chemotherapy. 25 Most children received rasburicase for 1 to 4 days, and only 40% were treated for 5 or more days. 25 Plasma uric acid levels were measured at baseline and 24 to 48 hours after the last dose. 25 Pretreatment and post-treatment urate values were obtained for 658 children, in whom rasburicase efficacy was thus evaluable. 25 Only 6 children with hyperuricemia at baseline did not respond to rasburicase therapy according to study criteria. 25 Notably, all 6 patients showed reductions in serum uric acid level while receiving rasburicase. 25 All children who were nonhyperuricemic at baseline maintained low uric acid levels on prophylactic rasburicase, despite receiving chemotherapy. 25 A significant decrease in uric acid level from 4.1 mg/dl at baseline to 0.5 mg/dl after treatment was observed to result from rasburicase prophylaxis (P <.001; Figure 1). 25 In children who were initially hyperuricemic, a marked decrease in uric acid level from a median of Uric acid, mg/dl 9.2 mg/dl at baseline to 0.5 mg/dl after treatment was also observed (P <.001). 25 Similarly, most adults received rasburicase for 1 to 4 days, and only 20.4% were treated for 5 or more days. A total of 338 adults were evaluable for efficacy. 25 All adult patients with hyperuricemia responded to rasburicase, and those who were nonhyperuricemic at baseline maintained low uric acid levels while receiving prophylactic rasburicase, despite receiving chemotherapy. 25 A significant decrease in urate from 4.8 to 0.7 mg/dl was seen in those patients who received rasburicase prophylaxis (P <.001; Figure 2). In adults who were initially hyperuricemic, a marked decrease in uric acid level from 10.8 to 0.7 mg/dl was also observed (P <.001). 25 In 44 patients, 69 adverse events occurred that were considered to be most likely related to rasburicase or of unknown etiology. 25 The total included 26 children (in whom 48 events occurred) and 18 adults (in whom 21 events occurred). Most adverse events were considered to be mild. 25 The most frequent adverse events during the first course of rasburicase were headache (0.7%), rash (0.4%), fever (0.3%), and vomiting (0.3%). 25 Thirteen patients (11 of whom were children) experienced 25 adverse events of grade 3 or 4 severity. 25 Ten of the events were considered to be most likely related to rasburicase; 15 events were of Figure 1. The Decrease in Serum Uric Acid in Hyperuricemic Versus Nonhyperuricemic Pediatric Patients After Rasburicase Administration 24 to 48 Hours After the Last Dose Baseline Post-treatment * Nonhyperuricemic (n = 260) Hyperuricemic (n = 398) Courses administered (#): 1 (n = 657); 2 (n = 22); 3 (n = 2); 4 (n = 1); 5 (n = 0) Efficacy-evaluable patients: n = 658 Responses: Nonhyperuricemic = 260/260; hyperuricemic = 392/392 *P <.001. Data from Jeha et al * 52 Vol. 4, No. 3 April 2006

5 Figure 2. The Decrease in Serum Uric Acid in Hyperuricemic Versus Nonhyperuricemic Adult Patients After Rasburicase Administration 24 to 48 Hours After the Last Dose Uric acid, mg/dl Baseline Post-treatment 4.8 Nonhyperuricemic (n = 126) 0.7* 0.7* Hyperuricemic (n = 212) Courses administered (#): 1 (n = 341); 2 (n = 32); 3 (n = 7); 4 (n = 4); 5 (n = 3) Efficacy-evaluable patients: n = 338 Responses: Nonhyperuricemic = 126/126; hyperuricemic = 212/212 *P <.001. Data from Jeha et al. 25 unknown etiology (ie, possibly related). 25 Grade 3 events included 4 cases of hemolytic anemia, 1 case of TLS, 1 case of fever, 1 case of albuminuria, 1 case of allergic reaction, and 1 case of dyspnea. 25 Grade 4 events included 2 cases of methemoglobinemia, 2 cases of hypoxia, 1 case of anaphylactic shock, 1 case of rigor, and 1 case of convulsion because of hypertensive encephalopathy. 25 All other grade 3 and 4 events were a result of electrolyte abnormalities. 25 In 45 patients (4.2%; 17 children and 28 adults), acute renal insufficiency developed during the study period. 25 Hemodialysis was required in 10 children (1.5%) and 20 adults (5.2%). 25 The reason for hemodialysis was acute renal failure/azotemia associated with sepsis or chemotherapy in 26 patients and hyperphosphatemia in 4 patients. 25 The median baseline uric acid level in patients in whom acute renal failure developed was 10.4 mg/dl (range mg/dl). All but 1 child had resolution of hyperuricemia while receiving rasburicase (median number of doses: 3; range 1 8). TLS developed in 15 patients in whom acute renal insufficiency developed, including in 6 of those who received hemodialysis. 25 These data confirm that rasburicase is safe and effective for the treatment and prophylaxis of malignancy-related hyperuricemia in children and adults An international compassionate use trial by Bosly et al evaluated the efficacy and safety of rasburicase in 166 children and 112 adults during the initiation of chemotherapy. 23 Diagnoses included lymphoma, leukemia, or solid tumors. Rasburicase 0.2 mg/kg was administered intravenously once daily for 1 to 7 days, and dosing was permitted every 12 hours during the first 72 hours. 23 In the 122 pediatric patients for whom uric acid levels were available after the first 24 to 48 hours, the median duration of treatment was 5 days, although more than 33% received treatment for 4 days or less. 23 In children with hyperuricemia (n = 29), mean uric acid level decreased from 15.1 to 0.4 mg/dl (P <.001) at 24 to 48 hours. 23 In 93 patients, rasburicase prophylaxis reduced uric acid levels from 4.4 to 0.8 mg/dl at 24 to 48 hours (P <.001). 22 Four children required dialysis, despite reduced uric acid levels. 23 In the adult group in which uric acid levels at 24 to 48 hours after the last dose were available for 97 patients, the median duration of treatment was 5 days for nonhyperuricemic adults and 6 days in adults with hyperuricemia. 23 In hyperuricemic adults (n = 27), the mean uric acid level decreased from 14.2 to 0.5 mg/dl (P <.001). 23 Prophylactic administration of rasburicase in 70 patients to prevent TLS during chemotherapy reduced uric acid levels from 4.8 to 0.4 mg/dl (P <.001). 23 One adult required dialysis, despite a decrease in uric acid level. 23 The most common adverse events (which occurred in >1% of patients) were headache, fever, and rigors. 23 Adverse effects included 1 grade 2 allergic reaction; 4 grade 3 reactions, which included arthralgia, gout, hypocalcemia, or methemoglobinemia; and 1 grade 4 increase in alanine aminotransferase. 23 The researchers concluded that rasburicase is safe and effective in the prevention and treatment of chemotherapy-induced hyperuricemia in children and adults and produced a 100% response rate. 23 RASBURICASE VERSUS ALLOPURINOL A randomized, multicenter, open-label trial compared the efficacy of allopurinol to that of rasburicase in reducing uric acid exposure in 52 children aged 4 months to 17 years with leukemia or lymphoma who were at high risk for developing TLS. 14 Patients received allopurinol 10 mg/kg orally every 8 hours or rasburicase 0.2 mg/kg intravenously once daily for 5 to 7 days. 14 The primary efficacy endpoint of the study was the area under the serum-urate-versus-time curve (from 0 96 h) or uric acid exposure during the first 4 days of Johns Hopkins Advanced Studies in Nursing 53

6 treatment. 14 Baseline uric acid levels were similar between treatment groups the rasburicase group was 7.7 mg/dl and the allopurinol group was 6.8 mg/dl. 14 Patients treated with rasburicase experienced a 2.6- fold lower exposure to uric acid compared to the allopurinol group during the first 96 hours of induction chemotherapy. 14 Four hours after the first dose, treatment produced an 86% reduction in serum uric acid compared to a 12% reduction for allopurinol (P <.0001). 14 Although the number of patients evaluated was too small to determine a difference in the incidence of renal failure or the need for dialysis, the association between renal function and treatment group was examined for patients who were initially hyperuricemic. 14 To facilitate a comparison, each patient s serum Cr was adjusted to be expressed as a percentage of the established mean for age and gender (Cr was adjusted by dividing the serum Cr value by the published mean Cr for age and gender 100%). 14 As shown in Figure 3, patients with hyperuricemia treated with rasburicase had a baseline Cr of 144% of their age- and gender-adjusted mean. This value decreased steadily during the next 4 days to an adjusted level of 102%. In contrast, allopurinol-treated patients with hyperuricemia had a baseline-adjusted Cr of 132%, which worsened during the next 4 days to 147%. Thus, in those patients at high risk for TLS, more rapid control and lower levels of uric acid were achieved in rasburicasetreated children than in allopu-rinol-treated children. 14 In a study of the compassionate use of intravenous allopurinol in 204 adult and 137 pediatric patients, 88% of the pediatric patients had a complete response (CR), which means the uric acid level became normal, whereas 7% had a partial response (PR), which means the urate level decreased by 1 mg/dl, but it did not become normal. 26 Five patients did not respond. In the adult group, a smaller percentage had a CR (57%), 30% had a PR, and 13% had no response. Regarding time-toresponse, the pediatric group had a mean time of 1 day, whereas the adults had a mean time of 5 days. Intravenous allopurinol is as effective as oral allopurinol and lowers uric acid levels in most patients. However, there is a delay in response with intravenous allopurinol compared to the response time of rasburicase, and some patients do not respond to intravenous allopurinol. 26 ADVERSE EVENTS AND DRUG INTERACTIONS: ALLOPURINOL AND RASBURICASE The key adverse effects and drug interactions for allopurinol and rasburicase are listed in Table 3. 20,27 If allopurinol is used, the clinician must keep in mind that allopurinol interferes with the metabolism of some antibiotics and purine analogues. For example, concomitant administration of allopurinol and mercaptopurine (6-MP) results in decreased 6-MP metabolism and may Figure 3. The Effects on Serum Creatinine Level in Pediatric Patients from Days 1 Through 4 After Rasburicase or Allopurinol Administration Serum creatinine (% of normal) Allopurinol Rasburicase Baseline After first dose, d Reprinted with permission from Goldman et al. Blood. 2001;97: Table 3. A Comparison of Adverse Events and Drug Interactions Associated with Rasburicase and Allopurinol Rasburicase Allopurinol Adverse effects Nausea, vomiting, diarrhea, Rash; less common: headache, and fever; less nausea, vomiting, renal common: acute hypersen- impairment, bone marrow sitivity, rash, hemolysis, and suppression, and methemoglobinemia (avoid liver enzymes in glucose-6-phosphate dehydrogenase deficiency) Drug None reported Azathioprine, mercaptointeractions purine ( metabolism), ampicillin, amoxicillin ( rash), warfarin, theophylline ( half-life), and cyclosporine ( serum level) = increase; = decrease. Adapted with permission from Lohr Vol. 4, No. 3 April 2006

7 increase toxicity, which predominantly results in bone marrow suppression. Therefore, if allopurinol and 6-MP must be administered simultaneously, the 6-MP dose must be decreased by 25% to 33%. No drug interactions have been reported with rasburicase. 28 When using allopurinol in patients with renal insufficiency, the dose must be reduced on the basis of kidney function. Conversely, the dose of rasburicase does not have to be reduced when renal function is uncompromised. However, if the patient is having hemophoresis, the dose of rasburicase may need to be repeated depending on the serum uric acid level. 29 Another important point to consider is that rasburicase can cause severe hemolysis in patients with glucose- 6-phosphate dehydrogenase (G6PD) deficiency; therefore, patients at high risk for G6PD deficiency should be screened before rasburicase treatment is considered. 30 In addition, rasburicase use has been associated with methemoglobinemia. Rasburicase should be immediately and permanently discontinued in any patient in whom methemoglobinemia develops. 25 COSTS OF URIC ACID-LOWERING THERAPY Intravenous allopurinol is significantly more expensive than the oral formulation. Whereas a tablet of allopurinol costs less than $0.25, a 500-mg vial of the intravenous formulation may cost nearly $500. Intravenous allopurinol has the same mechanism of action and potency as the oral formulation. Rasburicase is also expensive (a 1.5-mg vial costs approximately $385) and should be reserved for patients at high risk of tumor lysis. 31 Preliminary evidence indicates that rational use of rasburicase offers cost savings by preventing dialysis and other TLS complications for many patients with cancer. In the clinical studies reviewed in this article, most patients needed less than the prescribed 5 to 7 days of rasburicase, which resulted in decreased medical costs. 13,20,23,25 CONCLUSIONS Tumor lysis syndrome is a potentially life-threatening metabolic complication for patients with hematologic malignancies. The risk of renal deterioration and need for hemodialysis that may result from TLS further complicate the clinical picture. These events delay chemotherapy, may be life-threatening, and substantially increase the cost of care. Safe and rapid reduction in uric acid levels facilitates timely chemotherapy administration, improves patient outcomes, and reduces associated healthcare costs. Allopurinol and rasburicase are effective in lowering uric acid levels. However, rasburicase may have advantages because of its unique mechanism of action, which enables the purine metabolism cascade to proceed to its endpoint (uric acid), prevents the formation of all upstream metabolites, and dissolves all uric acid. Compared to oral and intravenous allopurinol, rasburicase has a rapid onset of action and its efficacy is measurable within a few hours of administration. Thus, rasburicase helps to avoid delays in chemotherapy because of electrolyte imbalances and other complications, has a good safety profile, and effectively reduces uric acid exposure. In addition, by breaking down urate, rasburicase reduces the potential for uric acid crystallization, which leads to renal failure and the need for dialysis. Q&A SESSION Question: If a patient develops antibodies to rasburicase, how does that event affect the overall clinical picture if retreatment with rasburicase is necessary? Does it mean an allergic reaction has occurred, or does it mean that the medication will not be effective? Dr Jeha: The concern regarding the development of antibodies to rasburicase is that you can have an allergic reaction or you can have a neutralizing antibody and then no response. Thus far, the data from retreatment is mostly from the compassionate use trial that involved more than 1000 patients. 25 Approximately 10% of patients who were retreated had an allergic reaction, or what was suspected to be allergic reaction. All reactions were reversible, but therapy was terminated in these patients to avoid anaphylaxis. Serum for antibody determination was sent to the laboratory; however, samples were batched, and we still do not have the correlation between which patient had the antibodies and which one had the reaction. The neutralizing antibodies definitely can be a concern. However, in the compassionate use study, only 1 of 71 retreated patients, including those who had the reaction, failed to respond. 25 Therefore, I think the main concern would be the allergic reaction itself because if you do not respond to rasburicase, then you will proceed to use your other options, whereas if you have a reaction, it can be fatal. Johns Hopkins Advanced Studies in Nursing 55

8 CASE STUDY AN AFRICAN-AMERICAN BOY WITH BURKITT S LYMPHOMA AND A HIGH LACTATE DEHYDROGENASE LEVEL The patient was a 9-year-old African-American boy named Larry who had Burkitt s lymphoma, a disease that puts him at high risk of tumor lysis syndrome (TLS). When he was initially seen for evaluation, he had bulky cervical adenopathy, a large abdominal mass, a uric acid level of 30.3 mg/dl, and a creatinine level of 2.2 mg/dl (Table), which is high for a 9-yearold. The phosphorus level was 4.1 meq/l, which was satisfactory, but the lactate dehydrogenase (LDH) level was U/L, which was high. Table. Laboratory Values Hours Days UO Rx UA (mg/dl) <0.7 <0.7 <0.7 < CR (mg/dl) P (meq/l) LDH (U/L) = dose administered; = data not available; CR = serum creatinine; LDH = lactate dehydrogenase; P = phosphorus; Rx = dose of rasburicase administered; UA = uric acid level; UO = urate oxidase. The physician consulted the renal and surgical staff, informing them that she planned to give Larry 1 dose of rasburicase and evaluate his uric acid level in 4 hours. Because they were unfamiliar with the ability of rasburicase to decrease uric acid levels rapidly, the renal and surgical staff were skeptical that the patient would respond so quickly, but they agreed to re-evaluate the patient s uric acid level in 4 hours. Four hours after rasburicase was administered, the uric acid level had decreased to 8.7 mg/dl, the creatinine level was 2.4 mg/dl despite hydration, which was to be expected, and the phosphorus level was still increasing because the patient was experiencing active tumor lysis. Nevertheless, the physician initiated a 5- day course of cyclophosphamide, vincristine, and prednisone chemotherapy and, at hour 12, administered another dose of rasburicase in expectation of continued TLS. After the second dose of rasburicase (at hour 24), uric acid reached an undetectable level, and the creatinine level had decreased to 1.6 mg/dl. Ongoing tumor lysis was indicated by an LDH level of U/L and a still elevated phosphorus level, despite a decreasing creatinine level and a low uric acid level. Larry received a total of 8 doses of rasburicase over 7 days. He maintained undetectable uric acid levels, despite ongoing chemotherapy, and his creatinine level continued to improve. Two weeks later, the uric acid level was 2 mg/dl, although rasburicase had been withdrawn for a week, the creatinine level was 0.5 mg/dl (which is normal for Larry s age), and all other laboratory values had reached normal levels. REFERENCES 1. Seidemann K, Meyer U, Jansen P, et al. Impaired renal function and tumor lysis syndrome in pediatric patients with non-hodgkin s lymphoma and B-ALL. Observations from the BFM trials. Klin Padiatr. 1998;210: Kalemkerian GP, Darwish B, Varterasian ML. Tumor lysis syndrome in small cell carcinoma and other solid tumors. Am J Med. 1997;103: Annemans L, Moeremans K, Lamotte M, et al. Incidence, medical resource utilisation and costs of hyperuricemia and tumour lysis syndrome in patients with acute leukaemia and non-hodgkin s lymphoma in four European countries. Leuk Lymphoma. 2003;44: Van Der Klooster JM, Van Der Wiel HE, Van Saase JL, Grootendorst AF. Asystole during combination chemotherapy for non-hodgkin s lymphoma: the acute tumor lysis syndrome. Neth J Med. 2000;56: Kaito E, Terae S, Kobayashi R, et al. The role of tumor lysis in reversible posterior leukoencephalopathy syndrome. Pediatr Radiol. 2005;35: Cabanillas F. Metabolic abnormalities in lymphoma. Clin Lymphoma. 2002;3(suppl 1):S32-S Chasty RC, Liu-Yin JA. Acute tumour lysis syndrome. Br J Hosp Med. 1993;49: Altman A. Acute tumor lysis syndrome. Semin Oncol. 2001;28(suppl 5): Hussain K, Mazza JJ, Clouse LH. Tumor lysis syndrome (TLS) following fludarabine therapy for chronic lymphocytic 56 Vol. 4, No. 3 April 2006

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