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ORIGINAL ARTICLE Reduced-dose rasburicase (recombinant xanthine oxidase) in adult cancer patients with

S Trifilio1,2, L Gordon2, S Singhal2, M Tallman2, A Evens2, K Rashid2, M Fishman2, K Masino2, JPi1 and J Mehta2

1Pharmacy Department, Northwestern Memorial Hospital, Chicago, IL, USA and 2Hematopoietic Stem Cell Transplant Program, Division of Hematology/Oncology, The Feinberg School of Medicine, The Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA

Recombinant (rasburicase) lowers Introduction levels rapidlyto verylow levels at the labeled dose of 0.15–0.2 mg/kg dailyfor 5 days.Our past experience Hyperuricemia is one of the metabolic abnormalities seen showed that a lower dose (3 mg) lowered uric acid levels in patients with (TLS).1 The standard sufficientlyin most patients. A retrospective review was management of hyperuricemia consists of hydration, conducted to determine the effect of a fixed 3 mg dose of alkalinization of the urine and the administration of rasburicase in 43 adult patients with cancer undergoing . Allopurinol, available in oral as well as hematopoietic stem cell transplantation or receiving intravenous formulations, affects purine metabolism by chemotherapywho had elevated or rising uric acid levels inhibiting xanthine oxidase, an responsible for the (6.4–16.8 mg/dl; median 9.6). Six patients received conversion of hypoxanthine to xanthine, and xanthine to a second dose of rasburicase (3 mg in four patients uric acid.2 It lowers serum and urine uric acid levels by and 1.5 mg in two patients) 24 h later. Patients received inhibiting uric acid formation, but has no direct effect on allopurinol, adequate hydration, as well as other existing uric acid in the . supportive therapyas required. Uric acid levels declined Urate oxidase is a peroxisomal enzyme catalyzing the by6–95% (median 43%) within the first 24 h after oxidation of uric acid to . This enzyme is present rasburicase administration, and levels at 48 h were in most mammals, except humans and certain other 9–91% (median 65%) lower than the baseline levels. primates.3 Murine urate oxidase has been used successfully Serum creatinine changed by p10% in 21 patients, to treat hyperuricemia.4 It reduces uric acid levels rapidly increased by 410% in four patients and decreased by converting uric acid to allantoin. Allantoin is five- to 10- by 410% in 18 patients. No significant renal dysfunc- fold more soluble than uric acid and is readily excreted. tion developed in anyof the patients. We conclude that Expression of the gene encoding urate oxidase in yeast rasburicase is effective in lowering uric acid levels at yields recombinant enzyme in therapeutically useful quan- a fixed dose of 3 mg, which is much lower than the tities.5 Recombinant urate oxidase (rasburicase) has been recommended dose. found to be useful prophylactically and therapeutically for Bone Marrow Transplantation (2006) 37, 997–1001. hyperuricemia in children6 and adults.7 doi:10.1038/sj.bmt.1705379 Rasburicase administration at the recommended dose of Keywords: tumor lysis syndrome; uric acid; rasburicase; 0.2 mg/kg for 3–7 days results in dramatically reduced levels hyperuricemia of serum uric acid, usually substantially lower than the lower limit of normal.6,7 Only one of 12 patients receiving 0.15 mg/ kg rasburicase (25% dose reduction) developed transient hyperuricemia,7 suggesting that the recommended dose may be higher than necessary. Limited experience suggests that lower doses of rasburicase are also effective in lowering uric acid levels.8,9 After seeing an excellent, sustained response with a single dose of rasburicase dose at 0.2 mg/kg ideal body weight (total dose 12 mg) in a significantly obese Correspondence: Dr J Mehta, Hematopoietic Stem Cell Transplant patient, we decided to use lower doses of the drug in adult Program, Division of Hematology/Oncology, The Feinberg School of patients. Our early experience with variable low doses (1.5– Medicine, The Robert H Lurie Comprehensive Cancer Center, North- 12 mg) suggested that 3 mg appeared to be effective in most western University, 676 North St Clair Street, Suite 850, Chicago, patients,10 and this dose was adopted in clinical practice. IL 60611, USA. E-mail: [email protected] We present a retrospective analysis of our experience Received 2 November 2005; revised 20 March 2006; accepted 25 March with a fixed 3 mg dose of rasburicase in 43 cancer patients 2006 with elevated or increasing uric acid levels. Low-dose rasburicase S Trifilio et al 998 Patients and methods 1.5 mg (n ¼ 2) or 3 mg (n ¼ 4) 24 h after the first dose based on biochemical assessment (persistent hyperuricemia). Records of all (n ¼ 43) adult patients with malignant diseases Serum uric acid levels declined by 6–95% (median 43%) who received 3 mg rasburicase for the therapy of hyperur- within the first 24 h after rasburicase administration, and icemia from June 2003 to May 2005 at the Northwestern levels at 48 h were 9–91% (median 65%) lower than the University Feinberg School of Medicine, The Robert H baseline levels. Every single uric acid level at 48 h was Lurie Comprehensive Cancer Center and Northwestern within the normal range (under 8 mg/dl). Figures 1 and 2 Memorial Hospital were reviewed after approval from the show the actual and percent changes in serum uric acid at Institutional Review Board. Patients were either receiving 24 and 48 h compared to baseline. conventional for their disease or were under- The uric acid levels at baseline, 24 and 48 h in the six going hematopoietic stem cell transplantation (HSCT). patients who received an additional dose of rasburicase at Oral allopurinol was administered as required to inhibit 24 h were 11.6/8.4/6.5, 16.4/8.4/6.2, 8.6/7.0/2.5, 9.5/8.9/3.2, uric acid formation. Patients were hydrated, and received 9.6/3.6/2.0and 11.4/7.9/5.9, respectively. Although the chemotherapy as well as other supportive therapy (includ- baseline uric acid levels were comparable between these six ing urine alkalinization and hemodialysis) as required patients and the rest (median 10.5 vs 9.5; P ¼ 0.31), the 24-h based upon frequent clinical and biochemical monitoring, levels were higher (median 8.2 vs 5.3; P ¼ 0.034), and and the assessment of the treating physician. the percent reduction at 24 h lower (median 29 vs 43%; Table 1 shows patient characteristics. All patients had P ¼ 0.11). However, the 48-h levels (median 4.5 vs 3.8; hematologic malignancies and were on chemotherapy (in- P ¼ 0.44) and percent reduction at 48 h (median 64 vs 65%; cluding high-dose chemotherapy) or were about to start P ¼ 0.88) were comparable. receiving it, hyperuricemia being secondary to tumor burden and therapy. Two of the three patients undergoing hemodia- lysis had myeloma with end-stage renal disease, and were on hemodialysis before receiving high-dose melphalan for auto- 18 transplantation. The third patient had relapsed following an 16 allograft for acute myeloid , and was on hemodia- lysis after developing renal failure on salvage chemotherapy. 14 At baseline, 15 patients had additional laboratory 12 manifestations (two or more of the following: elevated lactate dehydrogenase (LDH), elevated phosphorus, ele- 10 vated potassium and low calcium) suggestive of TLS. Five of the 10non-Hodgkin’s (NHL) patients had 8 high-grade disease and the rest had follicular or small 6 lymphocytic lymphoma.

Serum uric acid (mg/dL) 4

Results 2

0 Thirty-seven patients received a single 3 mg dose of Baseline 24 hours 48 hours rasburicase. Six patients received an additional dose of Figure 1 Change in serum uric acid levels with rasburicase.

Table 1 Patient characteristics

n 43 100 Age (years) 57 (31–88) Male 31 (72%)

Diagnosis 80 Plasma cell dyscrasias 20(47%) Non-Hodgkin’s lymphoma 10(23%) Acute myeloid leukemia 7 (16%) Chronic lymphocytic leukemia 3 (7%) 60 Myelodysplastic syndrome 3 (7%) %

Pre-existing hemodialysis 3 (7%) 40 Weight (kg) 86 (50–146)

Treatment Hematopoietic stem cell transplantation 22 (51%) 20 Chemotherapy 21 (49%) Baseline uric acid (mg/dl)a 9.6 (6.4–16.8) Baseline creatinine (mg/dl)b 2.1 (1.0–6.4) 0 Baseline 24 hours 48 hours a571 (381–999) mmol/l. b 186 (88–566) mmol/l. Figure 2 Percent change in serum uric acid levels with rasburicase.

Bone Marrow Transplantation Low-dose rasburicase S Trifilio et al 999 The uric acid reduction in patients weighing p80kg amount of rasburicase used at the dose of 0.2 mg/kg daily (n ¼ 18; median 42%) was comparable (P ¼ 0.21) to that for 5 days (3789 mg) would have been $977 562. seen in heavier patients (n ¼ 25; median 43%). Similarly, the reduction in patients with a baseline uric acid level of o10mg/dl ( n ¼ 25; median 43%) was comparable Discussion (P ¼ 0.92) to that with X10mg/dl ( n ¼ 18; median 46%). The weights of the six patients requiring a second dose Our data show that in most clinical situations, a low dose of of rasburicase (70, 77, 77, 99, 99 and 103 kg) were not rasburicase is sufficient to lower uric acid levels and significantly different from those who did not need a second appears as effective as the significantly higher dose explored dose (50–146 kg; median 86; P ¼ 0.94). in previous studies.6,7,11 It should be noted that in the At 24 h, serum creatinine changed by p10% in 21 United States, rasburicase is approved for therapy only in patients, increased by 410% in four patients and decreased children. Therefore, there is no recommended dose for by 410% in 18 patients. In the four patients experiencing adults who may require it under appropriate clinical increased creatinine, the baseline and 24-h values were 1.7/ circumstances. 2.3, 1.9/2.3, 2.8/3.3 and 1.5/1.7, respectively. However, the Rasburicase is an extremely expensive drug. Based on its 48-h and 7-day values in these patients were 1.8/1.4, 2.3/1.7, Red Book price ($387 for a 1.5 mg vial) and published dose 3.4/3.0and 1.6/1.1, respectively, suggesting stabilization of 0.2 mg/kg,7 a day’s dose of the drug for a 70kg adult or improvement in renal dysfunction. Figure 3 shows costs $3870. The economic burden of using this widely, the change in serum creatinine over 48 h. No clinically including in diseases where TLS is an insignificant concern, significant renal dysfunction developed in any of the for several days as advocated by some7 is enormous. patients over a period of a week after rasburicase However, because of the efficacy of the drug in preventing administration, with no patient (excluding the three already TLS and its sequelae, its use has apparently been found to on hemodialysis) requiring dialysis. There was no difference be cost-effective at the recommended doses.11 In contrast, in outcome between patients who had undergone HSCT oral allopurinol costs 14 cents per day for 300 mg. Of and those who had not. course, it should be noted that the use of the two is not The extent of decline in uric acid at 24 h was comparable mutually exclusive. Allopurinol inhibits uric acid forma- for the 15 patients with laboratory features of TLS and the tion, whereas rasburicase enhances uric acid excretion. rest (P ¼ 0.88). Similarly, the extent of change in the serum Indeed, under most circumstances, it would make sense to creatinine levels at 24 h (P ¼ 0.72) and 48 h (P ¼ 0.61) was use both drugs together. also comparable between those with and without features Wossmann et al.12 analyzed the incidence and complica- of TLS. tions of TLS in children with acute lymphoblastic leukemia The actual dose administered, 3 mg (n ¼ 37), 4.5 mg (ALL) or Burkitt’s lymphoma and elevated LDH who did (n ¼ 2) and 6 mg (n ¼ 4), was a fraction of what the not or did receive urate oxidase prophylactically with recommended dose would have been at 37.5–109.5 mg chemotherapy. Among children with lymphoma who did (based on 0.15 mg/kg daily for 5 days) or 50–146 mg (based not receive urate oxidase prophylactically, the incidence of on 0.2 mg/kg daily for 5 days). Based on the Red Book TLS and anuria was 16 and 9%, not significantly different price of rasburicase, $387 for a 1.5 mg vial, the cost of the from 12 and 6% for those who did. The incidence of sepsis total amount of rasburicase used (144 mg) for these 43 was comparable (5%). In children with ALL, the incidence patients was $37 152. The cost of the total amount of of anuria was significantly higher (15%) without urate rasburicase used at the dose of 0.15 mg/kg daily for 5 days oxidase than with (4%; P ¼ 0.03). However, it was unclear (2842 mg) would have been $733 172. The cost of the total if this conferred a survival benefit. Similarly, a randomized study of rasburicase and allopurinol in children showed faster decline in uric acid with rasburicase therapy without 7 any obvious short-term survival advantage for rasburicase- treated patients.6 6 A European multi-center study of rasburicase in 100 patients with aggressive NHL – only 11% of whom were 5 hyperuricemic – found normalization of serum uric acid levels within 4 h of the first dose.7 The dose of rasburicase used in the study was 0.2 mg/kg daily for 3–7 days (median 4 3). This single-arm study concluded that rasburicase was ‘the treatment of choice’ to control uric acid and prevent 3 TLS in adult patients with aggressive NHL. This study was not designed to address questions of improved outcome, 2 but focused solely on biochemical parameters. Addition- Serum creatinine (mg/dL) ally, allopurinol use was not permitted in this study for the 1 first week. As the mechanisms of action of rasburicase and allopurinol are different, it would appear to be more logical 0 biochemically to reduce grossly elevated uric acid levels Baseline 24 hours 48 hours with one dose of rasburicase with concomitant allopurinol Figure 3 Change in serum creatinine levels with rasburicase. use to reduce uric acid formation.

Bone Marrow Transplantation Low-dose rasburicase S Trifilio et al 1000 Based on published data with the full dose of the drug, it Although formal dose-finding studies of lower doses may is clear that the rate of fall of uric acid levels was slower be desirable, we suggest 3 mg as the initial dose for most with the 3 mg dose. What is not clear is if a rapid decline in adults followed by additional 3 mg doses as required based uric acid to very low levels offers any practical benefit. The upon close monitoring of uric acid levels. Unlike clinical limited available data do not suggest any such benefit.6,7,12 trials where allopurinol was not used,7 oral (or intravenous While our data are insufficient to support such a for those unable to take the drug orally) allopurinol recommendation, it may be desirable to use a higher dose must be used in conjunction with rasburicase and other (6 mg) in those with uric acid levels that are over twice the supportive measures as is essential in prophylaxis or upper limit of normal. The half-life of rasburicase is 21 h, therapy of hyperuricemia or TLS. and thus daily administration would not be expected to Whether rasburicase should be used routinely or not, and be necessary. This is borne out by our observations, which whether it offers benefits that are more tangible than a make it clear that continued daily administration of the rapid decline in uric acid levels – such as significantly drug is unnecessary in most patients because uric acid levels reduced renal failure, elimination of the requirement for remain low for a prolonged period after a single dose. dialysis or improved survival – remains to be determined. Monitoring uric acid levels regularly and repeating drug However, the successful use of lower doses of rasburicase, administration only if necessary is adequate. as demonstrated here and elsewhere,8,9 represents an In the context of the activity of the drug,6,7,12 strong attractive alternative at an expense that could be justifiable advocacy for its widespread use7 and its cost, we believe our in patients at risk of complications of hyperuricemia. observations, despite their limitations, are of value in We conclude that in appropriate clinical circumstances, designing new studies and managing patients. The limita- using a low dose of rasburicase and repeating the dose as tions of these data are their retrospective and non- required based on frequent serum uric acid monitoring is systematic nature. It should be emphasized that this was safe and effective in correcting hyperuricemia. We recom- not a systematic dose–reduction study, but clinical practice mend using a single 3 mg dose of rasburicase initially adopted based on a serendipitous observation in a single followed by regular monitoring of uric acid levels. Another patient. The strength of our analysis is that the observa- dose of 3 mg should be administered if the tempo of uric tions have been made under actual clinical circumstances acid decline is slow or the magnitude of the decline is (not according to a tightly defined monitoring and insufficient. treatment protocol but based on laboratory parameters and clinical circumstances), and therefore are likely to be easily applicable to daily practice. Indeed, it could be argued that some of the patients References treated by us had only modestly elevated uric acid levels with normal renal function, and need not have received 1 Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, rasburicase at all. This only serves to underscore the fact Schreiber MJ. Pathophysiology, clinical consequences, and Am J Med that the drug need not be overused or overdosed. treatment of tumor lysis syndrome. 2004; 116: 546–554. The decline in uric acid and creatinine was similar for 2 Smith GW, Wright V. Allopurinol. Br J Clin Pract 1987; 41: patients who had evidence of TLS and those who did 710–711. not (i.e. those with isolated hyperuricemia). This is not 3 Wu XW, Lee CC, Muzny DM, Caskey CT. Urate oxidase: surprising because one would not expect any other primary structure and evolutionary implications. Proc Natl abnormality of TLS apart from hyperuricemia and renal Acad Sci USA 1989; 86: 9412–9416. dysfunction secondary to hyperuricemia to be impacted by 4 Leach M, Parsons RM, Reilly JT, Winfield DA. Efficacy of rasburicase. It also suggests that the lower dose is urate oxidase (uricozyme) in tumour lysis induced urate appropriate even in patients with TLS. nephropathy. Clin Lab Haematol 1998; 20: 169–172. The importance of using the drug judiciously is in 5 Bayol A, Capdevielle J, Malazzi P, Buzy A, Bonnet MC, et al. limiting the high expenditure associated with a potentially Colloc’h N Modification of a reactive cysteine explains differences between rasburicase and uricozyme, a natural useful supportive care measure – but one that has not been Aspergillus flavus uricase. Biotechnol Appl Biochem 2002; 36: shown to influence survival beneficially – in an era of 21–31. skyrocketing health-care costs. Cost of newer medica- 6 Goldman SC, Holcenberg JS, Finklestein JZ, Hutchinson R, tions is a matter of grave concern even with drugs that Kreissman S, Johnson FL et al. A randomized comparison affect survival beneficially.13 The French study advo- between rasburicase and allopurinol in children with lympho- cated the use of rasburicase in all patients with lymphoid ma or leukemia at high risk for tumor lysis. Blood 2001; 97: diseases including chronic lymphocytic leukemia. This 2998–3003. recommendation is not based upon any data, and if 7 Coiffier B, Mounier N, Bologna S, Ferme´ C, Tilly H, Sonet A followed, could cost more than $500 million a year in et al. Efficacy and safety of rasburicase (recombinant urate the US. oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin’s Hematopoietic stem cell transplantation is an expensive lymphoma: results of the GRAAL1 (Groupe d’Etude des procedure, and controlling drug cost during or after Lymphomes de l’Adulte Trial on Rasburicase Activity in Adult HSCT is desirable. If rasburicase use is required to treat Lymphoma) study. J Clin Oncol 2003; 21: 4402–4406. hyperuricemia post transplant, our data support the use of 8 Lee AC, Li CH, So KT, Chan R. Treatment of impending the drug at a low dose to achieve desired results at an tumor lysis with single-dose rasburicase. Ann Pharmacother acceptable cost. 2003; 37: 1614–1617.

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