Rasburicase in the management of tumor lysis: an evidence-based review of its place in therapy

Figures & data

Clinical impact summary for rasburicase in tumor lysis syndrome

Outcome measure	Evidence	Implications
Disease-oriented outcomes
Reduction of PUA levels	Level 1, with two systematic reviews and two RCTs	Reliable, rapid, and effective reduction of PUA, which should in theory prevent or mitigate adverse TLS sequelae, eg, AKI
Reduction of LTLS incidence	Level 2 with one RCT	Prevention of LTLS, a potentially life-threatening condition which, in turn, should lead to prevention of CTLS Additionally, this may allow for earlier initiation and more effective dosing of chemotherapy
Patient-oriented outcomes
Prevention of CTLS/AKI/need for RRT	Level 3 from pooled results of CCTs in the pediatric population (some of these studies used Uricozyme ^®, a nonrecombinant urate oxidase, rather than rasburicase) and multiple observational studies and cross-trial comparisons	May represent an effective and safe alternative to RRT and all of the short/long-term sequelae (physical, emotional, financial) associated with RRT. May also allow for earlier initiation and more effective dosing of chemotherapy
Reduction in ICU admissions and hospital/ICU LOS Mortality	Level 3 (only ICU LOS in the pediatric population) from matched case control studies with potential bias	May have some of the same physical, emotional, and financial benefits that are associated with decreased ICU stay and duration of hospitalization.
	Level 3 from pooled results of CCTs in the pediatric population (some of these studies used Uricozyme^®, a nonrecombinant urate oxidase, rather than rasburicase)	Only TLS, not overall, mortalitybenefit
Economic outcomes
Cost-effectiveness	Level 5 based on descriptive studies	Unclear overall health care cost benefit
Dose reduction	Level 1 with meta-analysis of dose reduction studies showing non-inferior efficacy	Uses of lower doses than FDA-approved makes rasburicase more cost-effective

Table 1 Cairo-Bishop criteria for laboratory tumor lysis syndrome

Metabolic	Criteria for classification of laboratory tumor	Criteria for classification of clinical tumor
abnormality	lysis syndrome	lysis syndrome
Hyperuricemia	Uric acid >8.0 mg/dL (475.8 μmol/liter) in adults or above the upper limit of the normal range for age in children
Hyperphosphatemia	Phosphorus >4.5 mg/dL (1.5 mmol/liter) in adults or >6.5 mg/dL (2.1mmol/liter) in children
Hyperkalemia	Potassium >6.0 mmol/liter	Cardiac dysrhythmia or sudden death probably or definitely caused by hyperkalemia
Hypocalcemia	Corrected calcium <7.0 mg/dL (1.75 mmol/liter) or	Cardiac dysrhythmia, sudden death, seizure, neuromuscular
	ionized calcium <1.12 (0.3 mmol/liter)	irritability (tetany, paresthesias, muscle twitching, carpopedal spasm, Trousseau’s sign, Chvostek’s sign, laryngospasm, or bronchospasm), hypotension, or heart failure probably or definitely caused by hypocalcemia
Acute kidney injury	Not applicable	Increase in the serum creatinine level of 0.3 mg/dL (26.5 μmol/liter) (or a single value >1.5 times the upper limit of the age-appropriate normal range if no baseline creatinine measurement is available) or the presence of oliguria, defined as an average urine output of <0.5 ml/kg/hr for 6 hr

Note: From The tumor lysis syndrome, Howard SC, Jones DP, Pui CH,N Engl J Med. 364(19):1844–1854. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.²

Figure 1 Search strategy used and number of articles found in each category.

Table 2 Disease-oriented outcomes: reduction of plasma uric acid levels

Reference	Design/number of patients	Adults, children or both	Intervention/method	Comparison	Measured outcome	Conclusion
Goldman et al^18	RCT (n=52)	Children	Rasburicase 0.2 mg/kg IV over 30 minutes daily for 5-7 days	Allopurinol 300 mg/m^2/day or 10 mg/kg in divided doses every 8 hours	PUA reduction over 4 hoursPUA concentrations (mean uric acid AUC) over 96 hours	Significant reduction (p<0.0001) of PUA levels over the first 4 hours in the rasburicase group (86%) versus the allopurinol group (12%)Significant reduction (p< 0.0001) of PUA concentrations (mean uric acid AUC) over 96 hours in the rasburicase group (128±70 mg/dL - hour) compared with the allopurinol group (329± 129 mg/dL · hour)
Cortes et al^19	RCT (n=280)	Adults	Rasburicase 0.2 mg/kg/day IV on days 1 -5	Allopurinol 300 mg/day orally on days 1-5 OrRasburicase 0.2 mg/kg/day IV days 1-3 followed by oral allopurinol 300 mg/day on days 3-5	PUA RR (percentage of patients achieving or maintaining PUA ≤7.5 mg/dL during days 3-7)PUA reduction over 4 hoursPUA AUC from days 1-7 Median time to PUA control	Significantly increased PUA RR for rasburicase only (87%) versus allopurinol only (66%)Significantly reduced PUA with rasburicase (88%) versus allopurinol (14%) over 4 hours Significantly reduced PUA AUC over days 1-7 in both the rasburicase and the rasburicase + allopurinol groups compared with allopurinol alone (p<0.00l) Significantly reduced median time to PUA control in both rasburicase groups (4 hours) versus allopurinol alone group (27 hours)
Lopez- Olivo et al^16	Systematic review/ attempted meta-analysis (n=913)*	Adults	Pooled 16 studies from August 7, 2012 or earlier that reported data on use of rasburicase for either treatment or prophylaxis of tumor lysis syndrome	None reported	Mean reduction in PUA	Pooled analysis of 21 studies showed a mean reduction in PUA of 5.3-12.8 mg/dL (88%). Other studies have shown that allopurinol only decreases PUA by 12%-l4%. These pooled data correlate with the results of the RCTs listed above
Cheuk et al^17	Systematic review/ attempted meta-analysis (n=306)**	Children	Pooled three studies from February 2013 or earlier that reported serial PUA measurements after use of rasburicase or Uricozyme^®(nonrecombinant urate oxidase)	Allopurinol	Mean reduction in PUA at days 1, 2, 3, 4, 5, and 7	Significant decrease in PUA at day 2 with rasburicase compared with allopurinol in all three trials with 95% Cl (-7.37, -0.24) Significant decrease in PUA at day 3 with rasburicase compared with allopurinol in trials reported by Rényi and Sanchez-Tatay with 95% Cl (-6.12, -0.14) Significant decrease in PUA at day 4 with rasburicase compared with allopurinol in trials reported by Rényi and Sanchez-Tatay with 95% Cl (-6.39, -2.81) Significant decrease in PUA at day 7 with rasburicase compared with allopurinol in trial reported by Sanchez-Tatay with 95% Cl (-3.01, -0.47)No significant decrease in PUA at day 1 in all three trials (95% Cl -7.61, 1.60) or at day 5 in trial reported by Sanchez-Tatay (95% Cl -2.24, 0.20)

Notes: *Results of pooled response in PUA were only reported by Lascombes,⁴⁶ Jeha,³¹ Bosly,⁴⁷ Coiffier,⁴¹ Pohlreich,⁴⁸ Wang,⁴⁹ Ho,⁵⁰ Hutcherson,⁵¹ Llinares,⁵² Campara,⁵³ Knoebel,⁵⁴ Vines,⁵⁵ Yim,⁵⁶ Trifilio,^57,58 Steel,⁵⁹ and Chow⁶⁰ instead of all 21 studies, which is reflected by n=913 instead of n=1,261; **results of serial PUA levels were only reported by Pui,²⁴ Rényi,²³ and Sanchez-Tatay,²⁵ instead of all seven studies, which is reflected by n=306 instead of n=1,274. Additionally, only Rényi²³ and Sanchez-Tatay²⁵ reported results for days 3 and 4; only Sanchez-Tatay reported results for days 5 and 7.

Abbreviations: CI, confidence interval; PUA, plasma uric acid; AUC, area under the curve; IV, intravenous; RCT, randomized controlled trial; RR, response rate.

Table 3 Patient-oriented outcomes: LTLS, CTLS, need for RRT, hospital/ICU LOS, mortality

Reference	Design/number of patients	Adults, children or both	Intervention	Comparison	Measuredoutcome	Conclusion
Goldman et al^18	RCT (n=52)	Children	Rasburicase 0.2 mg/kg IV over 30 minutes daily for 5-7 days	Allopurinol 300 mg/m^2/day or 10 mg/kg/day in divided doses every 8 hours	Incidence of LTLS, CTLS, and need for RRT	No significant reduction in LTLS, CTLS, or renal failure in the rasburicase arm
Cortes et al^19	RCT (n=280)	Adults	Rasburicase 0.2 mg/kg/day IV on days 1 -5	Allopurinol 300 mg/day orally on days 1-5 OrRasburicase 0.2 mg/kg/day IV on days 1-3 followed by oral allopurinol 300 mg/day on days 3-5	Incidence of LTLS, CTLS, and need for RRT	Significant reduction of LTLS in the rasburicase arm compared with the allopurinol only arm (21 % versus 41%, p <0.05)No significant reduction in CTLS or renal failure in the rasburicase arm
Galardy et al^20	Prospective single cohort study (n=76)	Children	Rasburicase 0.2 mg/kg IV prior to treatment (day 0) with optional doses at days +1, +2, +3, and +4 if needed	No direct comparison, indirect comparison with other studies with similar chemotherapy backbones using allopurinol	Incidence of LTLS,CTLS and need for CVVH or hemodialysis	Total incidence of LTLS 21% versus up to 42% in older trials with similar high-grade NHL using allopurinol Total incidence of CTLS 1 1% versus 6%— 18% in older trials with similar high-grade NHL using allopurinol Total incidence of patients requiring CVVH or hemodialysis was 8%. No comparisons made.
Ahn et al^27	Retrospective cohort study (n=396)	Children	Rasburicase 0.2 mg/kg/day as second-line therapy until PUA normalized	Allopurinol alone for children in the “pre- rasburicase era” (January 2000 to August 2003) for whom rasburicase would have been indicated had it been available	Incidence of TLS, CTLS, and requirement for RRT	No significant differences between the incidences of TLS (67.9% versus 76.9%), CTLS (57.1% versus 69.2%), or need for RRT (57.1% versus 53.8%) amongst children receiving rasburicase as second-line treatment for allopurinol-resistant hyperuricemia versus those only receiving allopurinol
Cheuk et al^17	Systematic review/ attempted meta-analysis (n=992)*	Children	Pooled five studies from February 2013 or earlier that reported need for RRT after use of rasburicase or Uricozyme^® (nonrecombinant urate oxidase)	Allopurinol	Incidence of renal failure requiring RRT	Significant reduction in the need for RRT in the children receiving rasburicase compared with those receiving allopurinol (risk ratio 0.26, 95% Cl 0.08-0.89)
Lopez-Olivo et al^16	Systematic review/ attempted meta-analysis (n=42 for TLS, n=702 for AKI)^+	Adults	Pooled 16 studies from August 07, 2012 or earlier that reported data on use of rasburicase for TLS treatment or prophylaxis	None reported	Incidence of TLS and AKI	Total incidence of patients developing TLS in patients receiving rasburicase was 7.4% (95% Cl 1.7-16.7) versus up to 42% in older trials using allopurinol.Total incidence of AKI in patients receiving rasburicase was 4.4% (95% Cl 3.0-6.0). No comparison made.
Eaddy et al^37	Retrospective case control study (n= 126)	Children	Rasburicase IV within 2 days of hospital admission	Allopurinol	Cost per hospitalization, hospital/ICU LOS	Significant reduction in mean ICU LOS in the rasburicase group versus the allopurinol group (1.4 days versus 2.5 days, p=0.0001) No significant reduction in mean hospital LOS in the rasburicase group versus the allopurinol group (13.8 days versus 14.9 days, p=0.69) or in total hospitalization cost ($30,470 versus $35,165, p=0.427)
Eaddy et al^36	Retrospective case control study (n=l 32)	Adults	Rasburicase IV within 2 days of hospital admission	Upfront allopurinol followed by rasburicase combination therapy within 2 days of hospital admission	Cost per hospitalization, hospital/ICU LOS	Significant reduction in mean hospital LOS in the upfront rasburicase group versus the upfront allopurinol followed by rasburicase combination group (10.0 versus 15.4 days, p=0.0067)No significant reduction in mean ICU LOS in upfront rasburicase group versus upfront allopurinol followed by rasburicase combination group (2.4 days versus 2.9 days, p=0.3389) or in total hospitalization cost ($35,843 versus $46.672, p=0.0820)
Cheuk et al^17	Systematic review/ attempted meta-analysis (n=396 for mortality due to TLS, n=406 for all-cause mortality)^††	Children	Pooled three studies from February 2013 or earlier that reported mortality after use of rasburicase or Uricozyme (nonrecombinant urate oxidase)	Allopurinol	Mortality due to TLS and all-cause mortality	Significant reduction in mortality due to TLS among children receiving rasburicase compared with those receiving allopurinol (risk ratio 0.05,95% Cl 0.00-0.89) but none in all-cause mortality (risk ratio 0.19,95% Cl 0.01-3.42)
Lopez-Olivo et al^16	Systematic review/ attempted meta-analysis (n=221)^‡	Adults	Pooled nine studies from August 7, 2012 or earlier that reported data on mortality after use of rasburicase	None reported	Estimated death rate	Estimated death rate 0.03 (95% Cl 0.01-0.05, standard error 0.32, 95% Cl 0.20-0.45). Lack of comparison with a pooled estimated death rate for allopurinol- treated controls precludes concluding that mortality is reduced by rasburicase in adults

Notes: *Pooled results for need for RRT were only reported by Patte,³⁴ Pui,²⁴ Rényi,²³ Sanchez-Tatay,²⁵ and Wössmann³⁵, which is reflected by n=992 instead of n=1,274; ^†pooled results for TLS were only reported by Ho,⁵⁰ Hutcherson,⁵¹ and Llinares⁵². Pooled results for need for RRT were only reported by Lascombes,⁴⁶ Jeha,³¹ Bosly,⁴⁷ Coiffier,⁴¹ Pohlreich,⁴⁸ Wang,⁴⁹ Ho,⁵⁰ Hutcherson,⁵¹ Llinares,⁵² Campara,⁵³ and Steel⁵⁹. This is reflected by n=42 for TLS and n=702 for AKI instead of n=1,261; ^††pooled results for mortality due to TLS were only reported by Patte,³⁴ Rényi,²³ and Sanchez-Tatay²⁵, which is reflected by n=396 instead of n=1,274, and pooled results for all-cause mortality were only reported by Rényi,²³ Sanchez-Tatay,²⁵ and Wössmann³⁵, which is reflected by n=406 instead of n=1,274; ^‡pooled results for mortality were only reported by Jeha,³¹ Coiffier,⁴¹ Pohlreich,⁴⁸ Wang,⁴⁹ Ho,⁵⁰ Hutcherson,⁵¹ Llinares,⁵² Campara,⁵³ and Steel⁵⁹. This is reflected by n=221 instead of n=1,261.

Abbreviations: PUA, plasma uric acid; RR, response rate; TLS, tumor lysis syndrome; CTLS, clinical tumor lysis syndrome; LTLS, laboratory tumor lysis syndrome; CVVH, continuous venovenous hemofiltration; RRT, renal replacement therapy; LOS, length of stay; ICU, intensive care unit; CI, confidence interval; IV, intravenous; AKI, acute kidney injury; NHL, non-Hodgkin’s lymphoma; RCT, randomized controlled trial.

Table 4 Safety/tolerability of rasburicase

Reference	Design/number of patients	Adults, children or both	Intervention	Comparison	Measured outcome	Conclusion
Cheuk et al^17	Systematic review/ attempted metaanalysis (n=345)*	Children	Pooled three studies from February 2013 or earlier that reported AEs after use of rasburicase or Uricozyme^® (nonrecombinant urate oxidase)	Allopurinol	Nature and frequency of AEs with recombinant urate oxidase versus rasburicase	Significant increase in AEs in the urate oxidase group versus the rasburicase group (7% versus 0%, relative risk 9.10,95% Cl 1.29-64.00, p= 0.03; ITT analysis).Adverse events included: allergic reaction (n=6), methemoglobinemia (n=l), fever (n=2), nausea (n=l), abdominal pain (n=l), and mucositis (n=2).
Lopez-Olivo et al^16	Systematic review/ attempted metaanalysis (n=875)**	Adults	Pooled ten studies from August 7, 2012 or earlier that reported data on AEs after use of rasburicase	None reported	AEs	Reported total AEs of 2.6% (95% Cl 1.7-3.8) when combining all studies.
Malaguarmera et al^40	Systematic review (n=762)	Both	Rasburicase	None reported	Nature and frequency of AEs	AEs included: nausea/vomiting (n=2), hypersensitivity/allergic reactions (n=5), hemolytic anemia (n=4), albuminuria (n=l), dyspnea (n=l), fever (n=2), methemoglobinemia (n=2), hypoxia (n=2), anaphylactic shock (n=l), rigor (n=l), convulsion (n=l), headache (n=3), and electrolyte abnormalities (n=l).

Notes: *Pooled results for AEs were only reported by Patte,³⁴ Rényi,²³ and Sanchez-Tatay,²⁵ which is reflected by n=345 instead of n=1,274; **pooled results for AEs were only reported by Jeha,³¹ Coiffier,⁴¹ Pohlreich,⁴⁸ Wang,⁴⁹ Ho,⁵⁰ Hutcherson,⁵¹ Llinares,⁵² Campara,⁵³ Trifilio,^57,58 and Steel⁵⁹. This is reflected by n=875 instead of n=1,261.

Abbreviations: AE, adverse event; CI, confidence interval; ITT, intention to treat.

Table 5 Economic outcomes (including studies comparing single with daily dose rasburicase)

Reference	Design/number of patients	Adults, children or both	Intervention	Comparison	Measured outcome	Conclusion
Kikuchi et al^33	RCT (n=30)	Children	0.15 mg/kg/day of rasburicase for 5 days	0.2 mg/kg/day of rasburicase for 5 days	Decrease in PUA levels	No significant different in mean PUA concentrations for 0.15 versus 0.2 mg/kg of rasburicase at 4 hours (84.8%, 95% Cl 76.7-92.9 versus 92.9%, Cl 95% 88.7-97.0). PUA reduction remained similar between the two groups at 24 hours after the last administration of rasburicase on day 6.
Vadhan-Raj et al^11	RCT (n=82)	Adults	SDR 0.15 mg/kg/day with additional doses only if PUA was still >7.5 mg/dL	DDR 0.15 mg/kg/day for 5 days regardless of PUA levels	Decrease in PUA levels	A single dose of rasburicase was effective in producing a sustained PUA response in most (85%) patients without requiring a repeat dose compared with 98% of patients with the 5-day dosing (98%).p-value not reported.
Feng et al^12,*	Meta-analysis (n=269)	Adults	SDR	DDR for 5 days OrAllopurinol	PUA RR with SDR versus DDR PUA RR with SDR versus allopurinol	No significant difference between combined SDR arm (88.15%) and DDR arm (90.18%) in terms of PUA RR (p=0.542).Significant difference between the combined SDR arm (88.15%) and the allopurinol arm (66%) in terms of PUA RR (p<0.0005).
			Low SDR (3 mg and 0.05 mg/kg)	Standard SDR (6 mg, 7.5 mg, 0.15 mg/kg,2 mg/kg)	Control of PUA below 4 mg/dL at 24 hours Response of PUA	Low SDR was unable to control PUA below 4 mg/dL at 24 hours whereas standard SDR was. No significant difference between low SDR (84.44%) compared with standard SDR (91.80%) in terms of PUA RR (p=0.095).
McBride et al^13	Retrospective medical record review (n=373)	Adults	SDR 3 mg	Rasburicase 6 mg, 7.5 mg, and weight-based dosing (mean 0.16 mg/kg)	PUA RR	No significant difference between the 3 mg, 6 mg, 7.5 mg, and weight-based dosing groups in terms of PUA RR (92.9% versus 97.6% versus 100% versus 98%, p=0.1238).
Azim et al^14	Case series (n=6)	Adults	SDR 7.5mg	Pre-rasburicase laboratory values	PUA RR, creatinine, phosphate, and potassium RR	Significant decrease in PUA (100%, p=0.008994), creatinine (p=0.0439), phosphate (p=014326), and potassium (p=0.002008).
Herrington et al^15	Retrospective medical record review (n=45)	Adults	SDR 3 mg	SDR 1.5 mg, 4.5 mg, and 6 mg	PUA reduction	Median reductions in PUA levels 24 hours following doses of 1.5, 3, 4.5, and 6 mg were 5.5, 5.8, 3.8, and 10.05 mg/dL, respectively p-values not reported).
Annemanset al^38·^39 (2003)	Retrospective chart review (n=755)	Both	Rasburicase	Allopurinol	Cost per life-year saved based on assumption that if rasburicase was used prophylactically, it would prevent all TLS-related deaths (0.9% of overall cancer patient population, 17.5% of TLS population)	Cost of hyperuricemia without TLS 672 Euros, that of TLS 7,342 Euros and that of TLS requiring dialysis 17,706 Euros. However, no high-quality evidence that rasburicase prevents TLS with 80%-100% efficacy as this paper assumed, so no reliable conclusions can be drawn.

Note: *Pooled results from Trifilio,^57,58 Campara,⁵³ Vadhan-Raj,¹¹ Knoebel,⁵⁴ Vines,⁵⁵ Reeves,²² McDonell,⁶¹ Chiang,⁶² Steel,⁵⁹ Giraldez⁶³ and Cortes.¹⁹

Abbreviations: PUA, plasma uric acid; RR, response rate; SDR, single-dose rasburicase; DDR, daily dose rasburicase; TLS, tumor lysis syndrome; CI, confidence interval; RCT, randomized controlled trial.