What is the evidence to support lower doses (1.5mg - 3mg) of rasburicase for treatment of tumor lysis syndrome?

Comment by InpharmD Researcher

Several studies have been conducted investigating the use of 1.5 to 3 mg doses of rasburicase for treatment of tumor lysis syndrome (see Table 1). These studies have generally concluded effectiveness of low doses for normalizing uric acid levels, potentially allowing for substantial cost-savings compared to the use of higher doses.

Background

The 2008 American Society of Clinical Oncology (ASCO) guidelines recommend rasburicase at various doses depending on the patients’ tumor lysis syndrome (TLS) profile and baseline uric acid levels. Patients at high risk with a baseline uric acid level > 7.5 mg/dL should receive rasburicase 0.2 mg/kg for 1-7 days (based on plasma uric acid levels). The intermediate risk with a baseline uric acid <7.5 mg/dL should receive rasburicase 0.15 mg/kg for 1-7 days (based on plasma uric acid levels). Low risk with a baseline uric acid <7.5 mg/dL should receive rasburicase 0.1 mg/kg for a duration based on clinical judgment. The average duration of therapy (regardless of risk) is 2 days, but it can vary from 1 to 7 days. [1]

It is also worth noting that the doses recommended may be below the FDA-approved doses; this is based on data from compassionate-use trials that showed rasburicase activity at lower doses for shorter durations than approved. In certain cases, such as in patients experiencing massive tumor lysis, it may be necessary to increase the administration schedule to twice daily. The length of treatment is related to control of plasma uric acid levels, and therefore clinical judgment should be used. Treatment is not necessary when uric acid is extremely low or no longer detectable. [1]

A 2016 meta-analysis investigated the optimal single-dose regimen of rasburicase (1.5, 3, 4.5, 6, 7 mg, and 0.05 and 0.15 mg/kg) in TLS management for hematological malignancies to balance the cost and effectiveness in practical settings. Based on the pooled results from 906 adults and 92 children, the overall response rates for 6 mg, 7.5 mg, and 0.15 mg/kg single doses were 90% (95% confidence interval [CI] 0.825 to 0.974), 98.6% (95% CI 0.957 to 1.015), and 93.6% (95% CI 0.864 to 1.007), respectively, which were higher than other examined doses. Response rates for single doses of 1.5 mg and 3 mg doses were 0.83 (95% CI 0.54 to 1.13) and 0.84 (95% CI 0.75 to 0.94) and was 0.83 (95% CI 0.73 to 0.94) for weight-based dose of 0.05 mg/kg. No significant difference was observed between a single dose of 1.5 mg, 3 mg, 6 mg, or a weight-based dose of 0.05 mg/kg. However, a single dose of 7.5 mg was significantly higher than 3 mg and 0.05 mg/kg doses, but not significantly higher than other doses. [2]

A decrease in uric acid levels was more significant in 6 mg and 0.15 mg/kg dosing regimens than the others with a mean reduction of 8.45 mg/dL (95% CI 7.51 to 9.38) and 10 mg/dL (95% CI 8.58 to 11.42), respectively. Reduction of uric acid with 1.5 and 3 mg doses was 5.50 mg/dL (95% CI 3.86 to 7.14) and 3.92 mg/dL (95% CI 2.87 to 4.97). A significantly lower incidence of renal replacement therapy (RRT) was reported with the 4.5 mg dose (0.22, 95% CI 0.15 to 0.29) compared to 1.5 mg (0.93, 95% CI 0.74 to 1.12). The incidence of RRT was not significantly different between 3 mg, 6 mg, 7.5 mg, 0.05 mg/kg, and 0.15 mg/kg groups. Based on these findings, the authors suggested that a single 6 mg rasburicase dose appeared effective in normalizing and sustaining lower uric and creatinine levels in adult patients with TLS. The authors noted that a single dose of 3 or 4.5 mg could also be considered for patients if a baseline uric acid level <12 mg/dL with close laboratory monitoring. A single dose of 1.5 mg or 0.15 mg/kg appeared to be sufficient in normalizing uric acid levels in children with TLS. [2]

A 2016 review recommends administering rasburicase at a dose of 0.1 to 0.2 mg/kg daily from four hours before chemotherapy up to five days. During rasburicase treatment, uric acid levels should be monitored to determine the appropriate duration of treatment. A randomized study conducted in 2012 demonstrated that a single weight-based rasburicase dose was effective in 100% potential risk patients and 71.4% high-risk patients. Some studies also suggest fixed-dose rasburicase (3 mg to 6 mg) may also be useful in reducing serum uric acid in high-risk patients, regardless of baseline levels. Overall, a fixed-single dose of rasburicase is non-inferior to weight-based dosing in normal-weight and obese patients. If clinically indicated, rasburicase can be repeated until serum uric acid levels normalize. [3]

References:

[1] Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review [published correction appears in J Clin Oncol. 2010 Feb 1;28(4):708]. J Clin Oncol. 2008;26(16):2767-2778. doi:10.1200/JCO.2007.15.0177.
[2] Yu X, Liu L, Nie X, et al. The optimal single-dose regimen of rasburicase for management of tumour lysis syndrome in children and adults: a systematic review and meta-analysis. J Clin Pharm Ther. 2017;42(1):18-26. doi:10.1111/jcpt.12479
[3] Criscuolo M, Fianchi L, Dragonetti G, et al. Tumor lysis syndrome: review of pathogenesis, risk factors and management of a medical emergency. Expert Rev Hematol. 2016;9(2):197-208. doi:10.1586/17474086.2016.1127156.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the evidence to support lower doses (1.5mg - 3mg) of rasburicase for treatment of tumor lysis syndrome?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Table 1 for your response.

 

Studies evaluating lower doses of rasburicase for treatment of tumor lysis syndrome
Citation/ Study design Objective Patients Intervention Outcomes/Conclusions

Majumdar et al., 2023

Single center, non-randomized, phase 2 study

 To investigate the plasma uric acid response rate in patients with acute leukemia and high-grade lymphomas

N= 61

Adults in India with Eastern Cooperative Oncology Group Performance Status (ECOG PS) scores of 0-3, and either laboratory or clinical tumor lysis syndrome (TLS)

Rasburicase was given at a fixed dose of 1.5 mg (dissolved in 50 mL normal saline over 30 minutes). Prior to rasburicase, pheniramine 25 mg and paracetamol at a dose of 15 mg/kg were administered 30 minutes earlier. Additional rasburicase doses of 1.5 mg each were given only if plasma uric acid levels did not decrease by more than 50% on day 2, as decided by the physician.

In the first phase, 14 out of 17 patients achieved normalization of plasma uric acid (PUA) levels within 48 hours.

The overall PUA response rate, defined as normalization at 48 hours sustained until day 5, was 52% (32 out of 61 patients)

The rates of PUA normalization were 70% at 24 hours, 71% at 48 hours, and 80% at day 5.

Conclusion: We demonstrate that a low-dose rasburicase strategy leads to rapid and sustained reductions of uric acid in about 52% patients. 

Marjoncu et al., 2023

Multi-center, retrospective analysis

 To determine whether a single fixed dose of 3 mg of rasburicase was as effective as a 6 mg dose in achieving uric acid normalization

N= 79

Rasburicase 3 mg (n= 22)

Rasburicase 6 mg (n= 57)

Adult cancer patients who received rasburicase for hyperuricemia associated with TLS

Patients received either a single fixed dose of rasburicase 3 mg or rasburicase 6 mg (standard institutional policy).


Despite lower baseline uric acid levels in the 3 mg arm compared to the 6 mg arm, the study showed no significant difference in 24-hour uric acid normalization between the two groups (95% in the 3 mg arm and 82% in the 6 mg arm, p= 0.134). Implementing the protocol could save over $300,000 annually.

Conclusion: A single, fixed rasburicase dose of 3 mg was effective in normalizing uric acid levels within 24 h, and is associated with significant cost-savings.

Hossain et al., 2022

Retrospective, single-center, observational cohort study

 To assess the uric-acid lowering effectiveness and provider adherence to the institutional protocol, as well as the cost efficiency of this dosing strategy

N= 154

Rasburicase 1.5 mg (n= 49)

Rasburicase 3 mg (n= 105)

Adults cancer patients who received at least 1 dose of rasburicase for treatment of hyperuricemia secondary to TLS

 Patients received a fixed dose of rasburicase 1.5 mg (patients with UA between 8-12 mg/dL) or rasburicase 3 mg (UA > 12 mg/dL). Repeat doses were permitted after 24 hours of the initial rasburicase dose.

Mean uric acid reduction at 24 hours was 2.88 ± 0.88 mg/dL (p< 0.0001) in the 1.5 mg group and 4.83 ± 1.39 mg/dL (p< 0.0001) in the 3 mg group.

In the per-protocol subgroup, reductions were 2.83 ± 0.62 mg/dL in the 1.5 mg group (n= 42) and 6.12 ± 1.87 mg/dL in the 3 mg group (n= 42). Implementing the low fixed-dose approach led to a cost-saving of $138,077.30 annually.

Conclusion: Low fixed-dose rasburicase was an effective treatment, with a dose of 1.5 mg being sufficient to reach a goal uric acid of less than 8 mg/dL for serum uric acid levels below 12 mg/dL, while a 3 mg dose is appropriate for levels above 12 mg/dL. Cost analysis indicates this strategy is more cost-efficient than the FDA-approved weight-based dose.

Gupta et al., 2021

Prospective, nonrandomized, single-arm  study

 To evaluate the safety and efficacy of a fixed (weight-based) dose of rasburicase to manage TLS

N= 55

Patients diagnosed with leukemia/lymphoma 

 Rasburicase 0.05 mg/kg was the selected dose. Patients were categorized into weight groups, with doses rounded to the nearest 1.5 mg vial. Four dose groups were established: 1.5 mg for those ≤30 kg, 3 mg for >30 to ≤60 kg, 4.5 mg for >60 to ≤90 kg, and 6 mg for >90 kg.

Rasburicase was given prophylactically to 43 patients (78.2%) and for treating TLS to 12 patients (21.8%).

The mean baseline serum uric acid was 9.2 ± 1.8 mg/dL, decreasing significantly to 3.2 ± 2.1 mg/dL at 24 hours (p< 0.001), along with creatinine. This response was sustained for up to 72 hours.

A single dose of rasburicase proved effective in 94.5% of patients. Implementing a single low-dose strategy resulted in 95% direct cost savings compared to the recommended dose.

Conclusion: Single-dose rasburicase with frequent laboratory monitoring is effective in the management of TLS and offers significant cost
reductions.

Vachhani et al., 2021

Open-label, randomized, non-comparative, phase 2 trial 

To prospectively determine the efficacy and safety of two single low doses of rasburicase

N= 24

Rasburicase 1.5 mg (n= 12)

Rasburicase 3 mg (n= 12)

Adult patients with acute leukemia and elevated plasma uric acid 

 Rasburicase (1.5 mg or 3 mg) was administered intravenously over 30 minutes on day 1. All patients received allopurinol 300 mg daily from days 1 to 6, with adjustments for reduced calculated creatinine clearance (CrCL). Allopurinol doses were reduced to 150 mg daily for CrCL 20-49 mL/min, 100 mg daily for CrCL 10-19 mL/min, and 100 mg every other day for CrCL < 10 mL/min.

Twenty patients had acute myeloid leukemia, three had acute lymphoblastic leukemia, and one had acute promyelocytic leukemia. The median initial uric acid level was 9.8 mg/dL. 83% of patients in both groups achieved uric acid levels < 7.5 mg/dL within 24 hours after therapy.

Five patients (21%; 2 from 1.5 mg group and 3 from 3 mg group) needed additional rasburicase doses. The majority (23 out of 24) achieved uric acid goals after 1-2 doses of rasburicase.

No patients experienced worsening renal function, and both doses were well-tolerated without any reported treatment-related adverse events.

Conclusion: Single doses of rasburicase (as low as 1.5-3 mg) used in addition to allopurinol were well tolerated and highly efficacious (83% response rate) in decreasing UA levels within 24 h of administration in adult acute leukemia pts with hyperuricemia.

Pei et al., 2020

Single-center,  retrospective, cohort study

 To explore the safety and efficacy of low-dose rasburicase in critically ill children with hematological malignancies who are at high risk of TLS

N= 37 

Standard-dose group (>0.1 mg/kg/day; n= 22) 

Low-dose group (≤0.1 mg/kg/day; n= 15)

Critically ill pediatric patients 
Pediatric patients were divided into two groups based on their daily dose of rasburicase: standard-dose (> 0.1 mg/kg/day and ≤ 0.2 mg/kg/day) and low-dose (≤ 0.1 mg/kg/day). Follow-up data was collected from general ward or outpatient clinic visits. 

Within 12 hours, 90% of hyperuricemia patients saw their uric acid levels normalize (100% in standard-dose group, 75% in the low-dose group). Serious complications affected 84% of patients, including TLS (73%), acute kidney injury (59%), renal replacement treatment (24%), respiratory failure (24%), disseminated intravascular coagulation (16%), and heart failure (11%).

Incidence of serious complications didn't significantly differ between groups.

Overall, 7-day and 28-day survival rates post-intensive care unit (ICU) admission were 86% and 84% respectively. Average ICU stay was 9.92 ± 5.13 days. No significant differences were found between groups in short-term mortality or ICU stay duration.

Conclusion: Low-dose rasburicase is effective and may be an acceptable choice for critically ill children with hematological malignancies.

Thorat et al., 2018

Nonrandomized, phase 2 study 

 To prospectively evaluate the efficacy of single-dose rasburicase in patients with established TLS

N= 70

Patients (>15 years) with de-novo acute leukemia and high-grade lymphoma with hyperuricemia (laboratory or clinical TLS) and ECOG PS ≤ 4 

 Patients received rasburicase at a fixed dose of 1.5 mg over 30 min. Additional rasburicase doses were provided if PUA did not decline by at least 50% in 24 hours.

 

At 48 hours, plasma uric acid normalized in 70% (37/53) of patients, increasing to 87% (46/53) by day 5. For the entire cohort, these figures were 68% and 82%, respectively. Only 3 patients required hemodialysis, while 11 were managed as outpatients and the rest were admitted, with 3 needing ICU care.

Twenty patients needed additional doses of rasburicase; among them, 13 required 2 doses, 5 needed 3 doses, and 2 patients required 4 and 5 doses, respectively. 

No hypersensitivity reactions, cardiac dysfunction, or methemoglobinemia occurred. One patient experienced hemolysis post-rasburicase. Other adverse events included fever (25%), vomiting (10%), and abdominal pain (13%).

All 60 evaluable patients survived until the end of the study.

Conclusion: Lower dose of rasburicase is sufficient and cost-effective in established TLS. This strategy obviates the need for FDA approved higher doses.

Philips et al., 2018 

Retrospective analysis

 To evaluate the efficacy of single dose rasburicase 1.5 mg in prevention and management of TLS

N= 186

Patients with hematological malignancies who received rasburicase

 Adults received a single dose of rasburicase 1.5 mg.  Children received a single dose of 0.15 mg/kg (maximum 1.5 mg).

Rasburicase was administered prophylactically in 59 patients (31.7%), for treating laboratory TLS in 76 (40.8%), and for treating clinical TLS in 51 (27.4%) patients.

In the laboratory TLS group (n= 76), 78% had uric acid levels > 8 mg/dL, and a single dose prevented clinical TLS in 72%. The mean uric acid level was 10.6 mg/dl (range 3.4-30 mg/dL). Rasburicase was given 105 times, reducing uric acid per dose by 64%. Mean WBC count was 92,686/cumm (range 1,200–380,000/cumm). No clinical TLS occurred.

In the high-risk group for clinical TLS (n= 51), mean uric acid level was 12.8 mg/dL (range 3.7-31 mg/dL). Among them, 41% received 1 dose, 31% received 2 doses, 22% received 3 doses, 4% received 4 doses, and 2% received 5 doses. After rasburicase, mean uric acid level was 4.7 mg/dL, with a 61.4% reduction after a single dose. Two needed hemodialysis and 6 deaths occurred (11.3%). Spontaneous TLS happened in 92.2%, while 7.3% developed TLS post-chemotherapy.

Conclusion: Single dose of 1.5 mg rasburicase is efficient in preventing and managing laboratory TLS in majority of the patients and in patients with clinical TLS more doses are required. The optimal dosing of rasburicase needs to analyzed in well planned prospective studies.
References:

[1] Majumdar S, Sharma N, Sengar M, et al. A phase II study to evaluate the efficacy of low-dose rasburicase (1.5mg) in adolescent and adult acute leukemia and high-grade lymphomas with tumor lysis syndrome. Leuk Lymphoma. 2023;64(3):628-638. doi:10.1080/10428194.2023.2167491
[2] Marjoncu D, Holman K. The efficacy and cost-impact of rasburicase 3 mg versus 6 mg for the management of tumor lysis syndrome: A multicenter analysis. J Oncol Pharm Pract. 2023;29(4):893-898. doi:10.1177/10781552221087978
[3] Hossain S, Naber M, Yacobucci MJ. A retrospective observational study of a low fixed-dose rasburicase protocol for the treatment of tumor lysis syndrome in adults. J Oncol Pharm Pract. 2022;28(6):1326-1331. doi:10.1177/10781552211021147
[4] Gupta G, Seth T, Garg V, et al. Efficacy of Single Low-Dose Rasburicase in Management of Tumor Lysis Syndrome in Leukemia and Lymphoma Patients. Clin Lymphoma Myeloma Leuk. 2021;21(1):e99-e104. doi:10.1016/j.clml.2020.08.024
[5] Vachhani P, Baron J, Freyer CW, et al. A phase 2 trial of single low doses of rasburicase for treatment of hyperuricemia in adult patients with acute leukemia. Leuk Res. 2021;107:106588. doi:10.1016/j.leukres.2021.106588
[6] Pei Y, Li Y, Liang Y, et al. Evaluation of the safety and efficacy of low-dose rasburicase in critically ill children with haematological malignancies. Int J Clin Pharm. 2020;42(6):1440-1446. doi:10.1007/s11096-020-01144-8
[7] Thorat J, Majumdar S, Jain H, et al. A phase ii non-randomized study to evaluate the efficacy of single dose rasburicase (1.5mg) in adult acute leukemia and high grade lymphomas with established tumor lysis syndrome. Blood. 2019;134(Supplement_1):2914-2914.
[8] Philips A, Radhakrishnan V, Ganesan P, et al. Efficacy of Single Dose Rasburicase (1.5 mg) for Prophylaxis and Management of Laboratory Tumor Lysis Syndrome. Indian J Hematol Blood Transfus. 2018;34(4):618-622. doi:10.1007/s12288-018-0938-9