Efficacy of a Reduced-dose Rasburicase: Single-institution Experience in India

Keywords

Low dose - rasburicase - tumor lysis syndrome

Introduction

Tumor lysis syndrome (TLS) is an oncological emergency associated with potentially life-threatening metabolic abnormalities.[1] Hyperuricemia is a feature of TLS and is treated with hydration, urine alkalinization, and allopurinol. Allopurinol inhibits the conversion of hypoxanthine to xanthine and xanthine to uric acid (UA) by inhibiting xanthine oxidase. It has no direct effect on existing UA. Rasburicase being a recombinant urate oxidase is highly efficacious in TLS. Rasburicase lowers UA rapidly to very low levels at the labeled dose of 0.15–0.2 mg/kg daily for 5 days by converting UA to allantoin which is rapidly excreted. Despite this dramatic effect on UA, rasburicase has not been shown to have any beneficial impact on survival. There are various studies suggesting the effectiveness of a reduced dose of rasburicase (3 mg to 6 mg single dose). In a developing country like India where affordability is one of the major limitations to medical care, the use of rasburicase at the dose recommended by the US Food and Drug Administration (FDA) is not always possible. There is no convincing data from India suggesting the efficacy of a lower dose of rasburicase (1.5 mg or 3 mg) in the treatment of TLS.

Objectives

The objective is to study the efficacy of a reduced dose of rasburicase (1.5 mg or 3 mg) in adult patients with TLS.

Materials And Methods

A retrospective review from January 2015 to June 2016 was conducted in adult oncology patients who received rasburicase. We evaluated the efficacy of a reduced dose of rasburicase (1.5 mg or 3 mg) in patients aged 18–72 years presenting with clinical or laboratory TLS[1] [Table 1] to our institution. These patients were administered rasburicase, hydration (3 L/m²/day), and chemotherapy on day 1. Patient's biochemistry parameters such as serum UA, serum potassium, serum creatinine, and serum calcium were studied before and after giving rasburicase. All the patients with TLS [Bishop and Cairo definition of clinical and/or laboratory TLS is shown in [Table 1] received 1.5 mg of rasburicase on the 1^st day, and the response was studied in terms of decrease in UA levels or decrease in serum creatinine levels. Those patients who did not achieve normal UA level within 24 h of 1.5 mg of rasburicase were given one more dose of rasburicase (1.5 mg). All patients were also evaluated for the change in serum creatinine, serum calcium, and serum potassium levels, postrasburicase administration.

Table 1 Bishop and Cairo criteria for TLS

Laboratory tumor lysis	Clinical tumor lysis
2 or more of the following criteria	Laboratory tumor lysis plus
within 3 days prior to or 7 days	1 or more of the following
after initiation of chemotherapy	Seizure
Uric acid : ≥ 8 mg/dl or 25%	Cardiac dysthymias or
increase from baseline	sudden death
Potassium: ≥6 mEq/l or 25%	Creatinine >1.5 times of
increase	age adjusted reference
Phosphorus: ≥4.5 mg/dl or 25%	range
increase from baseline
Calcium: ≤7 mg/dl or 25%
decrease from baseline

Results

The median UA level was 9.9 mg/dl (8.2–13.4 mg/dl). A total of 90 patients received low-dose rasburicase. Out of 90 patients, 54 patients (60%) had normalization of UA levels after 1.5 mg of rasburicase and 16 (18%) patients required 3 mg of rasburicase for bringing down the UA level to normal. The low serum UA levels were maintained even on the 3^rd day of rasburicase. Twenty patients (22%) did not achieve normal UA levels even with 3 mg of rasburicase although they had more than 50% reduction in UA levels. All the patients who did not acheive normal UA levels after 3 mg rasburicase had high risk[2] [Table 2] of TLS. Rasburicase was well tolerated, and there was no death due to TLS among the patients studied. Out of 90 patients, 48 patients (53%) had elevated creatinine due to TLS. The median serum creatinine level was 3.8 mg/dl (1.9–5.4 mg/dl). Thirty-one patients (64%) had normalization in the serum creatinine levels after rasburicase. Two patients of Burkitt's lymphoma required hemodialysis due to acute renal failure. The cost of one dose (1.5 mg) of rasburicase was Rs. 6000 as compared to the usual FDA recommended dose (0.15 mg/kg/day) which comes out to be Rs. 36,000 per day.

Table 2 Risk stratification of TLS patients

Low risk	Intermediate risk	High risk
LDH - Lactate dehydrogenase; ULN - Upper limit of normal; NHL - Non-Hodgkin’s lymphoma; CML - Chronic myeloid leukemia;			CLL - Chronic lymphocytic leukemia; AML - Acute myeloid leukemia; ALCL - Anaplastic large cell lymphoma; GCT - Germ cell tumor;			SCLC - Small cell lung cancer; TLC - Total leukocyte count, ALL - Acute lymphoblastic leukemia
Multiple myeloma	Neuroblastoma, GCT, SCLC	AML with TLC >100,000/mm3
CML	CLL with TLC >50,000/mm3	ALL with TLC >100,000/mm3 or LDH >2 × ULN
CLL with TLC <50,000/mm3	AML with either TLC >25,000-1,00,000/ mm3 or with LDH >2 × ULN	Stage III/IV Burkitt’s lymphoma, any stage Burkitt’s lymphoma with LDH >2 × ULN
Hodgkin’s lymphoma	Intermediate-grade NHL with LDH >2 × ULN	Stage III/IV lymphoblastic lymphoma or any stage lymphoblastic lymphoma with LDH >2 × ULN
AML with TLC <25,000/mm3 and LDH <2*ULN	ALL with TLC <100,000/mm3 and LDH <2 × ULN	Intermediate-risk disease with renal dysfunction
Adult ALCL	Burkitt’s lymphoma with LDH <2 × ULN	Intermediate-risk disease with elevated serum uric acid or potassium levels

Discussion

TLS and hyperuricemia are serious complications with significant morbidity and potential mortality in patients with hematologic malignancies undergoing anticancer therapy. Allopurinol has been used for many years in the prevention and management of TLS-related hyperuricemia. However, allopurinol should be administered for ≥3 days for the achievement of significant reduction in UA levels. Rasburicase offers a potential advantage over allopurinol by its rapid onset of action, reducing preexisting pool of UA within few hours.[3] The results of our study demonstrate that a fixed low-dose rasburicase is a highly effective agent for the management of hyperuricemia associated with TLS. We also find that the cost of rasburicase reduces by one-sixth when using a fixed low dose for TLS. All patients at potential risk and majority of high-risk patients responded to a reduced dose, indicating that in appropriately monitored patients, single dose followed by dosing as needed can be cost saving. Our results are similar to the results of Hummel et al.[4] wherein fifty patients were studied to evaluate the efficacy of low-dose rasburicase in TLS [Table 3].[4],[5],[6],[7],[8],[9],[10],[11]

Table 3 Other studies on efficacy of low dose rasburicase

Study	n	Malignancy	Dose of rasburicase	Number of doses
NHL - Non-Hodgkin’s lymphoma; AML - Acute myeloid leukemia; CML - Chronic myeloid leukemia; CLL - Chronic lymphocytic leukemia;					GCT - Germ cell tumor; ALL - Acute lymphocytic leukemia; CMML - Chronic myelomonocytic leukemia; MDS - Myelodysplastic syndrome;					CMP - Common myeloid progenitors; DLBCL - Diffuse large B-cell lymphoma; ALL - Acute lymphoblastic leukemia
Lee et al. [5]	3	ALL	0.08-0.26 mg/kg	1
McDonnell et al. [6]	11	3 NHL B-cell, 1 Burkitt’s lymphoma, 3 AML, 1 CMML, 1 MDS	0.0232-0.1361 mg/kg	1
Liu et al. [7]	8	3 AML, 2 ALL, 2 NHL, 1 CML	0.141-0.118 mg/kg	1
Trifilio et al. [8]	43	20 plasma cell dyscrasias, 10 NHL, 1 AML, 3 CLL, 1 MDS	3 mg	1, except for 6 additional doses (2 doses, 1.5 mg; 4 doses, 3 mg)
Hutcherson et al. [9]	11		0.045-0.1 mg/kg	1, except for 1 additional dose (0.1 mg/kg)
Hummel et al. [4]	50	14 NHL, 9 AML, 1 CLL, 6 CMP/MDS 5 ALL, 5 multiple, 4 solid tumor	0.031-0.11 mg/kg	Given as 1 (25 of 50 patients) to 3 doses
Reeves and Bestul.[10]	17	14 NHL, 3 AML	1.5 mg	1
Campara et al.[11]	21	9 AML, 3 NHL, 3 multiple myeloma, 3 myelofibrosis, 2 chronic leukemia, 1 plasma cell leukemia	0.11-0.24 mg/kg	1
Our study	90	7 multiple myeloma, 10 CLL, 6 CML, 22 ALL, I7 GCT, 09 Burkitt’s lymphoma, 08 AML, 11 DLBCL	1.5 mg	1 or 2 doses depending on the response to single dose

Conclusion

As per our knowledge, this is the largest study conducted for evaluating the efficacy of low-dose rasburicase. A reduced dose of rasburicase at 1.5 mg single dose (repeated only if necessary clinically) is very efficacious in TLS. We conclude that a low dose of rasburicase (1.5 mg or 3 mg) is cost saving and effective in reducing serum UA (especially for low-risk and intermediate-risk TLS) and the higher dose as recommended by the US FDA probably is required only for patients with high risk of TLS.

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