Outcomes Of Repeated Administration Of Rasburicase In Recurrent Cycles For Patients With Leukemia
Authors: Wang Alice C. , McCue Deborah , Ravandi Farhad , Borthakur Gautam , Thomas Deborah A. , Faderl Stefan , Wierda William G. , Cortes Jorge E. 
Published: October 2019

Abstract

Introduction
Rasburicase, a recombinant urate oxidase, is effective at reducing plasma uric acid levels in patients who are at risk for tumor lysis syndrome. Since rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain using the cDNA from an Aspergillus flavus strain, it may cause anti-rasburicase antibodies to develop. Anti-rasburicase antibodies pose a major safety and efficacy concern in that they can contribute to hypersensitivity reaction and/or the loss of uricolytic activity in patients who receive more than one cycle of rasburicase. We sought to evaluate the efficacy and rate of adverse reactions in those patients who received more than one cycle of rasburicase.

Methods
Pharmacy records were used to identify patients treated on the adult leukemia service who received more than one cycle of rasburicase therapy during the time period of January 2003 to May 2013. To be classified as a new cycle, a break in rasburicase therapy of at least 21 days needed to occur. Electronic medical records were used to document demographic, laboratory and clinical course information for the first 3 cycles of rasburicase administered. Uric acid levels as well as adverse events possibly attributable to rasburicase were collected for up to 3 days following the first dose of a cycle. Tumor lysis risk was determined using the method described by Cairo, et al (Cairo MS, et al on behalf of the TLS expert panel. Br J Haematol 2010; 149: 578-586.).

Results
Two hundred and forty-two patients were identified that received at least 2 cycles of rasburicase therapy. Fifty-two of the patients received a third cycle of rasburicase therapy. Median patient age was 61 years for those patients receiving a second cycle and 56 years for those receiving a third cycle. The majority of the patients had AML (45%), ALL (20%) or CLL (16%). The second and third cycles of rasburicase were administered a median of 86.5 (range: 22-3736) and 52.5 (range: 21-690) days, respectively, from the previous cycle. The median uric acid level measured the day following the first dose of rasburicase therapy was below the laboratory normal range (2.6 – 7.1 mg/dL) on all cycles: 1.5 mg/dL on Cycle 1, 2.4 mg/dL on Cycle 2 and 2.15 mg/dL on Cycle 3. Seventeen patients (7%) experienced adverse events that could possibly be attributed to rasburicase therapy, including shortness of breath, chills, nausea, itching and rash. In 11 of the 17 patients, concomitantly administered agents, such as monoclonal antibodies, were more likely to be causative of the adverse events based on temporal or clinical findings. Only 1 patient (0.4%), who experienced shortness of breath and rash approximately 30 minutes following the rasburicase dose, had symptoms that would be consistent with a hypersensitivity reaction due to rasburicase. Despite the reaction, the patient’s uric acid level following rasburicase decreased into the normal range.

Conclusions
This study indicates that, in our population of adult patients with leukemia, subsequent cycles of rasburicase therapy remain safe and effective. Rasburicase was able to lower baseline uric acid levels to below the normal range following the first dose. Additionally, only 1 patient experienced a hypersensitivity reaction that was clearly attributable to rasburicase administration. Prospective studies evaluating antibody production in those patients who develop hypersensitivity reactions, or fail to have a clinical response, to rasburicase therapy would help validate our observations.

Disclosures:
Off Label Use: Rasburicase is not approved for the administration of repeated courses of therapy. Ravandi:Sanofi: Research Funding. Cortes:Sanofi: Research Funding.