Tumor lysis syndrome (TLS) is not uncommon on the oncology ward. A novel agent, rasburicase, has been used to treat the uric acid nephropathy with some success. A recent article in AJKD reviews the evidence for this agent in TLS. Authors Dr. Maria Lopez-Olivo and Dr. Abdulla Salahudeen (MLO&AS) discuss the findings with Dr. Kellie Calderon (eAJKD), eAJKD Advisory Board member.
eAJKD: As nephrologists, we are frequently asked to treat the electrolyte and fluid derangements that complicate TLS. What was your motivation for undertaking this review and meta-analysis?
MLO&AS: At MD Anderson, we encounter a large number of patients with TLS. Although rasburicase is widely used, we still see patients develop TLS in the setting of suppressed uric acid levels. Furthermore, the FDA approval of rasburicase in adults was based on the results of one trial showing its effectiveness in suppressing serum uric acid levels, and not on clinical outcomes such as acute kidney injury, length of hospital stays, or survival rates. Current clinical guidelines for adult patients are primarily based on pediatric studies. Rasburicase is a relatively new drug; it is expensive and adds financial burden to the health care system. Therefore, we undertook a systematic review and meta-analysis of the published literature to explore if its use actually improves clinical outcomes.
eAJKD: Your work eloquently illustrates an important area of clinical medicine, which is a cost-effectiveness analysis. After reading your article, I’m finding it difficult to justify use of a vastly more expensive agent that appears to offer little additional benefit over other, less expensive therapies. How would you identify a sub-population of patients that may benefit from rasburicase?
MLO&AS: Regarding subpopulations, Annemans et al reported that using rasburicase alone to treat TLS in hyperuricemic patients was associated with savings ($512.00) on the basis of the average number of life-years saved. The cost-effectiveness of TLS prevention with rasburicase was greater for patients with non-Hodgkin lymphoma and acute lymphoid leukemia than for patients with acute myeloid leukemia (maximum incremental cost-effectiveness ratio of $49,800.00 for non-Hodgkin lymphoma and $38,600.00 for acute lymphoid leukemia per life-year saved). The maximum incremental cost-effectiveness ratio for treatment was $6,090.00.
eAJKD: Can you discuss the pharmaceutical sponsorships of most of the studies you evaluated?
MLO&AS: One randomized, controlled trial has been published in the literature, and it was sponsored by the drug manufacturer. The other non-randomized clinical trials did not report funding sources. The randomized, controlled trial comparing treatment with rasburicase alone, allopurinol alone, or the 2 drugs in combination had an agreement between the PI and the sponsor that restricted the PI’s rights to discuss or publish trial results after the trial was completed. In addition, the sponsor could review communications of the results prior to public release and could embargo communications regarding trial results (clinicaltrials.gov).
Of the 6 studies before-and-after treatment that were included in our study, 4 were somehow related to the manufacturer (i.e., sponsored or conflict of interest). Two before-and-after and 10 retrospective studies did not disclose conflicts of interests. In one retrospective study, the senior/correspondence author participated in a TLS advisory board with the drug manufacturer.
As shown in Supplemental Table 1 of the article, all included clinical trials were rated as having a high risk for bias on 2 or more evaluated items. Of the 8 observational studies with high quality scores, 4 reported conflicts of interest. There is evidence that industry-sponsored trials may overestimate the treatment effect and safety. These data emphasize the importance of interpreting any results cautiously. See full information here.
eAJKD: Has your approach to prevention or treatment of TLS changed after this review?
MLO&AS: Our review demonstrates that rasburicase is effective in reducing baseline serum uric acid levels 24-72 hours after treatment in adults. The main advantage for its use is the rapid onset of action leading to a prompt decrease of uric acid levels. This factor should be weighed when managing hyperuricemia in patients with a high risk of developing TLS, especially when the hyperuricemia is not responding to allopurinol. The factors against rasburicase use are its cost and its unproven benefit on clinical outcomes. Studies are needed, preferably head-to-head trials, comparing treatment with rasburicase with alternative agents in both patients at high risk of developing TLS and patients with established TLS.