Re: Early treatment with rasburicase and risk of kidney replacement therapy and death in adults with tumour lysis syndrome: emulated target trial

Agreement: I Agree Body: Dear Editor Shenoy and colleagues have produced the most credible evidence yet that early rasburicase improves hard outcomes in tumour lysis syndrome (TLS), closing a gap left open since the drug's approval in 2001, when registration trials measured only the fall in uric acid.[1-3] The target trial emulation is done properly: time zero anchored at TLS onset, late-treated patients analysed as controls to mimic crossover, and moribund patients excluded to remove immortal time.[1,4] Manual chart abstraction with under 3% missing data stands in welcome contrast to one-click database studies, in which a diagnosis code can never say at what hour a syndrome began. Five caveats, however, deserve attention before the number needed to treat of 11 enters routine decision-making. First, residual confounding is acknowledged but not quantified. Weighting balances measured covariates,[5] not the clinical trajectory between TLS onset and the treatment decision, which is what actually drives the timing of rasburicase. The E-value[6] is about 2.3 for the point estimate of 0.67, but only about 1.5 for the confidence limit of 0.88: a confounder of modest strength could pull the interval across the null. Second, the intention-to-treat strategy has a cost specific to acute care. A patient treated at hour 20 is usually not an untreated patient but a rescue after failed conservative management, whose deterioration was invisible at baseline. Counting that patient's events against the control strategy will flatter early treatment. The authors' own window analysis, with the association holding at 18 hours but attenuating to non-significance at 24,[1] is compatible with both a genuine time-gradient of drug effect and a sicker-rescue-patient gradient, and the paper does not separate the two. Third, earlier anticancer therapy in the rasburicase group (adjusted hazard ratio 1.36) is presented as supporting benefit.[1] The reverse reading is equally plausible: aggressive tumours such as Burkitt lymphoma cause more TLS, demand rasburicase sooner, and require urgent chemotherapy regardless. This endpoint belongs in the descriptive column. Fourth, competing risks are handled for hospital-free days but not for the decomposed kidney outcomes. Death before kidney replacement therapy could distort those estimates; a Fine-Gray sensitivity analysis[7] would settle this within a revision cycle. Fifth, generalisability receives one sentence. Thirty-six tertiary centres achieved a median time to rasburicase of 5 hours. Where laboratory turnaround is slow and the drug is not stocked, a 12-hour window may not exist, and the attenuation of benefit by 24 hours then becomes the central implementation question rather than a footnote. None of this diminishes the study's achievement. In a field where the randomised trial will never come, an observational study this honest about its own construction is close to the best answer available. But the estimate carries the fingerprint of the centres that produced it, and replication in community settings should precede any change to guidelines. References [1] Shenoy T, Sanchez-Almanzar D, Dias JA, et al. Early treatment with rasburicase and risk of kidney replacement therapy and death in adults with tumour lysis syndrome: emulated target trial. BMJ. 2026;394:e100040. doi:10.1136/bmj-2026-100040 [2] Pui CH, Mahmoud HH, Wiley JM, et al. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol. 2001;19(3):697-704. [3] Cortes J, Moore JO, Maziarz RT, et al. Control of plasma uric acid in adults at risk for tumor lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol. J Clin Oncol. 2010;28(25):4207-4213. [4] Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol. 2016;183(8):758-764. [5] Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015;34(28):3661-3679. [6] VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167(4):268-274. [7] Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496-509. No competing Interests: Yes The following competing Interests: Electronic Publication Date: Friday, July 24, 2026 - 05:35 AI use: No, I have not used AI Highwire Comment Subject: Early treatment with rasburicase and risk of kidney replacement therapy and death in adults with tumour lysis syndrome: emulated target trial Workflow State: Released Full Title: Re: Early treatment with rasburicase and risk of kidney replacement therapy and death in adults with tumour lysis syndrome: emulated target trial Highwire Comment Response to: Early treatment with rasburicase and risk of kidney replacement therapy and death in adults with tumour lysis syndrome: emulated target trial Check this box if you would like your letter to appear anonymously:: Last Name: Tuersun First name and middle initial: Adili Email: 25111030024@m.fudan.edu.cn Address: Shanghai 201203, PR China Occupation: PhD Affiliation: School of Pharmaceutical Sciences, Fudan University BMJ: Additional Article Info: Rapid response
2026-07-24 05:38:48