Assessment of Tumor Lysis Syndrome in Patients with Chronic Lymphocytic Leukemia Treated with Venetoclax in the Clinical Trial and Post-Marketing Settings

Introduction: Venetoclax (Ven) has changed the chronic lymphocytic leukemia (CLL) treatment landscape with the ability to produce deep responses that result in improved long-term outcomes with well-tolerated fixed-duration regimens. Due to its potent pro-apoptotic effect on CLL cells, Ven poses a risk of inducing tumor lysis syndrome (TLS). If not managed promtly and appropriately, metabolic abnormalities (laboratory TLS) can progress to clinical TLS, including renal insufficiency, cardiac arrhythmias, seizures, and death. Current Ven TLS mitigation measures include TLS risk assessment, 5-wk dose ramp-up, prophylaxis with hydration and oral uric acid reducers, and close monitoring of blood chemistry based on risk level (Davids. Clin Cancer Res. 2018;24:4371). Debulking strategies have been effectively used to lower TLS risk before Ven therapy. In this analysis, rates of TLS and outcomes in the clinical trial and post-marketing settings are evaluated. Methods: Trial data from patients treated with current TLS mitigation measures implemented since May 2014 were pooled from 8 studies (N=1138; n=304 treatment naïve; n=834 relapsed/refractory [R/R]). This was a retrospective descriptive analysis of adverse events (AEs) of TLS and cases meeting laboratory and clinical TLS using Howard criteria (Howard. N Engl J Med. 2011;364:1844). Post-marketing data included reports of TLS from the AbbVie Global Safety Database (GSD) collected from Apr 2016 - Dec 2019 (N=236) and 5 publications of real-world usage (n=817 patients over all studies). The review of trial data focused on Ven ramp-up (ie, first 5 weeks of dosing). Results: In 1138 patients receiving Ven from pooled clinical studies, AEs of TLS and laboratory values meeting Howard criteria are shown in Table 1. With current recommended mitigation measures, the incidence of TLS AEs was 1.8% (n=20), with 15 laboratory TLS AEs (1.3%) and 5 clinical TLS AEs (0.4%) reported. TLS was transient in all cases, and patients resumed therapy without permanent sequelae. With the currently recommended measures, no deaths from TLS were reported in the 1138 patients in clinical trials. Approximately 20,000 patients with CLL have initiated Ven outside of clinical trials from 2016-2019 based on commercial tracking. In this post-marketing setting, 236 reports of TLS were identified in the GSD, and 17 had severe consequences that could be attributed to TLS (13 fatal, 4 requiring dialysis), all in patients with R/R CLL. These patients h