3,10, 14-18 NT after CAR-T cell therapy generally occurs after the onset of CRS, and higher grades of NT tend to occur concurrently with higher grades of CRS. However, these therapies are associated with unique, but common, adverse events that must be identified and managed appropriately: cytokine release syndrome (CRS) and neurological toxicity (NT). The efficacy and safety of CAR-T cell therapies have been extensively characterized in clinical trials and demonstrate a positive benefit:risk profile. ![]() The CRES and ASTCT scales, which measure immune effector cell-associated neurotoxicity syndrome, offer more accurate assessments of NT after CAR-T cell therapy. We conclude that CTCAE v4.03 was not designed for, and is suboptimal for, grading CAR-T cell therapy-associated NT. This is the first study to retrospectively apply CTCAE, mCRES, and ASTCT criteria to the same patient data set. Reevaluation according to the mCRES/ASTCT criteria downgraded 31 events deemed NT by CTCAE to grade 0. Among 111 patients infused with tisagenlecleucel (as of December 2017), the 4 experts identified 50 patients (45%) who had any-grade NT per CTCAE, 19 (17%) per mCRES, and 19 (17%) per ASTCT. According to the US Food and Drug Administration definition of NT using CTCAE, 62 of 106 patients infused with tisagenlecleucel had NT as of September 2017. Individual patient-level NT data from the phase 2, single-group, global, pivotal JULIET trial (NCT02445248) were retrospectively and independently graded, using CTCAE, ASTCT, and mCRES, by 4 medical experts with experience managing patients with 3 different CD19-targeted CAR constructs. ![]() We retrospectively assessed differences and concordance among 3 available grading scales (the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03, modified CAR-T Related Encephalopathy Syndrome, and American Society for Transplantation and Cellular Therapy scales) applied to the same set of NT data from the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Chimeric antigen receptor-T (CAR-T) cell therapy achieves durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), but may be associated with neurological toxicity (NT).
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