Fatal late-onset CAR T-cell–mediated encephalitis after axicabtagene-ciloleucel in a patient with large B-cell lymphoma

Abstract

Treatment with CD19-directed CAR T cells has evolved as a standard of care for multiply relapsed or refractory large B-cell lymphoma (r/r LBCL). A common side effect of this treatment is the immune-effector cell-associated neurotoxicity syndrome (ICANS). Severe ICANS can occur in up to 30-40% of patients treated with axicabtagene ciloleucel (axi-cel), usually within the first 4 weeks post dosing, and usually responding well to steroids. Here, we describe a case of progressive central neurotoxicity occurring 9 months post axi-cel in a patient with r/r LBCL having undergone a prior alloHCT. Despite extensive systemic and intrathecal immunosuppression neurological deterioration was inexorable and eventually fatal within 5 months. High CAR T cell DNA copy numbers and higly elevated levels of IL-1 and IL-6 were found in the CSF as clinical symptoms emerged, and CAR T cell brain infiltration was observed on autopsy, suggesting that CAR T cells played a major pathogenetic role. This case of unexpected devastating late neurotoxicity warrants intensified investigation of neurological off-target effects of CD19-directed CAR T cells and highlights the need for continuous monitoring for late toxicities in this vulnerable patient population.

Recapitulated Late-Onset Inflammatory Toxicities and Progressive Dysautonomia with Persistence of Central Memory CD4+ Chimeric Antigen Receptor T Cells in a Case of Transformed Follicular Lymphoma: Case Report

“…ICANS typically occurs within 2 weeks, simultaneously, after resolution of, or independently of, CRS. Jung et al [7] described a case with late-onset ICANS occurring 9 months after the administration of axicabtagene ciloleucel. In their case, the detection of CAR T-cell DNA in peripheral blood and cerebrospinal fluid suggested that the patient died due to fatal encephalopathy associated with CAR T cells.…”

Long‐term survivorship care after CAR‐T cell therapy

“…However, up to 10% of patients experience delayed onset ICANS with confusion and seizures occurring as late as 3–4 weeks after infusion, 31 underscoring the importance of ongoing neurologic monitoring throughout the first month. Case reports have also described severe and even fatal ICANS occurring as late as 6–9 months after treatment 32,33 . Owing to this potential for late‐onset and/or prolonged neurotoxicity, CAR‐T cell recipients are advised to refrain from driving or operating heavy machinery for 8 weeks 34 .…”

EASIX and Severe Endothelial Complications After CD19-Directed CAR-T Cell Therapy—A Cohort Study

“…Of the 121 patients of the validation cohort, 70 patients (58%) developed CRS grades 1-4 and 29 patients (24%) developed ICANS grades 1-4. Higher-grade CRS (grade ≥ 3) affected 10 patients (8%) with a median onset of 4 (0-14) days, while grade ≥ 3 ICANS occurred in 14 patients [12%; median onset 6 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) days]. A total of 70 patients (58%) experienced either CRS or ICANS or both (grade ≥ 3: 21 patients, 17%) (Table 1).…”

“…Neurotoxicity-classified as immune effector cell-associated neurotoxicity syndrome (ICANS)-is another frequent complication of CD19-directed CAR-T cell therapy, occurring in up to 67% of patients, with severe and potentially lethal courses in a substantial proportion of patients (grade ≥ 3) (5,6,8,9). ICANS can develop simultaneously with CRS, after CRS has ceased or independent from CRS (7).…”