Abstract
CAR T-cell therapy related neurotoxicity (NT) is common and can lead to fatalities. Early recognition may improve its management and treatment.
METHODS
Twenty-six patients with relapsed/refractory diffuse large B cell lymphoma who received commercial CAR T-cell therapy (25 axicabtagene ciloleucel [Yescarta®], 1 tisagenlecleucel [Kymriah®]) between December 2017 and September 2018 were assessed for NT based on CARTOX-10 score and Common Terminology Criteria for Adverse Events (CTCAE) version 4.
RESULTS
Twenty-three of 26 (88%) of patients developed NT, which was severe (Grade III-IV) in 8/26 (31%). Severe NT was associated with complete remission compared to progressive disease by both CTCAE (2.4 ±1.1 vs. 1.4 ± 1.3, p = 0.050) and CARTOX-10 score (8.3 ± 1.6 vs. 9.4 ± 1.5, p = 0.040). CARTOX-10 scores were lower for those transferred to the ICU compared to those transferred, respectively, on Days 8 (2.71 ± 4.78 vs. 9.28 ± 2.31, p = 0.010), 9 (2.71 ± 3.96 vs. 9.06 ± 2.50, p = 0.003) and 10 (2.86 ± 4.27 vs. 8.83 ± 3.37, p = 0.002). Depression was associated with poor overall survival (deceased 67% vs. alive 20%, p = 0.00004) and severe NT (severe NT 63% vs. non-severe NT 20%, p = 0.040). EEG findings of frontal intermittent rhythmic delta activity (FIRDA) in 22% (2/9) and triphasic waves in 33% (3/9) were exclusive found in severe NT. Tremulousness was present in 100% of severe NT compared to 67% of non-severe NT patients (p = 0.060). Delirium occurred in 2 patients, both of whom expired with severe NT.
CONCLUSION
Depression, tremor, delirium, encephalopathy, and EEG features of FIRDA and triphasic waves may represent early clinical signs that predict the development of severe NT in off-protocol CAR T-cell therapy. Paradoxically, severe NT is positively correlated with progression free survival and may indicate effective therapeutic response.