Abstract
Background and Objectives
Chimeric antigen receptor T-cell (CAR T-cell) therapy is associated with neurotoxicity, which may include acute symptomatic seizures (ASySs). Specific risk factors and short-term and long-term outcomes of ASyS associated with CAR T-cell therapy have not been well investigated.
Methods
This retrospective cohort study evaluated incidence and risk factors for ASyS during CAR T-cell therapy. We included patients treated at Mayo Clinic in Minnesota, Florida, and Arizona who underwent CAR T-cell therapy for hematologic malignancies from October 2019 to November 2023. Pretreatment demographics, clinical information, type of CAR T-cell therapy, neuroimaging, laboratories during treatment, and clinical features during admission were analyzed. Data on treatment and prevalence of seizures, EEG, and survival at the last follow-up were assessed. T-tests and nonparametric testing were performed on categorical and continuous data, respectively. Multivariable analysis was also performed.
Results
We included 180 patients (mean age 62.3 years, 57.2% women) with 8 (4.4%) developing ASyS at a mean of 8.0 ± 5.3 days after therapy. Earlier onset of cytotoxic release syndrome (odds ratio [OR] 1.81, 95% CI 0.62–2.99, p = 0.007), higher grade immune effector cell–associated neurotoxicity syndrome (ICANS) (OR −1.43, 95% CI −1.86 to −1.00, p < 0.001), focal neurologic deficits (OR 7.15, 95% CI 1.60–32.14, p = 0.007), and cefepime (OR 0.58, 95% CI 0.51–0.65, p = 0.022) exposure were significantly associated with a higher risk of ASyS. A multivariable model accounting for age and sex fit best using the lowest minimum immune effector cell encephalopathy score and highest ICANS grade (R2 = 0.555, χ2 = 28.507, p < 0.001). ASyS was associated with death at the last follow-up (OR 0.48, 95% CI 0.41–0.56, p = 0.007), although short-term outcomes were not affected by ASyS. Nonprotocolized antiseizure medication (ASM) prophylaxis did not affect ASyS incidence.
Discussion
This study suggests a low risk of ASyS because of CAR T-cell therapy, with certain risk factors that may be predictive of ASyS and lack of a definitive and direct association of ASyS with outcomes. The current approach to ASM prophylaxis should be reconsidered when ICANS is encountered. This study is limited by its retrospective nature and the use of ASM prophylaxis in all patients with ICANS, which requires further study to assess its necessity.
Introduction
Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized successful management in lymphomatous cancers.1 However, adverse effects of CAR T-cell therapy are common and may be life threatening, including immune effector cell–associated neurotoxicity syndrome (ICANS). ICANS is a serious complication and may occur in up to 77% of patients undergoing CAR T-cell therapy, manifesting as tremor, confusion, focal neurologic deficits, seizures and coma, and may be fatal.2-4 In addition, acute symptomatic seizures (ASySs) may occur in up to 30% of patients with ICANS complicating therapy through alteration of consciousness and/or seizures and status epilepticus, leading many clinicians to consider initiation of antiseizure medication (ASM) prophylaxis in certain cases before onset of seizures.3-11 These studies report on seizures related to CAR T-cell therapy but evaluated neurotoxicity without detailed analysis and data regarding the risk factors for ASyS and long-term risks of epilepsy in these patients. Furthermore, the specific risk factors for ASyS and how to approach ASM prophylaxis are not well-defined. In this multisite retrospective study, we aimed to determine the incidence and risk factors for ASyS during CAR T-cell, the use of ASM prophylaxis, and acute and long-term clinical implications of ASyS.
Methods
We performed a retrospective chart review of patients treated who underwent CAR T-cell therapy at Mayo Clinic hospitals in Florida, Minnesota, and Arizona between October 2019 and November 2023. All adult patients aged 18 years or older undergoing CAR T-cell therapy were included. We excluded those younger than 18 years and those unable or unwilling to undergo chemotherapy or CAR T-cell therapy because of patient preference or severe medical illness. We evaluated pretreatment demographics, medications, cancer diagnosis, type of CAR T-cell therapy, neuroimaging before treatment and at the time of ASyS and laboratory studies during treatment, and the prevalence of seizures before, during, and after CAR T-cell therapy up to the date of last follow-up. We also assessed survival at the last clinical follow-up because of the retrospective nature of this study and risk of the subject being lost to follow-up or deceased as the last follow-up time point. Metabolic abnormality on laboratory testing was defined as hyponatremia (sodium <135 mEq/L) or hypernatremia (>145 mEq/L), hypocalcemia (calcium <8.8 mg/dL) or hypercalcemia (calcium >10.2 mg/dL), acute kidney injury (increase in serum creatinine by 1.5 times the patient's baseline), elevated liver function tests (transaminitis) by at least twice the upper limit of normal, ammonia level above the upper limit of normal (30 μmol/L), and blood glucose greater than 200 mg/dL. The diagnostic criteria for cytotoxic release syndrome (CRS) and ICANS as well as the immune effector cell encephalopathy (ICE) score were used based on the American Society for Transplantation and Cellular Therapy Consensus Grading.12 The use of corticosteroids and interleukin (IL)-1 and IL-6 targeted therapies was left up to the discretion of the treating physician. The protocol for CAR T-cell infusion was standardized at all Mayo Clinic sites. All patients were provided lymphodepleting chemotherapy regimen before infusion, which typically included cyclophosphamide and fludarabine. The use of prophylactic ASMs was variable and nonprotocolized and determined by the treating physician. EEG was independently reviewed by a board-certified clinical neurophysiologist (B.E.F.) to confirm the findings reported in the chart, using the American Clinical Neurophysiology Society EEG terminology.13
The determination of ASyS was made by review of the patient's chart for references within the progress notes, history and physical, and discharge summaries. Furthermore, all EEGs performed were reviewed as noted above for seizures detected during recording. Semiology of seizures was obtained from reported description in the chart, adhering to the ILAE guidelines.14 Interventions to treat seizures acutely were not reported given the difficulty in ascertaining this through a retrospective chart review.
Statistical analysis was performed using SPSS 28.0 (IBM, Armonk, NY). Patient characteristics were summarized using descriptive statistics. Categorical variables were expressed as percentages. Continuous normally distributed variables were expressed as a mean ± SD. When a variable was not normally distributed, it was reported as a median (range). The normality of distribution was determined using the Shapiro-Wilk test (significance of p < 0.05). Covariables were compared across patient groups with Student t tests for normally distributed continuous variables, and if variance was deemed unequal (p < 0.05), a Welch t test was performed. The Mann-Whitney U test was used for non-normally distributed continuous variables and the χ2 test for categorical data. A p value <0.05 was significant. A multivariable forward stepwise analysis was performed to address the risk of ASyS with p < 0.1 in the univariable analysis being considered as the cutoff for inclusion in this analysis. Odds ratios (ORs) were presented with 95% CIs and were not calculated for categories with more than 2 possible variables.
Standard Protocol Approvals, Registrations, and Patient Consents
This study was approved by the Mayo Clinic Florida Institutional Review Board (IRB # 21–011203).
Results
A total of 210 patients were identified from a Mayo Clinic database using the electronic medical record (EPIC, Madison, WI), and 29 patients were excluded due to lack of receiving CAR T-cell therapy. Another patient was excluded due to being underage at the time treatment. After exclusion criteria were met, a total of 180 patients were evaluated. The demographic information of the study cohort is presented in Table 1. The mean follow-up for the entire cohort was 15.3 ± 11.7 months. In the total cohort, 8 (4.4%) developed ASyS at a mean of 8.0 ± 5.3 days after CAR T-cell therapy, with 3/8 occurring >7 days after treatment. At the time of seizure onset, 3 had transaminitis, of whom one had an elevated blood glucose between 200 and 220 mg/dL, and another patient had acute kidney injury with serum creatinine nearly twice their baseline. All were treated with cefepime at the time of seizure diagnosis.
Table 1.
Demographics of the Entire Cohort (n = 180)
| ASyS during CAR-T (n = 8) | No ASyS during CAR-T (n = 172) | Total | |
| Median age (range), total mean age ± SD | 60 (39–73) | 65 (18–85) | 62.3 ± 11.9 |
| Sex (male, female) | 4, 4 | 73, 99 | 77, 103 |
| History of epilepsy | 1 | 5 | 6 |
| History of stroke | 0 | 11 | 6 |
| History of MCI or dementia | 0 | 4 | 4 |
| Diagnosis | |||
| DLBCL | 6 | 73 | 79 |
| Mantle cell | 0 | 19 | 19 |
| MM | 1 | 57 | 58 |
| ALL | 1 | 4 | 5 |
| Follicular lymphoma | 0 | 11 | 11 |
| Gray Zone | 0 | 1 | 1 |
| CML/ALL | 0 | 1 | 1 |
| High-grade CLL | 0 | 1 | 1 |
| Primary mediastinal B-cell lymphoma | 0 | 1 | 1 |
| Double hit B-cell lymphoma | 0 | 3 | 3 |
| High grade B-cell lymphoma | 0 | 1 | 1 |
| CNS involvement of malignancy | 0 | 13 | 13 |
| History of brain irradiation | 0 | 4 | 4 |
| History of intrathecal chemotherapy | 1 | 11 | 12 |
Abbreviations: ALL = acute lymphoblastic leukemia; ASM = antiseizure medication; ASyS = acute symptomatic seizure; CLL = chronic lymphocytic leukemia; CML = chronic myelogenous leukemia; DLBCL = diffuse large B-cell lymphoma; MCI = mild cognitive impairment; MM = multiple myeloma.
EEG was performed in all 8 patients who had ASyS during their inpatient admission for CAR T-cell therapy, and 6/8 (75%) underwent continuous EEG monitoring. EEG demonstrated evidence of encephalopathy in all of these patients, as well as sporadic epileptiform discharges (2/8, 25%), lateralized periodic discharges (1/8, 12.5%), and generalized periodic discharges (GPD) with triphasic morphology (2/8, 25%). Lateralized rhythmic delta activity (1/8, 12.5%) and generalized rhythmic delta activity (GRDA) (1/8, 12.5%) were also recorded. Using continuous EEG monitoring, 2 had subclinical seizures and 2 had focal aware motor seizures of whom 1 also had a focal impaired awareness seizure. Based on clinical history, 2 had a focal impaired awareness seizure one of whom also had a focal aware aphasic seizure and 2 had a focal to bilateral tonic-clonic seizure. None of the patients were diagnosed with convulsive or nonconvulsive status epilepticus on EEG nor did they have an acute repetitive seizures occurring in clusters. CT was evaluated in all patients with ASyS to rule out an acute intracranial process when ASyS occurred. MRI was performed acutely after the diagnosis of ASyS in 7/8 of the patients. Five had no acute abnormalities or change when compared with pretreatment imaging. One patient had stable and extensive white matter disease, and another patient had reduced white matter changes as compared with previous imaging likely because of treatment effect. A third patient demonstrated mild increase in the size of the third and lateral ventricles without obstructive lesion or other new abnormality.
Patients with and without ASyS were compared during their treatment (Table 2). Notably, there was no significant difference between those with and without seizures regarding CNS involvement of the malignancy (OR 0.92, 95% CI 0.89–0.97, p = 1.000), history of epilepsy (OR 4.77, 95% CI 0.49–46.48, p = 0.242), or metabolic abnormality during admission (OR 1.32, 95% CI 0.31–5.70, p = 1.000). The use of ASM prophylaxis was also similar in both groups (p = 0.609) with levetiracetam being the most frequently prescribed ASM (6/8 in the ASyS group and 60/78 in those who did not have ASyS) at a starting dose of 1,000–1,500 mg/d. Of those who did not have seizures, 70/172 (40.7%) underwent at least one routine EEG and 32/172 (18.6%) underwent continuous EEG monitoring during their hospitalization to rule out nonconvulsive seizures and status epilepticus. The duration of continuous EEG monitoring was similar between those with ASyS (53.5 hours, 31–165) and without ASyS (32 hours, 6.5–85) (OR −38.87, 95% CI −90.69 to 12.96, p = 0.113). The prevalence of sporadic epileptiform discharges was not significantly different in the ASyS group (2/8, 25%) compared with those without ASyS (4/70, 5.7%) (OR 5.50, 95% CI 0.83–36.48, p = 0.113). Rhythmic and periodic patterns (RPPs) were also similar comparing those with (3/8, 37.5%) and without ASyS (28/70, 40%, OR 0.87, 95% CI 0.19–3.92, p = 1.000) with most RPPs in those without ASyS being GPDs (22/28) and GRDA (4/28).
Table 2.
Comparison of Those With and Without Acute Symptomatic Seizures
| Seizures during CAR-T (n = 8) | No seizures during CAR-T (n = 172) | p Value (OR, 95% CI) | |
| Age, y, median (range) | 60 (39–73) | 65 (18–85) | 0.255 (4.92, −3.59 to 13.42) |
| Gender (male, female) | 4, 4 | 73, 99 | 0.706 (0.74, 0.18 to 3.05) |
| History of epilepsy | 1 (12.5%) | 5 (2.9%) | 0.242 (4.77, 0.49 to 46.48) |
| ASM treatment before CAR-T | 2 (25%) | 11 (6.4%) | 0.107 (4.82, 0.87 to 26.72) |
| History of stroke or ICHa | 0 | 11 (6.7%) | 1 (0.97, 0.94 to 0.99) |
| History of MCI or dementia | 0 | 4 (2.3%) | 0.832 (0.98, 0.95 to 1.00) |
| Oncologic diagnosis | DLBCL: 6 MM: 1 ALL: 1 |
DLBCL: 73 Mantle cell: 19 MM: 57 ALL: 4 Follicular: 11 Gray zone: 1 CML and ALL: 1 High-grade CLL: 1 Double hit lymphoma: 3 Primary mediastinal B-cell lymphoma: 1 High-grade B-cell lymphoma: 1 |
0.679 |
| CNS involvement of malignancya | 0 | 13 (7.6%) | 1 (0.92, 0.89 to 0.97) |
| History of brain irradiation | 0 | 4 (2.3%) | 1 (0.98, 0.95 to 1.00) |
| History of intrathecal treatment | 1 (12.5%) | 11 (6.4%) | 0.431 (2.09, 0.24 to 18.54) |
| CAR-T used | Lisocabtagene maraleucel: 1 Idecabtagene vicleucel: 1 Axicabtagene ciloleucel: 4 Brexucabtagene autoleucel: 1 Zamtocabtagene autoleucel: 1 |
Lisocabtagene maraleucel: 8 Idecabtagene vicleuce: 35 Axicabtagene ciloleucel: 80 Ciltacabtagene autoleucel: 23 Brexucabtagene autoleucel: 18 Tisagenlecleucel: 6 ALLO-605: 1 Zevorcabtagene autoleucel: 1 |
0.002 |
| ASM for prophylaxis | 6 (LEV: 5, LCM: 1) | 78 (2 on 2 ASMs) (LEV: 60, LCM: 13, GBP: 1, PHT: 1, TPX: 1, BRV: 1, PGB: 2, LTG: 1) | 0.609 |
| Baseline EEG normal | 1/1 (100%) | 84/99 (84.8%) | 1 (0.85, 0.78 to 0.92) |
| Baseline EEG with epileptiform discharges | 0/1 | 1/99 (1.0%) | 1 (0.99, 0.97 to 1.01) |
| Cefepime exposure | 8 (100%) | 99 (57.6%) | 0.022 (0.58, 0.51 to 0.65) |
| Metabolic abnormality | 5 (62.5%) | 96 (55.8%) | 1 (1.32, 0.31 to 5.70) |
| CRS | 8 (100%) | 158 (91.9%) | 0.516 (0.92, 0.88 to 0.96) |
| Onset of CRS after treatment, days, median (range) | 1 (1–5) | 3 (0–12) | 0.007 (1.81, 0.62 to 2.99) |
| CRS worst grade, scale 1–4, median (range) | 1 (1–3) | 1 (0–4) | 0.786 (−0.89, −0.60 to 0.42) |
| ICANS | 8 (100%) | 106 (61.6%) | 0.028 (0.62, 0.55 to 0.69) |
| ICANS worst grade, scale 1–4, median (range) | 3 (3–4) | 2 (0–4) | <0.001 (−1.43, −1.86 to −1.00) |
| Onset of ICANS after treatment days, median (range) | 6.5 (2–20) | 6 (1–20) | 0.459 (−0.99, −3.61 to 1.64) |
| Focal neurologic deficits during ICANS | 4/8 (50%) | 13/106 (12.3%) | 0.017 (7.15, 1.60 to 32.14) |
| ICE worst score, scale 0–10, median (range) | 5 (0–10) | 9 (0–10) | 0.062 |
| Immunotherapy used to treat CRS/ICANS | Corticosteroids: 1 IL-6 inhibitor alone: 2 Corticosteroids and IL-6 inhibitor: 4 Corticosteroids, IL-6 inhibitor and IL-1 inhibitor: 1 |
None: 35 Corticosteroids: 11 IL-6 inhibitor alone: 32 Corticosteroids and IL-6 inhibitor: 81 Corticosteroids, IL-6 inhibitor and IL-1 inhibitor: 12 Corticosteroids and IL-1 inhibitor: 1 |
0.697 |
| Lowest platelet count, platelets/μL, median (range) | 43 (6–141) | 55 (2–304) | 0.565 (11.17, −27.07 to 49.42) |
| Duration of hospitalization, days, median (range) | 18 (13–25) | 15 (0–79) | 0.997 (0.15, −8.14 to 8.17) |
| No. of ASMs on discharge, mean ± SD | 1.29 ± 0.49 | 0.63 ± 0.57 | 0.006 (−0.66, −1.11 to −0.21) |
| Discontinued ASMs after discharge | 5/8 (62.5%) | 92/92 (100%) | 0.614 (0.369, 0.07 to 2.10) |
| Seizure recurrence after discharge | 0 | 2 (1.2%) | 1 (0.97, 0.94 to 1.00) |
| Alive at follow-up | 0 | 90 (52.3%) | 0.007 (0.48, 0.41 to 0.56) |
| Duration of follow-up before death, months, median (range) | 8 (0–38) (n = 8) | 9 (1–53) (n = 82) | 0.377 (5.00, −3.32 to 13.33) |
Abbreviations: ALL = acute lymphoblastic leukemia; ASM = antiseizure medication; BRV = brivaracetam; CAR T = chimeric antigen receptor T; CLL = chronic lymphocytic leukemia; CML = chronic myelogenous leukemia; CRS = cytotoxic release syndrome; DLBCL = diffuse large B-cell lymphoma; GBP = gabapentin; ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = immune effector cell encephalopathy; LCM = lacosamide; LEV = levetiracetam; LTG = lamotrigine; MM = multiple myeloma; OR = odds ratio; PGB = pregabalin; PHT = phenytoin; TPX = topiramate.
History confirmed by review of pretreatment neuroimaging.
All of those with ASyS were diagnosed with CRS and ICANS before seizure onset and received prophylactic treatment with at least 1 ASM before ASyS. There was no difference when comparing those with or without ASyS regarding the use of corticosteroids, IL-6 and IL-1 inhibitor treatments (p = 0.697). Those who developed ASyS received a number of different CAR T-cell therapies including axicabtagene ciloleucel (4/84, 4.8%), idecabtagene vicleuce (1/36, 2.8%), lisocabtagene maraleucel (1/9, 11.1%), brexucabtagene autoleucel (1/19, 5.3%), and zamtocabtagene autoleucel (1/1). CAR T-cell therapy used in the cohort in whom no seizures occurred during treatment included ciltacabtagene autoleucel (23), brexucabtagene autoleucel (18), tisagenlecleucel (6), ALLO-605 anti-BCMA allogeneic CAR T-cell therapy (1), and zevorcabtagene autoleucel (1).
Risk factors for ASyS included earlier onset of CRS after CAR T-cell infusion (1, 1–5 vs 3, 0–12, OR 1.81, 95% CI 0.62–2.99, p = 0.007), higher grade of ICANS (3, 3–4 vs 2, 0–4, OR −1.43, 95% CI −1.86 to −1.00, p < 0.001), presence of focal neurologic deficits (4/8 vs 13/106, OR 7.15, CI 1.60–32.14, p = 0.017), and exposure to cefepime (8/8 vs 99/172, OR 0.58, 95% CI 0.51–0.65, p = 0.022). In the multivariable analysis accounting for sex and age, a model including the lowest minimum ICE score and worst ICANS grade was significantly associated with ASyS (eTable 1).
Two of the patients who did not have ASyS later developed seizures: one attributed to CNS toxoplasmosis and the other related to progression of lymphoma with intracranial involvement. Overall, 8 patients who developed ASyS during CAR T-cell therapy did not have recurrent seizures in follow-up, and 5 patients had ASMs withdrawn within 8 months of initiation. Patients who developed ASyS were more likely to have died at their last follow-up appointment (survival rate 0% vs 52.3%, OR 0.48, 95% CI 0.41–0.56, p = 0.007). However, there was no effect on duration of follow-up before death (OR 5.00, 95% CI −3.32 to 13.33, p = 0.377) or on short-term outcome regarding duration of hospitalization (OR 0.15, 95% CI −8.14 to 8.17, p = 0.997).
Discussion
In a large heterogeneous population of patients with lymphomatous cancers undergoing CAR T-cell therapy, there was a low rate (4.4%) of ASyS. As previously described, the rates have been variable with up to 30% of patients having been reported to have ASyS, which was reported in patients with B-ALL; however, this may be related to the cancer type and CNS involvement,3,5 and our cohort had low rates of CNS malignancies which is not dissimilar to smaller heterogeneous cohorts.4,5 Focal neurologic deficits, cefepime exposure, higher grade ICANS, and earlier CRS onset were associated with ASyS, and patients with severe neurotoxicity represented by higher grade ICANS and worse ICE scores were more likely to have ASyS based on a multivariable model. ASyS did not prolong hospitalization but did demonstrate an association with death at the time of last follow-up. Furthermore, the use of ASM prophylaxis was not associated with lower risk of ASyS. This study adds to the growing literature on neurotoxicity and CAR T-cell therapy, expanding the understanding of risk factors for ASyS and long-term outcomes regarding seizure and epilepsy that have not previously been fully elucidated.
Cytokines released in response to CAR T-cell therapy are felt to underlie the pathophysiology of ICANS and seizures (Figure),15 and therefore, earlier onset of CRS and subsequent longer exposure to these cytokines could affect seizure risk, which was supported by univariable but not multivariable analysis in our study. In particular, IL-6, IL-8, and IL-1β are associated with a higher risk of seizures due to inflammation-induced changes within the CNS, although the pathophysiologic mechanisms of inflammation that leads to seizures involves multiple cell types and a complex cascade of events.16 In the univariable analysis, more severe neurotoxicity was also demonstrated to predict a higher risk of ASyS. This is consistent with the findings that more severe encephalopathies and coma have demonstrated a higher risk of EEG periodic patterns and nonconvulsive seizures and status epilepticus17-19 and may explain why critically ill patients are prone to ASyS.
Figure. Potential Pathophysiology Underlying ASyS due to CAR T-Cell Therapy.
CAR T-cell–mediated activation of macrophages and T cells and upregulation of cytokines, including those that potentiate seizures (i.e., IL-6, IL-8, and IL-1β) and lead to endothelial activation with capillary leak and blood brain barrier breakdown (TNF-α, VWF, etc). These cells and inflammatory mediators traffic into the CNS and lead to downstream effects with increased synthesis and release of other cytokines, chemokines, and neurotransmitters (not shown here) and subsequent changes in astrocytes, microglia, and neurons that promote neuronal hyperexcitability and synaptic changes resulting in a higher risk of seizures. Seizures themselves can further increase the release of these factors and further enhance development of seizures in the acute setting. Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved. Ang-2 = angiopoietin-2; ASyS = acute symptomatic seizure; BBB = blood brain barrier; CAR T-cell = chimeric antigen receptor T-cell; GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; TNF-α = tumor necrosis factor α; VWF = von Willebrand factor.
Previous studies have reported some risk factors for seizures during CAR T-cell therapy including female sex, primary mediastinal B-cell lymphoma, younger age, history of seizures, life-threatening and more severe neurotoxicity, and those treated with CD28-costimulated cell therapy.5,6,8,18,20 Furthermore, one study reported that seizures could occur in the absence of ICANS particularly when prophylaxis is withheld until the occurrence of ICANS.5 We also found the severity of neurotoxicity was associated with ASyS. ICE score and ICANS grading are objective end points that may be useful to elucidate the potential risk of ASyS which can be used in considering prophylaxis with ASM. Cefepime exposure, earlier onset of CRS, and presence of focal neurologic deficits were also found to be risk factors in the univariable but not the multivariate analysis but may also be factors worth considering in determining the use of ASM prophylaxis or closer monitoring and lower threshold for performing testing including EEG monitoring to rule out ASyS. The specific CAR T-cell therapy used did not predict seizures in our cohort, although these were not equally prescribed confounding interpretation. However, there are likely other risk factors beyond the specific CAR T-cell therapy that could have a greater effect on the incidence of ICANS and seizures.20
The presence of ICANS has been used in clinical decision making regarding ASM prophylaxis, and others have discussed ASM prophylaxis in specific populations.3,21,22 Our study did not demonstrate a benefit of using ASM prophylaxis, and the results do not support current clinical indications for using ASM prophylaxis as a standard of care during CAR T-cell therapy. Our study is biased in that all patients who developed ICANS received ASM prophylaxis, and therefore, it is not clear whether ICANS is necessarily an appropriate measure for the need for ASM prophylaxis. More severe neurotoxicity as manifested by lower ICE scores and higher grade ICANS as well as other factors described above may be clinical indicators of higher risk of seizures and could warrant ASM prophylaxis. ASMs may not necessarily indicated as a preventive measure, and their use should be approached similarly to other critically ill patients23,24 to decrease the risk of adding adverse medication effects given lack of definitive evidence of efficacy. Prospective studies are needed to confirm our findings and help determine the clinical risk factors that warrant ASM use during CAR T-cell therapy, specifically addressing the use of ASM prophylaxis in patients with ICANS.
ASyS during CAR T-cell therapy demonstrates varying effects on short-term and long-term outcomes which may be dependent on seizure and clinical characteristics. This includes both the frequency and duration of seizures that occur acutely, as well as the specific population studied.25,26 Seizures that occur in patients with cancer may be multifactorial in etiology. The presence of structural brain lesions, paraneoplastic syndromes, toxic or metabolic derangements, and disease severity affects long-term outcome, although the effects of ASyS are not well known and may correlate with more severe disease.27-29 One previous study demonstrated 2/3 patients with nonconvulsive status epilepticus during CAR T-cell therapy died after discharge because of progression of lymphoma without direct contribution from seizures.30 Chemotherapy is a direct risk for critical illness which is itself related to a higher risk for seizures.31 Furthermore, the lack of significant short-term effects from ASyS casts doubt on the direct association between ASyS and survival later in the course of the illness. There are also other factors that may affect life expectancy and may not have been evaluated in this study, and in general, there are poor survival outcomes in patients undergoing CAR T-cell therapy.32
Similar to our study, recurrent seizures and a subsequent diagnosis of epilepsy have not been demonstrated in patients undergoing CAR T-cell therapy who suffer ASyS.5,32 Although the pathophysiology of ASyS from CAR-T cell therapy likely has similar inflammatory underpinnings that leads to patients developing epilepsy,16 CAR T-cell therapy itself does not seem to possess an inherent risk for chronic epilepsy. This may be related to the relatively shorter duration that proepileptogenic mediators remain present, reducing the risk of inducing changes leading to chronic seizures. Our study did find 2 patients without ASyS who were later diagnosed with epilepsy, although with clear alternative causes, as described above. The follow-up period was over 1 year for most patients in our cohort, which is similar to previous studies.5 The times of withdrawal of ASMs in those with ASyS varied, although 5/8 had ASM withdrawn within 8 months of therapy without seizure consequences. Therefore, even in patients with ASyS, ASM withdrawal should be considered at follow-up after the acute effects related to CAR T-cell therapy have subsided and if seizures have not recurred.
There are limitations of our study. Retrospective evaluations may suffer from selection bias and may under identify seizures, although this cohort is unique in that all patients were admitted and/or closely followed with their oncologist in the outpatient setting, which limits the risk of underdiagnosis or misdiagnosis of seizures. We are also limited by potential loss to follow-up when using last clinical follow-up as a measure regarding survival. Nonetheless, our results were multicentered and therefore reflect multiple regions in the United States. Chart review may also exclude important clinical information regarding CAR T-cell therapy complications and seizure identification. Nevertheless, we objectively reviewed EEG and clinical documentation to confirm the findings before analysis. Furthermore, this cohort is one of the largest reported describing ASyS in patients undergoing CAR T-cell therapy. Still, a larger sample size would help to substantiate the significance of our findings, and we are also limited by the infrequency of ASyS in definitively determining risk factors for their occurrence. The low incidence of intracranial malignancies in our cohort limits generalizing our findings to other patients with CNS tumors.33
Another limitation to this study is the definition of ASyS in the setting of CAR T-cell therapy. The onset of seizures occurred after 7 days in some of our patients after CAR T-cell therapy. Seven days after brain injury or within 24 hours of exposure to high risk metabolic or medications are durations of time both used to define ASyS.34 However, this time frame may not be appropriate in cases of ASyS related to CAR T-cell therapy based on the effects of CRS and subsequently ICANS, which can occur in a delayed fashion and have effects weeks after treatment.2 Therefore, we included all patients who had seizures during the acute hospitalization for CAR T-cell therapy.
In our multicenter study, we found a low rate of ASyS in patients undergoing CAR T-cell therapy. Risk factors for developing ASyS include cefepime exposure, earlier onset of CRS, more severe neurotoxicity, and focal neurologic deficits, and in a multivariable analysis, lower ICE scores and worse grades of ICANS were found to be clinical indicators of critical illness. ASyS due to CAR T-cell therapy did not seem to affect short-term outcomes. However, ASyS was associated with greater mortality by the time of last follow-up, although we recognize this could be confounded by patients who were more critically ill. Although the need for ASM prophylaxis was not addressed in a controlled manner, most patients were able to discontinue therapy before last follow-up without seizure recurrence. Despite the significance of these results, the overall low incidence of ASyS affects the certainty of these findings. Given the low rates of ASyS in critically ill patients undergoing CAR T-cell therapy, we recommend selectivity in instituting the anticipated need for ASM prophylaxis during CAR T-cell therapy to avoid overuse of medications.
Glossary
- ASM
antiseizure medication
- ASyS
acute symptomatic seizure
- CAR T-cell
chimeric antigen receptor T-cell
- CRS
cytotoxic release syndrome
- GPD
generalized periodic discharge
- GRDA
generalized rhythmic delta activity
- ICANS
immune effector cell–associated neurotoxicity syndrome
- ICE
immune effector cell encephalopathy
- IL
interleukin
- OR
odds ratio
- RPP
rhythmic and periodic pattern
Author Contributions
B.E. Freund: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. A.M. Feyissa: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. O.E. Betiku: major role in the acquisition of data. A. Shar: major role in the acquisition of data. C. Drees: drafting/revision of the manuscript for content, including medical writing for content. W. Sherman: drafting/revision of the manuscript for content, including medical writing for content. H. Qin: drafting/revision of the manuscript for content, including medical writing for content. J.W. Britton: drafting/revision of the manuscript for content, including medical writing for content. M.S. Barrios: major role in the acquisition of data. A. Quinones-Hinojosa: drafting/revision of the manuscript for content, including medical writing for content. W.O. Tatum: drafting/revision of the manuscript for content, including medical writing for content; study concept or design.
Study Funding
No targeted funding reported.
Disclosure
The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
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