Abstract
Background and Purpose
Immune Cell Effector Associated Neurotoxicity Syndrome (ICANS) is common amongst patients receiving CD19 targeted Chimeric Antigen Receptor T-cell (CAR-T) therapy. The purpose of this study is to characterize the incidence of seizures and ictal-interictal continuum (IIC) abnormalities in patients with ICANS.
Methods
Retrospective review of consecutive patients treated with axicabtagene ciloleucel (axi-cel) for recurrent high-grade systemic lymphoma at Stanford Medical Center between 2/2016-6/2019. Electronic medical records (EMR) were reviewed for clinical features, treatment information, EEG data, CRS (cytokine release syndrome)/ICANS severity, and clinical outcomes.
Results
Fifty-six patients met inclusion criteria. 85.7% of patients developed CRS, and 58.9% developed ICANS. Twenty-eight patients had EEG monitoring, of whom 26 had ICANS. Median duration of EEG monitoring was 30 hours (range .5-126 hours). Four patients (7.1%) had seizures (1 patient had a clinical generalized seizure, 2 patients had clinical and nonconvulsive seizures, and 1 patient had an isolated non-convulsive seizure). Ictal-interictal continuum abnormalities were common, of which generalized periodic discharges (GPDs) with triphasic morphology and GPDs with epileptiform morphology were most frequently seen. Generalized periodic discharges with triphasic wave morphology were found across Grade 2-3 peak ICANS severity, however the majority (86%) of patients with epileptiform GPDs had Grade 3 peak ICANS severity.
Conclusions
Among patients receiving axi-cel, seizure occurred in 7.1% of the total cohort, representing 12% of patients with ICANS. Ictal-interictal continuum abnormalities are also seen in patients with ICANS, most commonly GPDs. 75% of patients with seizures had nonconvulsive seizures supporting the use of continuous video EEG monitoring in this population.
Keywords: Neurotoxicity Syndromes, Seizures, Electroencephalography, Medical Oncology, Neurohospitalist
Introduction
Cellular therapeutics are emerging as an effective oncologic treatment modality with broad applications. Chimeric-antigen receptor T-cell (CAR-T) therapy utilizes bioengineered native T-cell receptors encoded with both extracellular cancer-specific antigen recognition domains and intracellular T-cell signaling domains. After T-cells are extracted from an individual’s peripheral blood and the CAR of interest is inserted, T-cell reinfusion leads to proliferation and targeted cytotoxicity of malignant cells.1-4 Axi-cel is a 2nd generation CAR-T cell therapy with a CD19 antigen recognition domain and CD28/CD3ζ signaling domains that was approved in 2017 for treatment of adults with relapsed or refractory diffuse large B-cell lymphomas.1,3,5,6 Adverse events following axi-cel infusion are common and are primarily categorized into 2 clinical syndromes. Cytokine Release Syndrome (CRS) is a multi-system inflammatory response characterized by fever, hypotension, or hypoxia.7-9 Immune Cell Effector Associated Neurotoxicity Syndrome (ICANS), previously known as CRES (CAR-T related encephalopathy syndrome), is characterized by encephalopathy, altered level of alertness, and expressive language difficulty.9-12 Immune Cell Effector Associated Neurotoxicity Syndrome usually occurs in conjunction with CRS,10,11 and high grade neurotoxicity occurred in 32% of patients in the phase 1-2 trial of axi-cel. 13 Features of high grade ICANS include seizure, cerebral edema, or death. Rates of seizure in ICANS range from 3.7%– 7.4%.13-15 Data on ictal-interictal electroencephalography (EEG) findings in a series of 36 patients shows high frequency of rhythmic activity (53%) and epileptiform discharges (19%). 14 EEG as a diagnostic tool, biomarker of clinical severity, or as a prognostic tool of clinical outcome is of significant interest. This study aims to characterize seizure incidence and abnormal EEG patterns via prolonged video EEG monitoring in a consecutive cohort of CAR-T treated patients with ICANS.
Methods
Institutional approval (IRB #46582) was obtained to retrospectively review the electronic medical records and EEG recording data. Only patients who had received axi-cel CAR-T therapy at Stanford University Medical Center from February 2016 through June 2019 were included. Patients receiving axi-cel within clinical trials signed consent to analysis of further clinical data.
Per BMT treatment protocol, routine clinical, laboratory, clinical neurologic monitoring, and prophylactic levetiracetam for 28 days occurred for all patients after CAR-T infusion. Post-infusion, neurological screening occurred twice daily with bedside assessments including Mini Mental State Examination (2/2016-9/2017); CAR-TOX scoring (9/2017-1/2019); or ICE scoring (2/2019-6/2019). Grading utilized the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Per institutional protocol, any patient with ≥ Grade 2 ICANS or clinical suspicion for seizure required neurology consultation and video EEG monitoring at the time ICANS was identified. Patients with isolated non-focal neurological symptoms (headache, syncope) without encephalopathy were not considered ICANS and were excluded from EEG analysis.
Continuous video EEG was acquired with a digital Nihon-Kohden EEG machine with standard international system 10-20 electrode placements, 22 electrodes including T1/T2 and an EKG lead. All segments of the EEG were read by Epilepsy fellows and board-certified attending electroencephalographers, with a final report summarizing pertinent findings in the electronic medical record (EMR). Electrographic slowing was characterized as either focal or diffuse, and subsequently graded by severity (‘mild’ referred to normal architecture with slowed background, ‘moderate’ to abnormal architecture with slowed background, and ‘severe’ to lack of variability with slowed background). EEG slowing was noted as the most abnormal extent of slowing recorded on study. Periodic or rhythmic abnormalities were defined using the American Clinical Neurophysiology Society (ACNS) nomenclature. 16 In our analysis, frontally-predominant rhythmic delta activity was denoted as a subset of GRDA (FIRDA). Nonconvulsive seizures were defined as seizures seen on EEG with subtle or no clinical correlation. If the electrographic pattern was on the ictal-interictal continuum (IIC), 17 then they were identified using the ACNS criteria to define nonconvulsive status epilepticus (NCSE). 16
* FOOTNOTE: The ACNS recognizes the following patterns on the IIC: generalized rhythmic delta activity (GRDA), generalized periodic discharges (GPDs), lateralized rhythmic delta activity (LRDA), lateralized periodic discharges (LPDs), and bilateral intermittent periodic discharges (BIPDs). Any of these terms can be modified to be spontaneous or stimulus-induced (SI, previously known as SRPDs).
Data Analysis
Patients who developed any grade CRS or ICANS were identified by clinical documentation. Grading of all adverse events was determined by BMT physician consensus. Electronic medical records were reviewed for treatment data, patient characteristics, CRS/ICANS grading, seizure activity, EEG findings, anti-seizure drugs, and neurology consultation notes. EEG reports were analyzed for all features reported. Further review of EEG was completed in conjunction with epilepsy fellows and attendings per ILAE guidelines. As ICANS is a dynamic process, patient neurotoxicity grade was noted as the peak clinical grade.
Results
A total of 56 adults were treated with axi-cel CAR-T cell therapy between 2/2016- 6/2019 at Stanford University Medical Center. The mean age of patients was 56 (range 21-76 years), and 61% were male. The most common indication for CAR-T therapy was relapsed/refractory diffuse large B-cell lymphoma (n = 49, 87.5%). Mediastinal B cell lymphoma (n = 4, 7.1%), Mantle cell lymphoma (n = 2, 3.6%), and Burkitt Lymphoma (n = 1, 1.8%) were also treated. Patients receiving axi-cel as part of a clinical trial (n = 14) and standard of care (n = 42) were included and received the same clinical and neuromonitoring throughout their post-infusion course.
85.7% of patients in our cohort experienced CRS, predominantly Grade 2 (66.1%). 64.3% of patients (n = 37) incurred neurological symptoms, however 4 patients did not meet criteria for ICANS (headache or syncope without encephalopathy). 58.9% of patients (n = 33) experienced ICANS (Table 1). Five patients experienced Grade 1 ICANS (8.9% of total cohort), 14 had Grade 2 ICANS (25%), 10 had Grade 3 ICANS (17.9%), 3 had Grade 4 ICANS (5.4%), and 1 patient had Grade 5 ICANS (1.8%). All patients with ICANS had CRS preceding or coincident with the onset of neurologic symptoms. Clinical features of ICANS included somnolence, confusion, disorientation, and word finding difficulty (n = 13). The median onset of encephalopathy was 5 days after infusion (range 1-18 days post infusion). The average duration of encephalopathy amongst patients with ICANS and seizures was 10.8 days (median 12.5 days), whereas the average duration of encephalopathy amongst patients with ICANS without seizure was 7 days (median 5 days). Most presentations of ICANS were monophasic, however 6 patients (10.7%) had 2 distinct episodes of encephalopathy separated by a period of substantial improvement or resolution of symptoms. Univariate testing showed no significant difference between cefepime use and ICANS (p = .85).
Table 1.
Demographic Characteristics
| N | % | |
|---|---|---|
| Total # of patients | 56 | |
| Demographics | ||
| Age in years- mean (range) | 56 (21-76) | |
| Male | 34 | 60.71 |
| Female | 22 | 39.29 |
| Diagnosis | ||
| Diffuse large B cell lymphoma | 49 | 87.50 |
| Primary mediastinal (thymic) B cell lymphoma | 4 | 7.14 |
| Mantle cell lymphoma | 2 | 3.57 |
| Other (DLBCL vs Burkitt's) | 1 | 1.79 |
| Year treated | ||
| 2016 | 8 | 14.29 |
| 2017 | 5 | 8.93 |
| 2018 | 36 | 64.29 |
| 2019 | 7 | 12.50 |
| CRS | ||
| None | 8 | 14.29 |
| CRS Grade 1 | 9 | 16.07 |
| CRS Grade 2 | 37 | 66.07 |
| CRS Grade 3 | 1 | 1.79 |
| CRS Grade 4 | 1 | 1.79 |
| ICANS | ||
| None | 19 | 33.93 |
| Neurological toxicity without ICANS | 4 | 7.14 |
| ICANS (total) | 33 | 58.93 |
| ICANS Grade | ||
| Mild (Grade 1-2) | 19 | 33.93 |
| Severe (Grade 3-5) | 14 | 25.00 |
| Grade 1 | 5 | 8.93 |
| Grade 2 | 14 | 25.00 |
| Grade 3 | 10 | 17.86 |
| Grade 4 | 3 | 5.36 |
| Grade 5 | 1 | 1.79 |
| Symptom Onset | ||
| Monophasic | 27 | 48.21 |
| Biphasic | 6 | 10.71 |
| Median onset of first symptom in days (range) | 5 (1-18) | |
| Average onset of first symptom in days | 5.7 | |
A total of 28 patients underwent EEG monitoring, with a total of 31 EEGs analyzed (3 patients with 2 separate EEG recording periods). Twenty six patients had ICANS, and 2 patients had EEG due to a syncopal event without evidence of ICANS (Table 2). One patient with ICANS had EEG with electrocerebral silence completed as part of a brain death examination, thus was excluded from analysis of ictal-interictal EEG findings. EEG monitoring ranged from .5 to 126 hours, with a median duration of 29.5 hours. Background activity in 26 patients with ICANS was often abnormal-9 with mild slowing, 15 with moderate slowing, 3 with severe slowing, and 1 with electrocerebral silence. Only 1 patient with ICANS had a normal EEG with no evidence of background abnormalities or abnormal discharges.
Table 2.
Characteristics of EEG recordings
| Number of patients with EEG | 28 |
|---|---|
| Number of EEG recordings (total) | 31 |
| EEG Type (n = 31) | |
| Spot | 7 |
| Continuous | 24 |
| EEG Duration (n = 31) | |
| Average (hours) | 37 |
| Median (hours) | 29.5 |
| Range (hours) | .5-126 |
| EEG by peak Neurotoxicity Grade (n = 28) | |
| 0 (n = 23) | 2 |
| 1 (n = 5) | 0 |
| 2 (n = 14) | 12 |
| 3 (n = 10) | 10 |
| 4 (n = 3) | 3 |
| 5 (n = 1) | 1 |
| Slowing (n = 31) | |
| None | 3 |
| Mild | 9 |
| Moderate | 15 |
| Severe | 3 |
| Silent | 1 |
| Seizure (n = 4) | |
| Any seizure | 4 |
| Clinical (only) | 1 |
| Nonconvulsive (only) | 1 |
| Both (clinical & nonconvulsive) seizures | 2 |
| Status Epilepticus (clinical) | 1 |
| Status Epilepticus (nonconvulsive) | 2 |
Seven percent of patients developed seizures (n = 4). One patient had clinical generalized tonic-clonic seizures, 2 patients had both clinical and nonconvulsive generalized seizures, and 1 patient had isolated nonconvulsive generalized seizures. All patients with seizures had a peak grade ICANS of 3 or 4. The average duration of encephalopathy amongst patients with seizures was 10.8 days (range 5-13 days) (Figure 1). The median duration of EEG monitoring in patients with seizures was 84 hours. Of the 3 patients with clinical seizures at any point, 1 patient had a generalized tonic-clonic seizure (GTC) prior to EEG monitoring, 1 patient had a GTC during EEG monitoring, and 1 patient had generalized clinical status epilepticus (SE). Of the 3 patients with nonconvulsive seizures at any point, 2 were noted to have nonconvulsive seizures during their course that were felt to be consistent with NCSE. All patients with seizures necessitated change in seizure medication regimen and/or level of care.
Figure 1.
Encephalopathy duration amongst patients who had seizure (n = 4). Day of seizure onset is marked as day post-CAR-T infusion and denoted by a red circle.
Ictal-interictal continuum findings were common. Generalized periodic dischargess were the most frequently reported, characterized as either triphasic wave morphology (9 of 29 EEGs) or epileptiform morphology (7 of 29 EEGs) (Figure 2). Both GPDs with epileptiform and triphasic wave morphology were seen in peak Grade 2-3 neurotoxicity, though among patients with epileptiform GPDs, Grade 3 toxicity was more common than Grade 2 (86% vs 14%). One patient had multifocal epileptiform discharges (peak Grade 2 neurotoxicity), and no patients were observed to have LPDs or BIPDs. One patient had LRDA with peak grade 3 neurotoxicity, 2 patients were noted to have GRDA, and 1 patient had frontally predominant GRDA (FIRDA).
Figure 2.
Ictal-Interictal Continuum Patterns in ICANS. A total of 30 EEGs were analyzed. One EEG was excluded from this analysis as it was performed as part of a brain death assessment and showed electrocerebral silence. Patterns are described as they appear, with each finding counted once per patient and noted regardless of concurrent features. Neurotoxicity grade noted is peak clinical neurotoxicity.
While serological CAR-T expansion data was not available for all patients in our cohort, we investigated CAR-T expansion in 2 patients with severe ICANS and seizures (Figure 3). Patient 1 was noted to have encephalopathy onset during days 5-16 post infusion, clinical seizure on day 5, 2 subclinical seizures on day 6, and EEG monitoring from days 6-8 post infusion. Expansion data concurrently showed highest concentrations of CAR-T cells at day 7 post infusion, and downtrended over the subsequent course of the encephalopathy implying peak concentrations at or prior to day 7. In patient 2, encephalopathy was observed during days 8-21 post infusion, clinical seizure on day 11, non-convulsive status epilepticus on day 18, and EEG monitoring from days 8-14 and days 18-Day 21. In this patient, CAR-T expansion continued to occur and peaked much later at day 21 post infusion. Notably, both clinical seizure (day 11) and NCSE (day 18) occurred prior to peak expansion.
Figure 3.
CAR-T Expansion in 2 patients with seizures. Serum measurements of CAR-T cells/microliter were drawn at Days 7, 14, 21, and 28 post infusion. Duration of encephalopathy is noted by pink shading, of which EEG monitoring duration is denoted by dark pink shading. Seizures are denoted by vertical lines-- clinical seizure was noted by dark green vertical line, and nonconvulsive seizure noted by light green vertical line.
Discussion
The incidence of ICANS in our patients treated with axi-cel (58.9%) is consistent with previous reports (25-67%).9,14,15,18 The median onset of neurologic symptoms was 5 days, which is similar to other reported findings. 15 No patients in our cohort had a history of epilepsy or were taking anti-epileptic medications for seizures prior to CAR-T protocols ascribing prophylactic levetiracetam. Immune Cell Effector Associated Neurotoxicity Syndrome has been previously described as a monophasic illness 13 , however we had 6 patients who incurred 2 separate periods of encephalopathy post infusion suggesting some patients may experience clinical improvement and then a second period of worsening neurotoxicity symptoms, though the biologic mechanism and/or the role of concurrent pharmacotherapies and comorbid illness remains unclear.
Our cohort had 4 patients who had seizures as part of ICANS, representing 7.1% of total patients (n = 56) and 12% of patients with ICANS (n = 33). Two of 3 patients who had non-convulsive seizures had NCSE. This is higher than the 0-2% incidence of seizures in the Phase 1 study for axi-cel 3 and other published retrospective cohorts,10,14 though similar to a recent cohort of patients with continuous EEG monitoring. 15 A key factor in this discrepancy is likely due to systematic protocol of cEEG monitoring for patients with ICANS Grade 2 or higher, and long-term monitoring (in our cohort median of 29.5 hours in patients with ICANS, and median of 84 hours in patients with seizure). It is also possible that these results may underestimate the true incidence of seizures in ICANS, as patients did not undergo EEG monitoring for the entire duration of encephalopathy and all patients received prophylactic levetiracetam 500mg BID through day 28 post-infusion per CAR-T protocol.
While untreated seizure has been shown to impact patient mortality,19,20 abnormal periodic discharges or rhythmic patterns on EEG categorized on the spectrum of the IIC portend an unclear risk of seizure and mortality.17,21 Existing literature not involving individuals following CAR-T therapy suggests lower risk of mortality and seizure with GRDA, and a wider range of seizure risk with stimulus-induced-patterns. Both GPDs and LPDs have a risk of seizures and mortality, though BIPDs and LPDs remain the highest risk inter-ictal abnormalities for mortality and seizure respectively.16,17,21 In our cohort, GPDs were the most commonly encountered IIC periodic pattern. This is consistent with recent cohorts assessing periodic discharges on EEG.10,14,15 Both triphasic and epileptiform GPDs were found across a range of clinical severity (Grade 2-3), however the majority of epileptiform GPDs (86%) were found in patients with severe neurotoxicity (Grade 3). The significance of this is unclear, as it may reflect a more severe generalized cortical dysfunction, and/or represent a concomitant epileptogenic process. Rates of seizures in case series of non-CAR-T patients with GPDs range between 29-50%.22-24 In particular, Foreman et al showed a greater incidence of NCSC in patients with GPDs (22% vs 7% with matched non-GPD controls) 23 . Any corresponding clinical symptom, the electrographic presence of “plus” characteristics for GPDs, higher frequency (>2Hz), and absence of toxic-metabolic abnormalities, may prompt consideration of an anti-seizure drug treatment trial and additional continuous EEG monitoring. 17 Thus, while our observations are limited by small numbers, they suggest the presence of epileptiform GPDs in patients with ICANS accompany greater clinical severity, and support consideration of escalating anti-seizure drug treatment.
The prevalence of GPDs in patients with ICANS also raised the possibility of superimposed toxic encephalopathy. While our study did not detect a significant relationship between Cefepime exposure and ICANS, these results are limited in their significance due to small sample size and we recommend evaluation for and avoidance of pro-epileptogenic medications in CAR-T therapy protocols when able.
Notably no patients in our cohort had evidence of focal seizures, and very few had focal slowing or lateralized discharges on EEG despite EEG monitoring in 12 of 13 patients with language deficits on neurological examination. This is in line with a study of 20 patients with expressive language deficits noting predominantly generalized EEG abnormalities in ICANS patients with language dysfunction, 25 but in contrast to a recent cohort associating language abnormalities with focal EEG abnormalities. 15 While our sample size is small, this discrepancy is of note as the majority of our patients had long duration cEEG monitoring making the possibility of identifying focal slowing or periodic discharges more likely.
The pathophysiology of ICANS is not fully understood. Potential mechanisms discussed have included direct T-cell mediated toxicity (though unlikely as presence of T cells in CSF does not correlate to severity of neurotoxicity) and increased blood brain barrier permeability with direct toxic neuronal or glial effects through excitotoxic metabolites.10,11,26 In addition to severe CRS and serologic markers such as early peak serum IL-6 and higher peak blood CRP predicting severe neurotoxicity, 27 there are intrinsic features of CAR-T therapy that also predict neurotoxicity such as initial CAR-T dose, the rate of expansion, and peak in-vivo CAR-T serum concentration.3,10,28 Expansion data was not available for all patients in the cohort, however we reviewed CAR-T expansion in 2 patients with severe ICANS who developed seizures. These patients differed in their latency to peak concentration of serum CAR-T cells (Day 7 vs Day 21 post infusion), as well as duration of encephalopathy. Both patients had seizures prior to peak expansion while encephalopathy continued post-peak expansion. While more studies are needed on this subject, this data suggests that CAR-T expansion trends may be helpful in determining the need for seizure monitoring with EEG and level of care in patients with neurotoxicity.
Though our study raises important considerations in EEG as a diagnostic and management tool, it is limited in design as a retrospective cohort study and does not allow for inference of causal relationships between EEG findings and neurotoxicity. Emerging research on EEG abnormalities in ICANS would benefit from coordinated prospective data collection. EEG data collection from day of infusion or onset of neurological symptoms may capture the evolution of neurotoxicity and encephalopathy, as well as provide insight into the functional processes driving neurotoxicity. Prospective monitoring and quantitative EEG analysis could clarify and quantify the predictive value of EEG findings in prognostication for neurotoxicity severity, duration, or mortality. This study only examined axi-cel and may not reflect the neurotoxicity or seizure risk of other CAR constructs 27 , and given the retrospective study design did not have standardized data collection on all concurrent medications and/or illnesses that my impact encephalopathy. Lastly, all retrospective studies on neurotoxicity risks have been limited to CAR-T constructs in B-cell lymphomas, and may not be generalizable to ICANS risk in solid tumors, CNS malignancies, or intra-thecal CAR-T therapy.29,30
Conclusion
The frequent neurotoxicity associated with CAR-T therapy necessitates raising awareness amongst neurologists of the spectrum of neurotoxicity, and in particular, ICANS. The incidence of seizures in ICANS may be higher than previously thought with axi-cel, and continuous EEG monitoring in patients with ICANS is key in the detection of non-convulsive seizures. Ictal-interictal abnormalities are seen in patients with ICANS, particularly epileptiform GPDs. These are more common in patients with more severe neurotoxicity and may merit consideration of treatment or escalation of care in certain situations. Long term prospective studies with CAR-T expansion and continuous EEG monitoring will be key in understanding the complex pathophysiology of ICANS and identifying potential prognostic value of EEG monitoring.
Footnotes
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Dr. Markert reports the following: consultant in data science, speaker, and case review boards for Ceribell, an EEG device company. Dr. Muffly reports the following: Advisory Boards: Kite, Amgen, Pfizer, Medexus, CTI Biopharma. Honoraria/Consulting: Adaptive, Astellas, uptodate. Research funding: Jasper, BMS, Kite, Astellas, Adaptive. Dr. David Miklos reports the following: consultancy or advisory role for Kite, a Gilead Company, Adicet, Pharmacyclics, Janssen,Adaptive Biotechnologies, Miltenyi Biotechnologies; research funding from Kite, a Gilead Company, Allogene, Adicet, 2Seeventy Bio, Fate Therapeutics, and Adaptive Biotechnologies.patents, royalties, or other intellectual property from Pharmacyclics.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD
Sammita Satyanarayan https://orcid.org/0000-0002-0300-4969
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