Assessing and Management of Neurotoxicity After CAR-T Therapy in Diffuse Large B-Cell Lymphoma

Figures & data

Table 1 Neurological Events Noted with Approved CAR T-Cell Products for Large B-Cell Lymphoma

Axicabtagene Ciloleucel	Lisocabtagene Maraleucel	Tisagenlecleucel
Encephalopathy: Includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbed attention, hypersomnia, leukoencephalopathy, memory impairment, mental status changes, paranoia, somnolence, and stupor	Encephalopathy: Includes encephalopathy, confusional state, encephalopathy, mental status changes, somnolence, lethargy, amnesia, cognitive disorder, depressed level of consciousness, memory impairment, flat affect, depersonalization, disturbance in attention, incoherent, and hypersomnia	Encephalopathy: Includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, somnolence, and automatism
Delirium: Includes agitation, delirium, disorientation, hallucination, hyperactivity, irritability, restlessness, and delusion	Delirium: Includes delirium, agitation, disorientation, delusion, hallucination, visual hallucination, and irritability	Delirium: Includes delirium, agitation, hallucination, hallucination visual, irritability, and restlessness
Headache	Headache: Includes headache and migraine	Headache: Includes headache and migraine
Dizziness: Includes dizziness, presyncope, syncope	Dizziness: Includes dizziness and syncope	Sleep disorder: Includes sleep disorder, nightmares, and insomnia
Aphasia: Includes aphasia, dysphasia	Aphasia: Includes aphasia, dysarthria, dysphemia, dysphonia, slow speech, and speech disorder	Anxiety
Tremor	Tremor: Includes tremor and essential tremor
Ataxia	Ataxia: Includes ataxia and gait disturbance
Motor dysfunction: Includes muscle spasms, muscular weakness	Cerebellar: Includes cerebellar syndrome, dysmetria, balance disorder, dyskinesia and impaired hand-eye coordination
Seizure
Dyscalculia
Myoclonus

Note: Data from references.^3–6

Table 2 Encephalopathy Assessment Tools for Neurotoxicity Grading

CARTOX-10	ICE
Orientation: Time (year, month), place (city, hospital), president/prime minister of country of residence: 5 points Naming: Ability to name three objects (eg, point to clock, pen, button): 3 points Writing: Ability to write a standard sentence (eg, “our national bird is the bald eagle”): 1 point Attention: Ability to count backwards from 100 by 10: 1 point	Orientation: Time (year, month), place (city, hospital): 4 points Naming: Ability to name 3 objects (eg, point to clock, pen, chair): 3 points Writing: Ability to write a standard sentence (eg, “our national bird is the bald eagle”): 1 point Attention: Ability to count backwards from 100 by 10: 1 point Following commands: Ability to follow simple commands (eg, “Show me 2 fingers” or “Close your eyes and stick out your tongue”): 1 point
Total: 10 points	Total: 10 points

Notes: Data from references.^6,8 Scoring: 10, no impairment; 7–9, grade 1 ICANS; 3–6, grade 2 ICANS; 0–2, grade 3 ICANS; 0 due to patient unarousable and unable to perform ICE assessment, grade 4 ICANS.

Abbreviations: CARTOX-10, CAR-T-cell-therapy-associated toxicity 10-point neurological assessment; ICE, immune effector cell-associated encephalopathy.

Table 3 Grading of CAR T-Cell-Related Encephalopathy Syndrome (CRES)

Symptom or Sign	Grade 1	Grade 2	Grade 3	Grade 4
Neurological assessment score (by CARTOX-10*)	7–9 (mild impairment)	3–6 (moderate impairment)	0–2 (severe impairment)	Patient in critical condition, and/or obtunded and cannot perform assessment of tasks
Raised intracranial pressure	N/A	N/A	Stage 1–2 papilledema**, or CSF opening pressure <20mmHg	Stage 3–5 papilledema**, or CSF opening pressure ≥20mmHg, or cerebral edema
Seizures or motor weakness	N/A	N/A	Partial seizure, or non-convulsive seizures on EEG with response to BZD	Generalized seizures, or convulsive or non-convulsive status epilepticus, or new motor weakness

Notes: Data from reference.⁸ *As noted on Table 2; **Papilledema grading according to modified Frisén scale.¹²

Abbreviations: CAR, chimeric antigen receptor; CARTOX-10, CAR-T-cell-therapy-associated toxicity 10-point neurological assessment; N/A, non-applicable; CSF, cerebrospinal fluid; EEG, electroencephalogram; BZD, benzodiazepine.

Table 4 ASTCT Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Consensus Grading for Adults

Neurotoxicity Domain	Grade 1	Grade 2	Grade 3	Grade 4
ICE score*/**	7–9	3–6	0–2	0 (patient is unarousable and unable to perform ICE)
Depressed level of consciousness^†	Awakens spontaneously	Awakens to voice	Awakens only to tactile stimulus	Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma
Seizure	N/A	N/A	Any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention	Life-threatening prolonged seizure (>5 min); or Repetitive clinical or electrical seizures without return to baseline in between
Motor findings^‡	N/A	N/A	N/A	Deep focal motor weakness such as hemiparesis or paraparesis
Elevated ICP/ Cerebral edema	N/A	N/A	Focal/local edema on neuroimaging^¥	Diffuse cerebral edema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema; or Cushing’s triad

Notes: Data from reference.⁸ ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who has generalized seizure is classified as grade 3 ICANS. *As noted on Table 2. **A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. †Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication). ‡Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, but they do not influence ICANS grading. ¥Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may be graded according to CTCAE v5.0.

Abbreviation: N/A, not applicable.

Table 5 Management of ICANS

ASTCT ICANS Grade	Management
Grade 1	-Consider seizure prophylaxis with levetiracetam if not already started. -Review of medications, avoid medications that can cause CNS depression. -Swallowing assessment and aspiration precautions. -Neurocognitive assessment Q6hrs using ICE scoring system. -Neurology consult. -Consider EEG. -Consider lumbar puncture with opening pressure and samples for chemistry, cytology, virology, & culture. -Brain imaging (MRI preferred if no contraindication). Spinal MRI based on neurological findings. -For febrile patients, infectious workup per institutional guidelines. -Consider tocilizumab if concurrent CRS.
Grade 2	-Supportive care and workup per Grade 1. -Consider dexamethasone 10mg IV every 6hrs or methylprednisolone equivalent. -Tocilizumab if concurrent CRS. -Consider transfer to intensive care unit.
Grade 3	-Supportive care and workup per Grade 1. -Transfer to intensive care unit. -Dexamethasone 10–20mg IV every 6 hours or methylprednisolone equivalent. -High-dose methylprednisolone (1000mg/day) for focal/local edema. -Seizure control with benzodiazepines (for short-term control) and levetiracetam ± lacosamide. -If evidence of increased ICP (stage 1–2 by fundoscopy or opening pressure >20 mmHg), urgent neurology consultation to guide management. -Repeat neuroimaging if persistent grade ≥3 ICANS.
Grade 4	-Supportive care and workup per Grade 1. -Transfer to intensive care unit, may need mechanical ventilation for airway protection. -High-dose methylprednisolone 1000mg/day for 3 days followed by taper. -Seizure control per Grade 3. -Management of raised ICP per neurology/neurosurgery intensive care recommendations. May use hyperosmolar therapy (mannitol/hypertonic saline), hyperventilation strategy.

Note: Data from references.^6,8,17,18

Abbreviations: ASBMT, American Society for Transplantation and Cellular Therapy; ICANS, immune effector cell‐associated neurotoxicity syndrome; CRS, cytokine release syndrome; EEG, electroencephalogram; ICE, Immune effector Cell‐associated Encephalopathy; ICP, intracranial pressure; IV, intravenous.

Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56. doi:10.1056/NEJMoa1804980

 PubMed Web of Science ®Google Scholar

Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–195. doi:10.1182/blood-2014-05-552729

 PubMed Web of Science ®Google Scholar

Maus MV, Alexander S, Bishop MR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events. J Immunother Cancer. 2020;8(2):e001511. doi:10.1136/jitc-2020-001511

 PubMed Web of Science ®Google Scholar

Locke FL, Neelapu SS, Bartlett NL, et al. Preliminary results of prophylactic tocilizumab after axicabtageneciloleucel (axi-cel; KTE-C19) treatment for patients with refractory, aggressive Non-Hodgkin Lymphoma (NHL). Blood. 2017;130(Supplement 1):1547.

 Google Scholar

Jacobson CA, Hunter BD, Redd R, et al. Axicabtagene ciloleucel in the non-trial setting: outcomes and correlates of response, resistance, and toxicity. J Clin Oncol. 2020;38(27):3095–3106. doi:10.1200/JCO.19.02103

 PubMed Web of Science ®Google Scholar

Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US lymphoma CAR T consortium. J Clin Oncol. 2020;38(27):3119–3128. doi:10.1200/JCO.19.02104

 PubMed Web of Science ®Google Scholar