Neurologic Toxicity Post-CAR T-Cell Therapy and CRS: Differentiating Symptoms and Individual Management
The patient is a 64-year-old man with a medical history of hypertension, chronic migraines, and relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) involving the several lymph nodes above and below the diaphragm without bone marrow involvement. He was initially treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), with end-of-treatment response imaging and bone marrow testing demonstrating a complete response to therapy. He was disease-free for 6 years until his first relapse, at which time he received rituximab, gemcitabine, and oxaliplatin. After his first cycle of this regimen, unfortunately his disease progressed into the lymph nodes with and without evidence of pre-existing disease. He was referred for CAR T-cell therapy evaluation and, after determining eligibility, he was prescribed tisagenlecleucel. In preparation for CAR T-cell therapy, the patient was referred to a neurologist who performed a clinical neurologic evaluation, complete with baseline brain MRI, EEG, and electrophysiological measurements. The patient was cleared from a neurological standpoint and went on to receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by tisagenlecleucel.
On Day 3 post-product infusion, initial vital signs for the patient were as follows: blood pressure (BP), 110/85 mm hg; heart rate (HR), 87; respiratory rate (RR), 20; temperature, 100.4°F; oxygen saturation (SpO2), 99% on room air. A full infectious workup (chest x-ray, blood, and urine cultures) was negative, and the patient was non-neutropenic. He was given 650 mg of Tylenol orally and observed.
On Day 4, however, vital signs taken in the morning were as follows: BP, 95/70 mm hg; HR, 100; RR, 20; temperature, 100.4°F; SpO2, 95% on room air. A low-flow nasal cannula was initiated, but no vasopressor was required. Symptoms were responsive to fluids (1L normal saline 0.9%). A cytokine panel determined that IL-6 levels were elevated, so the advanced practice provider discussed the case with the attending bone marrow transplant physician. The patient was then administered one dose of tocilizumab (8 mg/kg) for grade 2 cytokine release syndrome (CRS). By the evening of Day 4, the patient’s fever had abated and his oxygen and blood pressure normalized.
Workup, Diagnosis, and Treatment
On Day 5, although the CRS symptoms resolved with therapy, the patient complained of mild fatigue and noted having trouble sleeping overnight. He remained alert and oriented to person, place, and time (x3) and was not experiencing fever, visual changes, dysgraphia, expressive aphasia, decreased level of consciousness, headache, migraine, confusion, tremors, altered mental status, gait balance, hallucinations, disturbed consciousness, or seizures. The patient scored a 9 on the Immune Effector Cell-Associated Encephalopathy (ICE) score, missing one number while counting backwards from 100. Pre-emptively, a neurology consult was called, and the patient was placed on levetiracetam 750 mg twice daily for seizure prophylaxis. Given vague stable symptoms and an unremarkable repeat brain MRI, the decision was to observe overnight and further medically intervene if symptoms worsened.
The morning of Day 6, the patient’s IL-6 levels were noted to decrease, but he had trouble complying with requests from staff and a slight bilateral hand tremor. His fatigue had worsened overnight; he was spontaneously arousable and could have a conversation, yet his responses were slower overall, and he scored a 7 on the ICE assessment. Neurology evaluated the patient and performed a cranial CT, MRI, EEG, and diagnostic lumbar puncture, with no significant pathologic findings. The patient was diagnosed with grade 1 ICANS. Seizure prophylaxis was continued, and 40 mg daily of dexamethasone was initiated. Neurologic symptoms rapidly resolved over a 6-hour period.
It has been estimated that ICANS occurs in up to 62% of patients with lymphoma who undergo CAR T-cell therapy.1 Although there is heterogeneity across neurologic effects associated with each available CAR T-cell therapeutic product, ICANS most commonly occurs with CD19-directed therapies and has not been observed post-CAR T-cell infusion for solid tumors. Although ICANS often accompanies cytokine release syndrome, it is a separate entity with different interventions and symptoms. ICANS-related symptoms can sometimes wax and wane with CRS-related fever, reappearing after CRS resolution. Early signs of ICANS include tremor, dysgraphia, impaired attention, mild lethargy, apraxia, and mild expressive aphasia. Other symptoms include delirium, encephalopathy, and seizures, although the appearance of seizures often occurs after the development of severe or global aphasia. Progression of ICANS may happen over a few hours or several days.4 In severe cases, apraxia, dysarthria, motor aphasia, and/loss of consciousness may develop, with or without brain edema. Researchers have reported ICANS-related death in 3% of patients.5
Neurologic imaging—cranial CT and, preferably, MRI—is valuable in the determination of ICANS, although these can often read normally despite the presence of symptoms. Researchers at the University Hospital, Montpellier, France, are conducting a trial on the use of MRI to evaluate ICANS based on the evolution of tissue microcirculatory parameters (NCT05510596). Karschnia and colleagues found that periodic or rhythmic EEG patterns on the interictal continuum corresponded with development or existence of high-grade ICANS, leading them to suggest that EEG results may be useful for monitoring of patients with ICANS symptoms.6 The 10-point Immune Effector Cell-Associated Encephalopathy (ICE) score is used in the grading of multiple encephalopathy terms included in the available CAR T-cell products, and it evaluates patients based on Impact, Confidence, and Ease, including assessment of receptive aphasia. The American Society for Transplantation and Cellular Therapy (ASTCT) developed a grading system for ICANS that uses a combination of the ICE score and evaluation of other neurologic domains including degree of consciousness, presence of seizures, signs of elevated cerebral edema/intracranial pressure, and motor skills, as well as of EEG findings related to nonconvulsive seizures, to establish clear and distinct grades and treatment recommendations.4
There is no specific therapy for ICANS, and it has been suggested that prophylactic tocilizumab, which may reduce incidence of severe CRS post-infusion, may actually worsen ICANS symptoms.1 Therefore, corticosteroids and supportive care are commonly given, with dexamethasone or methylprednisolone being commonly used to treat moderate or severe ICANS. One study found neurologic symptoms to improve within the first few days of dexamethasone administration, and duration of treatment (≥7 days vs. < 7 days) was not found to be a prognostic marker for PFS or OS. The same study noted, however, that corticosteroid use > 10 days was a negative prognostic marker for OS but not for PFS.6 As GM-CSF has been associated with ICANS, a patient-derived xenograft model has shown that GM-CSF neutralization to reduce neuroinflammation and decrease myeloid and T-cell infiltration in the central nervous system. In addition, IL-1 secreted by activated myeloid cells also was found to be associated with development of ICANS, with a mouse model showing elimination of ICANS-related symptoms after administration of the IL-1 antagonist anakinra.1
- Siegler EL, Kenderian SS. Neurotoxicity and cytokine release syndrome after chimeric antigen receptor t cell therapy: Insights into mechanisms and novel therapies. Front Immunol. 2020;11:1973.
- Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119:2709-20.
- Santomasso BD, Park JH, Salloum D, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8:958-71.
- Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25:625-38.
- Mӧhn N, Bonda V, Grota-Levi L, et al. Neurological management and work-up of neurotoxicity associated with CAR T cell therapy. Neurol Res Pract. 2022;4. https://doi.org/10.1186/s42466-021-00166-5
- Karschnia P, Jordan JT, Forst DA, et al. Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. Blood. 2019;133:2212-21.