CAR-T and ICANS immune effector cell associated neurotoxicity syndrome

This patient received CAR-T therapy for diffuse large B-cell lymphoma 6 days ago. She has had grade 1 cytokine release syndrome that has been treated with tocilizumab, and she is also at high risk for developing immune effector cell encephalopathy or immune effector cell-associated neurotoxicity syndrome (ICANS) from CAR-T therapy. Numerous ICANS severity scoring scales exist to assess the severity of the syndrome. ICANS of any severity occurs in up to 70% of patients receiving CAR-T therapy. Clinical risk factors associated with increased risk of ICANS include younger age, preexisting neurologic comorbidities, increased intensity of chemotherapy, and early severe cytokine release syndrome. ICANS is a neurological presentation of a systemic process that is thought to occur owing to an inflammatory cascade within the central nervous system that results from disruption of the blood-brain barrier from endothelial cell activation from high levels of circulating cytokines.

Patient clinical presentation with ICANS ranges from mild alterations in consciousness to coma. ICANS often develops 3 to 10 days after CAR-T administration and within 2 to 4 days of the onset of cytokine release syndrome. Initial neurological symptoms usually involve inattention and language deficits, but neurological symptoms can be rapidly progressive over hours.

Treatment of ICANS is high-dose glucocorticoids, usually 10 mg of dexamethasone every 6 h. Most patients who develop ICANS have already received at least one dose of an IL-6 receptor antagonist like tocilizumab, and although repeat doses are often administered, treatment of ICANS is more dependent on high-dose glucocorticoids. In patients with ICANS who do not have concurrent cytokine release syndrome, there is no role for tocilizumab. Many patients with ICANS have seizures, and antiepileptics (preferably levetiracetam) are often administered empirically. With prompt recognition and appropriate treatment, the acute symptoms of ICANS are reversible in almost all patients, usually resolving completely within 7 to 10 days of onset with appropriate management.

Patients with lymphopenia or neutropenia are at increased risk for infections. Clinicians need to be hypervigilant in evaluating for infections in these patients. However, patients with cytokine release syndrome and/or ICANS often have high fevers without infection because of the high level of circulating cytokines. Other than the fever, this patient does not have any obvious signs of meningitis, and her neurological symptoms and clinical presentation are more consistent with ICANS than meningitis. Broad-spectrum antibiotics should be started, given her leukopenia and fevers, but she does not need meningitis coverage.

Cerebral edema is rare in patients with ICANS, although it does occur, but her head CT scan does not demonstrate edema. She does not need emergent initiation of hypertonic saline to treat significant cerebral edema.123456

A 35-year-old woman with diffuse large B-cell lymphoma was admitted for conditioning chemotherapy and chimeric antigen receptor T-cell (CAR-T) therapy 6 days ago. Her CAR-T treatment has been complicated by fevers and tachycardia, thought to be grade 1 cytokine release syndrome related to her CAR-T treatment. She has received one dose of an IL-6 antagonist for this cytokine release syndrome.

Yesterday morning, she had new onset resting tremors in both of her upper extremities. Overnight, she was transferred to the ICU with altered mental status and worsening fevers. On arrival, she had some aphasia and difficulty speaking but followed simple commands. This morning, she is nonresponsive to verbal or tactile stimuli, breathing 24/min with a heart rate of 138/min. Her temperature is 39.1 °C, and she is flushed in appearance. Her BP is 158/92 mm Hg. She is areflexic in all four extremities and does not move any of her extremities, even to painful stimuli. She has a weak gag reflex, and her pupils are 5 mm bilaterally and constrict to 2 mm in response to light. Her neck is supple, and she does not have Brudzinski or Kernig signs on flexion of her neck or knees. Notable laboratory values are listed in Figure 1. She undergoes intubation for airway protection given her mental status, cefepime and vancomycin are started, and she is sent for head CT scanning using the acute stroke protocol, the results of which show no abnormalities, ischemia, or perfusion deficits.

What is the most appropriate next step in management?

Footnotes

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  3. 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(20):2212-2221. PubMed ↩

  4. 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(4):625-638. PubMed ↩

  5. Rubin DB, Al Jarrah A, Li K, et al. Clinical predictors of neurotoxicity after chimeric antigen receptor T-cell therapy. JAMA Neurol. 2020;77(12):1536-1542. PubMed ↩

  6. Rubin DB, Danish HH, Ali AB, et al. Neurological toxicities associated with chimeric antigen receptor T-cell therapy. Brain. 2019;142(5):1334-1348. PubMed ↩