Immune effector cell-associated neurotoxicity syndrome (ICANS)

INTRODUCTION — Immune effector cell-associated neurotoxicity syndrome (ICANS) is a clinical and neuropsychiatric syndrome that can occur in the days to weeks following administration of certain types of immunotherapy, especially immune effector cell (IEC) and T cell engaging therapies. It has previously been referred to as cytokine release encephalopathy syndrome (CRES) and chimeric antigen receptor T (CAR-T) cell-related encephalopathy or neurotoxicity.

ICANS is seen at varying degrees of severity and has been associated with fatal outcomes in rare cases. Given the rapidly expanding use of IEC therapies, it is imperative for all clinicians involved in the care of treated patients to be familiar with the manifestations and management of ICANS.

CAR-T cell therapies are available for treatment of relapsed and refractory hematologic malignancies and are also under investigation in a range of solid tumors. CD19-targeting CAR-T cell products approved by the US Food and Drug Administration (FDA) include:

●Tisagenlecleucel for relapsed/refractory B cell acute lymphoblastic leukemia and relapsed/refractory large B cell lymphoma

●Axicabtagene ciloleucel for relapsed/refractory large B cell lymphoma and relapsed/refractory follicular lymphoma

●Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma

●Lisocabtagene maraleucel for relapsed/refractory large B cell lymphoma

●Idecabtagene vicleucel for relapsed/refractory multiple myeloma

●Ciltacabtagene autoleucel for relapsed/refractory multiple myeloma

This topic will discuss the epidemiology, pathophysiology, clinical features, evaluation, and management of ICANS. Cytokine release syndrome (CRS) is reviewed separately. (See "Cytokine release syndrome (CRS)".)

INCIDENCE AND RISK FACTORS — The incidence of ICANS varies depending on the type of therapy being delivered, disease and patient characteristics, and because the definition and recognition of the syndrome has changed over time [1,2].

Specific products — Therapies most commonly associated with ICANS are chimeric antigen receptor T (CAR-T) cell therapies and certain T cell engaging therapies such as blinatumomab and teclistamab.

●CAR-T cell therapies – ICANS of any severity occurs in 20 to 70 percent of patients treated with CAR-T cell therapy [3-9]. Severe ICANS has been observed in the pivotal studies of all five products (table 1) [5,8-10].

Differences in the costimulatory domains of each product affect neurotoxicity risk [11-13]. Among the available products, rates and severity of ICANS are generally higher with axicabtagene ciloleucel and brexucabtagene autoleucel, which have CD28-containing CAR-T constructs and are associated with more rapid T cell expansion kinetics, effector memory T cell differentiation, and glycolic metabolism [14,15], compared with tisagenlecleucel, lisocabtagene maraleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel, which have a 4-1BB-containing CAR construct that supports more oxidative metabolism with slower T cell expansion kinetics, a central memory T cell phenotype, and potentially longer-term persistence [16].

Structural differences and manufacturing variability also affect risk, making comparisons of incidence based purely on transgene structure limited. Across different products, higher CAR-T cell doses and peak CAR-T cell expansion are associated with increased ICANS incidence.

Comparisons of toxicity across early trials is difficult due to differences in grading systems (Common Terminology Criteria for Adverse Events [CTCAE] version 4.03 versus Penn Criteria) as well as use of different management algorithms, with earlier studies intervening at higher grades due to concerns of impacting treatment efficacy. With improved management strategies, there has been a relative reduction in toxicities; however, key product differences remain.

●T cell engaging therapies – The frequency and pattern of ICANS associated with T cell engaging therapies is less well characterized than with early-generation CD19-targeted CAR-T cell therapies, and data are evolving.

Neurologic toxicity occurs in approximately 65 percent of patients treated with blinatumomab, a CD19/CD3 bispecific T cell engager for treatment of B cell acute lymphoblastic leukemia [17,18]. The most common manifestations are headache and tremor. CTCAE grade 3 or higher toxicities (severe, life-threatening, or fatal) have been seen in approximately 13 percent of patients, including encephalopathy, seizures, disturbances of speech and consciousness, confusion, disorientation, and imbalance. Blinatumomab-associated neurotoxicity is the most common reason for dose interruption; however, neurologic symptoms usually resolve with drug hold and typically decrease with subsequent cycles [19].

The risk of ICANS of any severity is also elevated (>50 percent) with teclistamab, a B cell maturation antigen (BCMA)/CD3 bispecific T cell engager for treatment of multiple myeloma [20]. By contrast, the risk of ICANS appears to be very low with mosunetuzumab, a CD20/CD3 T cell engager for follicular lymphoma [21].

Clinical risk factors — Across different products and studies, clinical risk factors associated with increased risk of ICANS include [2,7,22-26]:

●Younger patient age

●Preexisting neurologic and medical comorbidities

●High disease burden of the underlying malignancy

●Increased intensity of lymphodepleting therapy and cytopenias

●Early and severe cytokine release syndrome (CRS) with high levels of inflammatory cytokines

Of note, the pivotal studies of all approved CAR-T cell therapies excluded patients with active central nervous system (CNS) disease given concern for increased risk of ICANS. However, subsequent work has demonstrated that CAR-T can be used safely in patients with CNS malignancies with appropriate management, as ICANS is likely a neurologic manifestation of an otherwise systemic process [27,28].

PATHOPHYSIOLOGY — The pathophysiology of ICANS and the mechanisms underlying many of the symptoms are not fully understood.

In general, it is thought that systemic inflammation and high levels of circulating cytokines result in endothelial cell activation and blood-brain barrier (BBB) disruption, which in turn causes an inflammatory cascade within the central nervous system (CNS), subsequent alterations in cortical and subcortical function, and diffuse cerebral edema in some cases.

Both ICANS and cytokine release syndrome (CRS) are considered an enhanced or supraphysiologic immune response to immune-modulating therapy that activates or engages T cells and/or other immune effector cells (IECs). CAR-T-related ICANS is commonly associated with, and follows, CRS, suggesting a potential mechanistic link. Clinical correlates of severe ICANS often overlap with severe CRS, including elevations in C-reactive protein (CRP), ferritin, and cytopenias [29]. (See "Cytokine release syndrome (CRS)", section on 'Pathophysiology'.)

While there was early speculation that neurotoxicity was antigen specific, since ICANS was observed both with the CD19-specific T cell engager, blinatumomab, and with CD19-specific chimeric antigen receptor T (CAR-T) therapies, subsequent reports have clearly identified ICANS in other, non-CD19-associated applications and diseases [30]. Based on one clinical trial experience, it is possible that some delayed toxicities may be antigen specific, however. (See 'Delayed parkinsonism' below.)

Endothelial activation and disruption of the BBB have been identified as potential mechanisms [22,31]. The angiopoietin (ANG) and angiopoietin receptor (TIE) axis is disrupted during an initial inflammatory insult, likely mediated, in part, by tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 6, and IL-1. This results in endothelial activation and microvascular permeability, including BBB breakdown. With increased BBB permeability, patients with severe ICANS also exhibit elevated CNS levels of cytokines, protein, and T cell infiltrates [32-35].

In addition to CAR-T activation, recruitment and activation of other immune competent cells have been implicated, including myeloid cells, monocytes, and macrophages. Studies in patients with CAR-T cell-associated neurotoxicity have shown elevations in inflammatory cytokines (eg, interferon gamma [IFN-gamma], IL-6, IL-8, IL-10, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], monocyte chemoattractant protein 1 [MCP-1], interferon gamma-induced protein 10 [IP-10]), markers of astrocyte injury (eg, glial fibrillary acidic protein [GFAP], S100 calcium-binding protein B [S100B]), and neurotoxic substances (eg, glutamate and quinolinic acid) [22,23,36-38].

CLINICAL FEATURES

Clinical presentation — The clinical presentation of ICANS ranges from mild alterations in the level of consciousness to varying degrees of neurologic dysfunction, including [1,7,22,23,39]:

●Encephalopathy with confusion and behavioral changes

●Visual and auditory hallucinations

●Language dysfunction, speech alterations, and apraxia

●Headache, fatigue, and tremors

●Dysgraphia and other fine motor impairment

●Clinical or subclinical seizures, including status epilepticus

●Cerebral edema with coma

●Death secondary to malignant cerebral edema

ICANS most often develops within 3 to 10 days after chimeric antigen receptor T (CAR-T) cell administration, but the timing can vary among CAR-T cell products and disease indications [7,22,23]. ICANS usually occurs in the context of cytokine release syndrome (CRS), with neurologic symptoms beginning within two to four days of the onset of CRS. However, CRS is not required for ICANS, and the syndromes can occur at different times. (See "Cytokine release syndrome (CRS)", section on 'Clinical presentation'.)

Initial neurologic symptoms are usually characterized by inattention and language deficits [7,24,40,41]. Clinical symptoms can be rapidly progressive within hours to a few days. Close monitoring during this time is critical.

Mildly affected patients may be disoriented but able to communicate, with mild expressive and/or receptive language dysfunction (table 2). Worsening signs of encephalopathy include decreased level of consciousness, slowness to respond, and disorientation to time and location. Severely affected patients can have language dysfunction or mutism, experience seizures, and be difficult to arouse (ie, only responsive to tactile or noxious stimulation). (See 'Grading' below.)

The frequency of clinical seizures in patients with ICANS is difficult to estimate, in part because some patients have involuntary movements and intermittent neurologic symptoms that do not correlate with an ictal pattern on electroencephalography (EEG). In addition, seizure risk may be influenced by use of prophylactic antiseizure medications, which was not standard in early trials but has become more widely adopted. Based on early studies, the risk of seizure was estimated to be as high as 50 percent in patients with ICANS and 30 percent of all patients treated with CAR-T cell therapy [23]. Later studies report a seizure incidence between 1 and 30 percent in patients with ICANS and 0 to 10 percent of patients treated with CAR-T cells in general [7,24,42].

The acute symptoms of ICANS are considered reversible and usually resolve within 7 to 10 days of onset with adequate management. Nevertheless, neurotoxicity can be life threatening and/or extended, with some patients requiring prolonged intensive care unit (ICU) monitoring and mechanical ventilation for airway protection and management of elevated intracranial pressure (ICP). In fatal cases, the cause of death has primarily been attributed to malignant cerebral edema [39,43].

Laboratories — Laboratories in patients with ICANS often, but not always, show evidence of systemic inflammation due to concomitant CRS.

Blood biomarkers that have been associated with higher risk for developing neurotoxicity include high lactate dehydrogenase (LDH) levels (as a marker of disease burden), significant thrombocytopenia (as a marker of bone marrow toxicity in heavily pretreated patients), and rising inflammatory markers such as ferritin, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR; as evidence of cytokine release and immune activation) [7,26].

Patients with severe ICANS exhibit high serum levels of proinflammatory cytokines such as interleukin (IL) 2, IL-6, IL-15, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). While such biomarkers have so far not been routinely used in clinical practice, CRP and ferritin levels are easily obtained, and rising CRP/ferritin is a clinically helpful biomarker associated with an elevated risk for ICANS [7].

Cerebrospinal fluid (CSF) findings in patients with ICANS are nonspecific. CSF may be normal or may show mild protein elevation and pleocytosis [24,26].

Electroencephalography — Most patients with ICANS have an abnormal EEG, reflective of some degree of encephalopathy and, less commonly, electrographic seizures.

Frontal or diffuse theta-delta background slowing is the most commonly observed pattern [44,45]. Other findings include generalized periodic discharges (GPDs), generalized rhythmic delta activity (GRDA), bilateral periodic discharges (BiPEDs), and frank electrographic seizures and status epilepticus [42,45,46].

It is not yet clear whether the degree of ICANS correlates with specific EEG findings. In an analysis of the continuous EEGs of 81 patients with neurotoxicity after CAR-T cell therapy, the degree of background slowing and loss of posterior-dominant rhythm correlated with neurotoxicity severity but not with duration [45]. Rhythmic or periodic patterns such as GRDA were common but did not invariably correlate with higher neurotoxicity grade. Among five patients with clinical seizures (6 percent), all but one had focally abnormal EEGs within the ictal-interictal continuum and/or with rhythmic/periodic patterns.

Neuroimaging — Most patients with ICANS have normal neuroimaging studies, even in the context of clinically established CRS and ICANS [35].

In severe ICANS complicated by increased ICP, computed tomography (CT) and magnetic resonance imaging (MRI) of the brain may show diffuse white matter changes and sulcal effacement, indicative of diffuse cerebral edema (image 1) [43,47]. Other abnormal findings that have been described infrequently in patients with ICANS include cerebral infarctions, subarachnoid or subdural hemorrhage, and focal or diffuse white matter injury [7,23,24].

Focal vascular abnormalities on CT angiography have been described in a minority of patients, including at least one case of vasospasm suggested by partial resolution on two-week follow-up imaging [24].

GRADING — Grading of ICANS (table 2) has evolved since early clinical trials of chimeric antigen receptor T (CAR-T) therapy. Guidelines from the American Society for Transplantation and Cellular Therapy (ASTCT) attempt to harmonize earlier scales, including the CAR-T Cell Therapy-Associated Toxicity (CARTOX-10) criteria, and recognize the growing diversity in immune effector cell (IEC) therapies and the potential for neurotoxicity outside of CAR-T applications [1,40,48].

The ASTCT grading scale includes a 10-point encephalopathy assessment, termed the "immune effector cell-associated encephalopathy" (ICE) score, which builds on the previous CARTOX-10 element for assessing receptive aphasia. The ICE score has five components: orientation, naming, following commands, writing, and attention.

Patients are graded according to the most severe symptom attributable to ICANS in five domains: encephalopathy (ICE score), level of consciousness, seizure, motor findings, and elevated intracranial pressure (ICP)/cerebral edema (table 2). As examples:

●Grade 1 (mild) – A patient with grade 1 ICANS may demonstrate inattentiveness, mild disorientation, and mild expressive and/or receptive language dysfunction but will be able to communicate.

●Grade 2 (moderate) – A patient with grade 2 ICANS may have a moderately impaired level of consciousness but is responsive to voice, usually slow to respond, and disoriented to time and location.

●Grade 3/4 (severe) – Grade 3/4 ICANS includes patients with more severe and significant language dysfunction or mutism, those who are difficult to arouse (ie, only responsive to tactile or noxious stimulation), and potentially those with seizures.

Although the ICE assessment is useful for screening adults for encephalopathy, it is not optimized for children. For children age <12 years, or those with developmental delay, the Cornell Assessment of Pediatric Delirium (CAPD) is recommended to aid in the overall grading of ICANS [49]. Other domains are the same as in adults: level of consciousness, motor symptoms, seizures, and signs of raised ICP.

Of note, neurotoxicity associated with non-IEC therapies (eg, bispecific antibodies) is graded using the standard Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (table 3 and table 4) [48], as the ICANS/ICE system only pertains to IEC therapies [1]. IECs can be any cell used to modulate an immune response for therapeutic intent, such as dendritic cells, natural killer cells, T cells, and B cells. This includes genetically engineered CAR-T cells and therapeutic vaccines [50].

EVALUATION AND DIAGNOSIS — ICANS is a clinical diagnosis of neurologic toxicity attributed to recent administration of an immune effector cell (IEC) therapy or T cell engaging therapy. It is a diagnosis of exclusion after other potential causes of mental status changes or altered neurologic function have been ruled out.

Clinical monitoring — Patients who receive chimeric antigen receptor T (CAR-T) cell therapy, blinatumomab, and teclistamab require close monitoring for the development of cytokine release syndrome (CRS) and ICANS.

Decisions to treat patients as inpatients or outpatients should be based on product-specific toxicity profiles, the time course of toxicity, and center-specific infrastructure for safety and monitoring.

In the United States, the US Food and Drug Administration (FDA) has mandated risk evaluation and mitigation strategies (REMS), and all centers providing commercial CAR-T cell products must be authorized prior to treating patients. Some FDA-approved products (such as axicabtagene ciloleucel) require daily clinical evaluations for the first week following CAR-T infusion.

A baseline neurologic examination should be performed prior to administration of CAR-T cells in order to establish a patient-specific neurologic baseline.

Standard daily clinical assessment for ICANS includes:

●Physical examination and review of vital signs – More frequent clinical evaluations and bedside assessments are recommended in patients at higher risk for neurotoxicity, such as in patients with fever and other signs of CRS, preexisting neurologic deficits, and any evidence of change in mental status.

●Routine neurologic examination – There should be particular focus on subtle deficits in attention and changes in alertness and language function, as these are usually the earliest signs of ICANS. Family members and the nursing team may have insight into subtle personality changes or other deviations from baseline not readily detected by routine examination. Assessment should be repeated at least twice a day and with any change in status.

●Bedside funduscopy – Funduscopy is particularly important in patients with altered mental status and visual changes, to assess for signs of increased intracranial pressure (ICP) and possible cerebral edema.

●Immune effector cell-associated encephalopathy (ICE) score – The ICE score (table 2) should be performed as part of any routine assessment during the at-risk period (typically the 30-day period following CAR-T infusion). This helps to standardize, quantify, and trend a patient's neurologic status. (See 'Grading' above.)

●Laboratory review – Serial monitoring of laboratory tests helps to inform the index of suspicion for CRS and ICANS. ICANS usually presents in a temporal relationship to CRS, and most patients develop neurologic deficits within days after CRS onset. Daily laboratory tests should include complete blood counts, chemistry profile, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and routine inflammatory markers, such as ferritin and C-reactive protein (CRP).

Changes in the neurologic examination should be interpreted in the context of a broad differential diagnosis. Patients receiving CAR-T cell therapy are usually heavily pretreated with chemotherapy and at risk for multiple causes of altered mental status, including medication side effects, infection, new or worsening renal or liver dysfunction, and changes in electrolytes and endocrine function. (See 'Differential diagnosis' below.)

Additional testing — Additional testing of patients with suspected ICANS may include the following:

●EEG – EEG is an important tool in the evaluation of suspected ICANS. Any patient with unexplained altered mental status, including ICANS, should undergo EEG recording to diagnose or rule out subclinical or nonconvulsive seizures that otherwise would not be readily detectable by a clinical bedside examination.

While ICANS does not have a specific EEG signature, EEG is often uniquely helpful to support the diagnosis and degree of encephalopathy and offer clues regarding the potential differential diagnosis (eg, seizures versus metabolic causes). Additionally, as seizure activity is required for ICANS grading, patients should be evaluated for seizure activity as part of routine ICANS assessment. Long-term EEG monitoring can be helpful in patients with prolonged or fluctuating encephalopathy and mental status changes to guide management and adjustment of antiseizure medications [51].

●Neuroimaging – A noncontrast head CT is indicated in patients with rapidly worsening mental status or acute focal deficits to rule out cerebral edema or other acute abnormalities (eg, bleeding) and to guide further management, such as escalating care and need for intensive care unit (ICU) monitoring.

When possible, brain MRI is strongly recommended in patients with worsening ICANS as part of the workup for other etiologies of neurologic dysfunction and to evaluate for cerebral edema and more subtle changes in cerebral white matter. This may be difficult in patients with agitated delirium; MRI can be deferred in such cases pending patient stability.

●Lumbar puncture – We perform lumbar puncture (LP) selectively in patients with ICANS. The cerebrospinal fluid (CSF) findings in ICANS are nonspecific and do not rule in or out the diagnosis. The main indication for LP is when there is clinical suspicion for central nervous system (CNS) infection or neoplastic CNS involvement. Neuroimaging, as well as platelet count and coagulation studies, should be reviewed before LP to ensure safety.

Particular caution is required before performing an LP in a patient with severe (grade 3 or 4) ICANS, as an LP can trigger herniation in the setting of diffuse cerebral edema. In addition, many of these patients have a coagulopathy and increased risk for bleeding complications; therefore, clinical risk/benefit should be assessed. If there is significant clinical concern for meningitis or other CNS infection and a contraindication to LP, appropriate antimicrobial therapy should be started empirically.

Differential diagnosis — The differential diagnosis of ICANS is broad, and evaluation can be challenging. Patients treated with CAR-T cells are often quite ill and deconditioned, are often heavily pretreated, and commonly present with more than one clinical symptom (eg, mental status changes in combination with fever, low blood counts, and/or electrolyte abnormalities).

The list of alternative diagnoses varies depending on the lead clinical symptom(s) (eg, encephalopathy versus new focal neurologic deficit), the temporal course (eg, acute, subacute, fluctuating, progressive), and the duration of the abnormality.

●Encephalopathy – In any patient with the acute or subacute onset of encephalopathy, initial considerations include adverse effects from medications (eg, opioids, other sedating medications), metabolic abnormalities (eg, renal or liver impairment), endocrine dysfunction (eg, adrenal insufficiency, thyroid dysfunction), infections (including systemic or CNS infections), seizures (clinical or subclinical), and even psychiatric etiologies.

Medication review and appropriate laboratories will identify most of these culprits. EEG can also be helpful and is often necessary to rule out subclinical seizures. (See 'Additional testing' above.)

●Focal or rapidly progressive deficits – Additional considerations in patients with focal or rapidly worsening deficits include seizure, intracranial hemorrhage, stroke, and intracranial infection.

A noncontrast head CT will serve to identify acute bleeding or evidence of life-threatening cerebral edema. A brain MRI with and without contrast will have better sensitivity for acute ischemia, white matter injury, leptomeningeal processes, and other alternative CNS etiologies. CSF testing is indicated if there is clinical suspicion for meningitis or encephalitis.

Many other neurologic disorders may present in the days to weeks following CAR-T cell therapy with shared features of ICANS. Repeated examinations and multidisciplinary input are often required to establish the correct diagnosis. As examples:

●Tumor progression within the CNS – Tumor progression within the CNS can occur at any time in relation to receipt of anticancer therapies. The index of suspicion is typically highest in patients being treated for CNS malignancies or with systemic lymphoma/leukemias with a high rate of spread to the nervous system. When neuroimaging and/or CSF are equivocal, repeated examinations and occasionally biopsy may be necessary.

●Fludarabine-associated neurotoxicity – Delayed neurologic complications from prior conventional cytotoxic chemotherapy can be a confounding factor. Specifically, fludarabine-associated neurotoxicity may present with delayed and slowly progressive cognitive decline, visual disturbances, peripheral neuropathy, weakness, ataxia, and even death from 20 to 250 days following drug exposure [52,53]. MRI may demonstrate areas of restricted diffusion and leukoencephalopathy.

Fludarabine is increasingly used as part of the lymphodepleting regimen prior to CAR-T cell administration, and clinicians should be cautious of fludarabine dosing and fluctuations in creatine clearance.

●Reversible posterior leukoencephalopathy syndrome (RPLS) – RPLS can be caused by numerous drugs and chemotherapy agents and can be seen in the context of elevated blood pressure [44,54,55]. Clinical symptoms may include headache, mental status changes, visual disturbances, and seizures. Brain MRI classically shows cortical or subcortical, posterior-predominant T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities and diffusion restriction, although central patterns are also seen. (See "Reversible posterior leukoencephalopathy syndrome".)

●Progressive multifocal leukoencephalopathy (PML) – PML is caused by reactivation of the JC polyomavirus and can be seen after chemotherapy or immunomodulatory therapy, or in other conditions associated with an immunocompromised state [56-58]. PML manifests as abnormal T2/FLAIR hyperintensity on brain MRI, usually beginning in the subcortical white matter of the parietal or occipital lobes. Cortex, cerebellum, and deep gray structures can also be involved. CSF JC virus testing can be diagnostic. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

MANAGEMENT — Management of patients with ICANS requires vigilance and close supportive care, and early recognition is paramount. Treatment is supportive and consists primarily of glucocorticoids and antiseizure therapy. While neurologic deficits are considered transient and are usually reversible with appropriate management, fatal outcomes have been reported secondary to malignant cerebral edema.

Treatment recommendations are based primarily on clinical experience and observational data. Consensus guidelines for patient evaluation and management are available from the Society for Immunotherapy of Cancer (SITC) and the American Society of Clinical Oncology (ASCO) [59,60].

General considerations — Management of patients with ICANS can be challenging, and neurologic symptoms may develop rapidly. Most patients have progressive cancer despite multiple prior therapies and as a result are often deconditioned and frail, medically complicated, and immunosuppressed.

●Daily monitoring – A baseline neurologic examination should be performed prior to administration of chimeric antigen receptor T (CAR-T) cell therapy and daily for at least the first week after treatment. Components of the daily assessment are reviewed above. (See 'Clinical monitoring' above.)

●Severity assessment – Management decisions are informed by ICANS severity. The American Society for Transplantation and Cellular Therapy (ASTCT) grading scale is the preferred tool (table 2). (See 'Grading' above.)

●Multidisciplinary care – A multidisciplinary team approach is recommended to evaluate clinical and neurologic status, which can rapidly change, to address the differential diagnosis in the context of changing neurologic function, and to decide whether specific treatments such as glucocorticoids or antiseizure medications should be given.

Clinical care setting — The clinical care setting should be reviewed on a daily basis to determine whether a patient can be managed on a regular medical floor or needs to be more closely monitored, such as in the setting of an intensive care unit (ICU).

ICU care is generally advised in patients with progressive mental status changes and impaired responsiveness potentially related to worsening cerebral edema and/or status epilepticus, and in patients with higher-grade (grade 3 or 4) ICANS, so that close monitoring of neurologic, cardiovascular, and respiratory function can be provided.

Glucocorticoids — Glucocorticoids are an important component in the supportive management of patients with ICANS. The optimal timing, dose, and duration are not established, however, and treatment decisions are often influenced not only by ICANS but also concomitant cytokine release syndrome (CRS).

When to start — Based on the potential for rapid decline, we begin glucocorticoids in all patients with moderate to severe (grade ≥2) ICANS (table 2). Many of these patients will already be receiving such therapy due to concomitant CRS; for those who are not, or who have been tapered to lower doses, high-dose therapy is recommended.

In the event that patients receive tocilizumab for early and rapid onset of CRS (within 72 hours of infusion), one to two doses of glucocorticoids (eg, dexamethasone 5 to 10 mg) may be considered with tocilizumab [61-63].

Short-term high-dose glucocorticoids are generally well tolerated, although they can worsen agitation and delirium in some patients, which can confound the assessment of ICANS. There are also concerns that high-dose steroids may dampen the efficacy of immune effector cell (IEC) therapy. However, in the absence of a clear alternative, the risks of worsening ICANS demand treatment, particularly for severely affected patients.

Observational evidence suggests that a brief course of steroids (eg, seven days or fewer) may shorten the course of ICANS without negatively affecting long-term cancer outcomes [7]. However, definitive data are not available and additional prospective follow-up studies are needed.

Dose and duration — While the specific dose and optimal daily dosing regimen is not established, most CRS and ICANS protocols suggest the use of dexamethasone at a starting dose of 10 mg every 6 to 12 hours with a plan to taper over the following two to five days [64]. In our experience, most patients will show rapid clinical improvement within hours to days of glucocorticoid initiation. Patients who do not show improvement over hours to days should be examined for alternative etiologies.

In the absence of clear life-threatening seizures or cerebral edema, we favor beginning a taper after two to five days of high-dose steroids, since prolonged steroid use has been associated with inferior outcomes and steroid-related complications, including delirium, infections, and adrenal insufficiency. A typical taper consists of a 25 to 50 percent reduction in the total daily dose of steroid every 24 to 48 hours.

Once patients appear to have returned to their previous neurologic baseline, steroids should be tapered completely off in an effort to avoid the potentially negative impact on the anticancer effect of CAR-T cell therapy. In one study, steroid use for less than 10 days appeared not to influence overall response to CAR-T cell therapy, although longer courses may be associated with worse clinical outcomes [7,65].

Depending on dose and duration of glucocorticoids, infectious prophylaxis may be indicated given an elevated risk of fungal, bacterial, and viral infections.

Refractory edema — Refractory cerebral edema with acutely increasing intracranial pressure (ICP) is a neurologic emergency. In the rare cases in which edema progresses rapidly despite steroids, patients require aggressive osmotic therapies such as mannitol and hypertonic saline in an attempt to lower ICP. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'General management'.)

Seizure prophylaxis and management — Patients with ICANS are at increased risk for seizures. It can be difficult or impossible at the bedside to distinguish fluctuating encephalopathy from seizures, however, and EEG may take time to obtain.

From a practical standpoint, we therefore suggest antiseizure medication therapy in most patients with suspected ICANS at the time of the initial presentation with neurologic symptoms. Prophylactic therapy is also reasonable to consider in patients deemed at high risk for seizures, such as those with prior seizure history, concerning EEG findings, or neoplastic brain lesions [59].

Levetiracetam is the preferred antiseizure medication in this patient population due to limited drug-drug interactions and less concern for added cardio- and hepatic toxicity [40]. The usual starting dose is 500 mg twice daily.

For patients with clinical or electrographic seizures, dose adjustments and other antiseizure medications (eg, lacosamide, benzodiazepines, valproic acid) may be needed [46]. Interpretation of EEG patterns can be difficult and often requires continuous monitoring with clinical correlation. Patients with frequent seizures or concern for possible nonconvulsive status epilepticus should be managed in an ICU setting.

The duration of antiseizure prophylaxis after recovery from ICANS has not been established, but the risk of recurrent seizures after the ICANS has resolved appears to be very low [45]. In the authors' experience, most patients can be tapered off treatment safely within several weeks after CAR-T cell therapy.

Role of other therapies

Tocilizumab — For patients with moderate to severe CRS with or without ICANS, the anti-interleukin (IL) 6 receptor tocilizumab is typically given in combination with glucocorticoids [40]. Earlier intervention with tocilizumab in a patient with both CRS and ICANS may possibly decrease the severity of ICANS, although this is controversial, and additional studies are needed. Use of tocilizumab in CRS is reviewed separately. (See "Cytokine release syndrome (CRS)", section on 'CAR-T cell-associated CRS'.)

In patients with ICANS who do not have concurrent CRS, there is no role for tocilizumab, which poorly crosses the blood-brain barrier (BBB). Prophylactic use of tocilizumab may potentially worsen ICANS by increasing IL-6 levels in cerebrospinal fluid (CSF) [22,32,38,66].

Investigational therapies — A number of novel approaches to block inflammatory cytokines are under investigation, including IL-6 blockade with siltuximab [66], IL-1 blockade with anakinra [67], and granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralization with lenzilumab [68]. However, their effects on CAR-T cell therapy and ICANS remain unknown, and such strategies are only appropriate in the context of a clinical trial.

LONG-TERM OUTCOMES — With prompt recognition and appropriate supportive interventions, the acute symptoms of ICANS are reversible in nearly all patients. Long-term neurologic outcomes after successful chimeric antigen receptor T (CAR-T) cell therapy are not yet well studied, but the available data are reassuring [69-71].

In a single-center study of 56 consecutive patients treated with CAR-T cell therapy for relapsed diffuse large B cell lymphoma, baseline and follow-up neurologic examinations were available for 27 patients who were alive without tumor progression at six months or longer after treatment [69]. Cognitive assessments were stable compared with the pretreatment baseline at a median of 7.6 months after treatment, including among 12 patients who developed acute neurotoxicity (all nonsevere). Self-assessment questionnaires highlighted clinically meaningful anxiety, depression, or cognitive difficulties at baseline in 63 percent of patients, improving to 44 percent at follow-up.

Another study focused on the trajectory of perceived cognitive function in the first year after successful CAR-T cell therapy in 118 patients with lymphoma [70]. Beyond three months posttreatment, questionnaires revealed mild changes in patient-reported global cognition, memory, language, executive function, and attention. Risk factors for such changes included more severe ICANS as well as baseline fatigue, anxiety, and depression.

Other studies have shown a similar profile of neuropsychiatric symptoms in survivors of CAR-T cell therapy, highlighting the importance of multidisciplinary follow-up and supportive care [72,73].

Delayed parkinsonism — A delayed-onset, progressive movement disorder has been reported in several patients following administration of B cell maturation antigen (BCMA)-targeted CAR-T cell therapy (idecabtagene vicleucel, ciltacabtagene autoleucel) [74,75].

The syndrome appears to be an on-target effect of CAR-T cells on BCMA-expressing astrocytes and neurons in the basal ganglia [74]. This is based on a case report of a 57-year-old male with advanced multiple myeloma who was treated with ciltacabtagene autoleucel in a phase II trial and, beginning at approximately 100 days posttreatment, developed progressive parkinsonism, including bradykinesia, postural instability, hypophonia, hypomimia, micrographia, and mild tremor, as well as impaired short-term memory. Brain MRI was unremarkable; fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism in the caudate nuclei bilaterally compared with a pretreatment baseline. Serum studies showed persistent high levels of circulating CAR-T cells in the peripheral blood from days 11 through 157 postinfusion. There was no clinical response to levodopa, nor to immunosuppressive therapy with glucocorticoids and cyclophosphamide. The patient succumbed to febrile neutropenia, acute respiratory distress syndrome, and multiorgan failure on day 162. Postmortem studies showed focal gliosis in the caudate nuclei as well as BCMA expression in a subset of neurons and astrocytes in the caudate and frontal cortex.

To date, the syndrome has only been described after BCMA-targeted CAR-T cell therapy. Two other patients with grade 3 parkinsonism were reported in phase II trials of ciltacabtagene autoleucel [74], and grade 3 parkinsonism is included as an adverse event in the idecabtagene vicleucel package insert [75]. Data are still evolving.

SUMMARY AND RECOMMENDATIONS

●Incidence – Immune effector cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome that occurs in up to 70 percent of patients following administration of certain types of immunotherapy (table 1), especially chimeric antigen receptor T (CAR-T) cell therapy and certain T cell engaging monoclonal antibodies. (See 'Incidence and risk factors' above.)

●Pathophysiology – The pathophysiology of ICANS is not well understood. It is thought that systemic inflammation and high levels of circulating cytokines lead to endothelial cell activation, blood-brain barrier (BBB) disruption, and an inflammatory central nervous system (CNS) cascade. (See 'Pathophysiology' above.)

●Clinical features – ICANS usually occurs in the context of cytokine release syndrome (CRS), beginning 3 to 10 days after CAR-T cell administration and within 2 to 4 days of CRS onset. (See 'Clinical presentation' above.)

•Signs and symptoms – The most common symptoms are alterations in level of consciousness, confusion, behavioral changes, and speech and language abnormalities. Patients are at increased risk for seizures, diffuse cerebral edema, and elevated intracranial pressure (ICP). (See 'Clinical presentation' above and 'Electroencephalography' above and 'Neuroimaging' above.)

•Severity and grading – ICANS is graded according to the most severe symptom in five domains (table 2): encephalopathy (immune effector cell-associated encephalopathy [ICE] score), level of consciousness, seizure, motor findings, and elevated ICP/cerebral edema. (See 'Grading' above.)

●Diagnosis – ICANS should be suspected in any patient who develops new neurologic symptoms in the setting of recent immune effector cell (IEC) therapy. It is a diagnosis of exclusion after other potential causes of mental status changes or altered neurologic function have been ruled out. (See 'Evaluation and diagnosis' above.)

Neuroimaging and EEG are required in most patients to evaluate for alternative etiologies and diagnose seizures. Cerebrospinal fluid (CSF) examination is indicated when there is suspicion for CNS infection. (See 'Additional testing' above and 'Differential diagnosis' above.)

●Management – Management of ICANS requires vigilance and close supportive care, and early recognition is paramount. Treatment is supportive and consists primarily of glucocorticoids and antiseizure medications. (See 'Management' above.)

•Monitoring – Intensive care unit (ICU) care is generally advised in patients with progressive mental status changes and impaired responsiveness potentially related to worsening cerebral edema and/or status epilepticus, and in patients with higher-grade (grade 3 or 4) ICANS (table 2). (See 'Clinical monitoring' above and 'Clinical care setting' above.)

•Glucocorticoids – Based on the potential for rapid decline, we treat all patients with moderate to severe (grade ≥2) ICANS (table 2) with glucocorticoids. Many of these patients will already be receiving such therapy due to concomitant CRS; for those who are not or who have been tapered to lower doses, high-dose therapy should be started. (See 'Glucocorticoids' above.)

•Seizure prophylaxis – Patients are at risk for seizures, but clinical diagnosis is complicated and often confounded by encephalopathy. We therefore suggest starting most patients on an antiseizure medication such as levetiracetam at the time of first neurologic symptoms. (See 'Seizure prophylaxis and management' above.)