Guideline Overview Chinese Expert Consensus on the Management of Nervous System Side Effects Related to Chimeric Antigen Receptor T-cell Therapy (2022 Edition)

Chimeric antigen receptor T cells (CAR-T cells) have developed into an effective treatment for refractory and recurrent hematological tumors
.

While its clinical application continues to increase, treatment-related toxic and side effects have received more and more attention
.

Nervous system complications are one of the common toxic and side effects during CAR-T cell therapy, with an incidence of 21% to 66%
.

With the continuous development of CAR-T cell therapy, there has been a deeper understanding of the diagnosis and management of treatment-related nervous system side effects at home and abroad.
The Hematopoietic Stem Cell Transplantation and Cellular Immunotherapy Group of the Professional Committee organized relevant experts to compile the "Chinese Expert Consensus on the Management of Nervous System Side Effects Related to Chimeric Antigen Receptor T-cell Therapy (2022 Edition)", which aims to help clinical medical workers understand CAR -Have a more systematic understanding of the occurrence and development of nervous system toxicity during T cell therapy, so as to achieve effective prevention and treatment, and improve the safety of CAR-T cell therapy
.

Definition and Mechanism In 2017, the Neelapu team first proposed the concept of "CAR-T cell-related encephalopathy syndrome (CRES)", which refers to the headache, delirium, tremor, and mental state that occur in some patients during CAR-T cell therapy.
Abnormal manifestations of the nervous system such as changes, decreased attention, and language disorders
.

In 2019, the American Society for Transplantation and Cell Therapy (ASTCT) further proposed the concept of "immune effector cell-associated neurotoxicity syndrome (ICANS)", that is, after immunotherapy including CAR-T cells, the patient's endogenous or exogenous Clinical manifestations of a series of neurological abnormalities caused by the activation or participation of sex T cells and/or other immune effector cells
.

The definition of ICANS more accurately reflects the pathophysiological characteristics of neurological lesions than CRES, and has gained wider recognition and application in current clinical diagnosis and treatment
.

This article uses ICANS to name CAR-T cell therapy-related nervous system toxicities
.

The mechanism by which ICANS occurs is not fully understood
.

It is currently believed to be related to the release of a large number of inflammatory factors mediated by monocyte/macrophage activation during CAR-T cell therapy, while endothelial cell activation leads to increased vascular permeability and destruction of the integrity of the blood-brain barrier, IL-6, Various cytokines such as IFN-γ and TNF-α selectively pass through the blood-brain barrier and enter the central nervous system, which promotes the development of ICANS
.

Brain tissue edema, perivascular space enlargement, fluid extravasation, cortical and white matter astrocyte damage, and microglia activation were found in the autopsy pathology of patients with severe ICANS, confirming that inflammation and blood-brain barrier disruption are involved in ICANS occurrence and development process
.

The incidence of ICANS related to the treatment of CD19 and BCMA CAR-T cell products currently on the market is 28%-87%
.

In two real-world studies of mantle cell lymphoma patients receiving CAR-T cell therapy, the incidence of ICANS was around 60%
.

A recent study reported that the incidence of ICANS in patients with relapse after allogeneic hematopoietic stem cell transplantation for acute B lymphoblastic leukemia treated with donor-derived CD19 CAR-T cells was 21%
.

The incidence of ICANS varies widely and is related to factors such as the patient's primary disease, disease state, CAR-T cell type, and infusion dose
.

It is currently believed that the tumor burden is high before CAR-T cell therapy, there is previous central nervous system injury or tumor involvement, high-dose CAR-T cell infusion, and the molecular structure of CAR contains mouse-derived single-chain variable fragments (scFv), using CD28 covalently Stimulatory molecules, etc.
, are associated with a high incidence of ICANS
.

Clinical manifestations ICANS has various clinical manifestations.
Early symptoms are often manifested as decreased attention, language impairment, and decreased writing ability, which can further develop into disorientation, abnormal mood, aphasia, lethargy, confusion, and tremor.
Most patients with ICANS have clinical symptoms.
Symptoms are reversible
.

A small number of patients may have severe clinical symptoms, such as seizures, confusion, and increased intracranial pressure
.

The most severe clinical manifestation of ICANS is acute cerebral edema, in which patients can progress from mild lethargy to confusion within a few hours, and further progress to death
.

Symptoms and signs of ICANS usually appear on the 3rd to 6th day after CAR-T cell infusion, peak on the 7th to 8th day, and gradually improve over time, lasting 2 to 3 weeks for the symptoms to disappear
.

Patients with early-onset cytokine release syndrome (CRS) often have severe ICANS
.

About 10% of patients developed delayed neurotoxicity such as epilepsy or delirium in the 3-4 weeks after CAR-T cell therapy
.

Given the complexity and diversity of clinical manifestations of ICANS, scales can be used to grade them to guide disease treatment
.

International scoring scales include Common Terminology Criteria for Adverse Events 5.
0 (CTCAE5.
0), CAR-T cell therapy-related toxicity score (CARTOX), and CARTOX-modified immune effector cell-related encephalopathy score (ICE)
.

The CARTOX-10 and ICE scoring systems are usually used in clinical work, and ICANS is divided into four grades
.

Auxiliary examinations In the diagnosis of ICANS, a comprehensive neurological examination is very important, especially in the early stage of the disease when the symptoms of neurological toxicity are not typical
.

Therefore, for patients with a history of central nervous system diseases or tumors involving the central nervous system, before CAR-T cell infusion, a comprehensive neurological evaluation is required, and a neurologist is consulted if necessary
.

For all patients after CAR-T cell infusion, a twice-daily neurological assessment using the CARTOX-10 or ICE scoring scale is recommended
.

When patients have clinical manifestations of ICANS, the number of assessments should be increased in a timely manner
.

In addition to closely monitoring the patient's blood routine, blood biochemistry, coagulation function, ferritin, cytokine levels and other indicators, the following aspects need to be tested
.

1 After cerebrospinal fluid examination has ruled out contraindications, lumbar puncture and cerebrospinal fluid (CSF) examination are feasible
.

When ICANS occurs, intracranial pressure is often increased, and CSF examination may show abnormal protein increase, occasionally exceeding 10 g/L.
Excessive CSF protein level is associated with poor prognosis
.

The CSF cell count is usually mildly elevated, mainly lymphocytes, and CAR-T cells can be detected in the CSF of some patients by flow cytometry
.

Most patients after CAR-T cell therapy are complicated with thrombocytopenia due to bone marrow suppression.
Before lumbar puncture, the risk of puncture should be carefully assessed, and if necessary, platelet transfusion should be performed before puncture
.

2 Brain CT/Magnetic Resonance (MRI) Brain CT helps to detect cerebral hemorrhage, cerebral infarction and cerebral edema
.

Brain MRI findings are diverse and nonspecific
.

T2WI or FLAIR showed hyperintensity in the paraventricular, thalamus, and medulla oblongata, sometimes involving bilateral lesions.
Some patients showed hyperintensity in the cortex on diffusion-weighted imaging (DWI), suggesting cytotoxic edema
.

Diffuse cerebellar edema has also been reported
.

Imaging abnormalities in most patients disappeared after symptom relief
.

Timely imaging examinations help to exclude other diseases, and also help to dynamically observe the patient's nervous system side effects
.

3 The common manifestations of EEG are diffuse slow waves with/without 1-2Hz triphasic waves, and spindle waves or epileptic waves appear in some patients
.

In most cases, EEG changes are consistent with the occurrence of clinical symptoms, and EEG abnormalities are related to the severity of nervous system toxicity.
For high-risk patients, dynamic EEG monitoring is recommended
.

Diagnosis and Differential Diagnosis In view of the diverse clinical manifestations of ICANS, a multidisciplinary diagnosis and treatment (MDT) model is recommended for clinical diagnosis and treatment
.

The diagnosis of ICANS is based on: neurological and/or psychiatric symptoms and corresponding signs in patients after CAR-T cell therapy
.

The CSF, cranial MRI, EEG and other examinations were consistent with ICANS manifestations
.

Other neurological diseases are excluded, including: (1) Intracranial infection: there may be mental symptoms, such as delirium, lethargy, etc.
, often accompanied by fever and other infectious manifestations.
It is recommended to evaluate the intracranial situation with enhanced CT or MRI.
CSF routine and culture can be performed.
, etiological metagenomic next-generation sequencing and other tests to further clarify the etiological basis
.

②Intracranial hemorrhage: The clinical manifestations vary according to the bleeding site and the amount of bleeding.
It mostly occurs in patients with severe thrombocytopenia during the period of bone marrow suppression; the onset is often acute, and the neurological symptoms and signs are aggravated in a short period of time, accompanied by severe thrombocytopenia.
When reducing, we should be alert to the possibility of intracranial hemorrhage, and head CT scan can further clarify whether there is intracranial hemorrhage
.

③ Central involvement of the primary disease: For high-risk patients with central involvement or possible central involvement before treatment, attention should be paid to identifying the progression of the primary disease.
If necessary, CSF flow cytometry and head MRI can be performed
.

Treatment The clinical management of ICANS is mainly stratified according to the scoring scale (Figure 1)
.

For patients with neurological symptoms, dynamic monitoring should be carried out according to the scale, and the treatment strategy should be adjusted at any time according to the changes of the patient's condition
.

For patients with ICANS scores of grades 3-4, it is recommended to be transferred to the intensive care unit and to be supported by mechanical ventilation if necessary
.

During the management of ICANS, multidisciplinary treatment is recommended
.

Figure 1 Classification and treatment process of immune effector cell-associated neurotoxicity syndrome (ICANS) 1 Symptomatic and supportive treatment Regardless of the ICNAS grade, patients should pay attention to rest after CAR-T cell therapy, and can choose to raise their head (usually the same as the bed) face at 30 degrees) to increase venous return and prevent aspiration
.

Oxygen inhalation and rehydration, temporary fasting and fasting, evaluation of swallowing function; strengthen nutritional support, pay attention to water and electrolyte balance
.

Actively control the body temperature.
Physical cooling measures and non-steroidal drugs such as ibuprofen can be given when fever occurs.
Patients with persistent high fever can use ice blankets to assist in cooling
.

2 Glucocorticoids In clinical practice, glucocorticoids are often used as the first-line treatment for ICANS
.

There is no consensus on whether the use of glucocorticoids will affect the efficacy of CAR-T cells
.

Therefore, under the premise of closely monitoring the changes of the patient's condition, glucocorticoids can be used in accordance with the principles of the lowest therapeutic dose, shortest treatment time, and rapid reduction.
Or methylprednisolone 1 mg/kg every 12 hours, until the ICANS grade is reduced to grade 1, then the dose is reduced, and the dose is reduced within 3 days
.

In particularly severe cases, pulse therapy with methylprednisolone 1 g per day can be given for 2 to 3 days
.

3 Anti-IL-6 therapy There is currently no evidence that anti-IL-6 therapy can reduce the occurrence and delay the progression of ICANS.
It is recommended to evaluate the presence or absence of CRS in patients with all grades of ICANS
.

For patients with ICANS complicated by CRS, anti-IL-6 therapy can be used, and the IL-6 receptor antagonist tocilizumab is recommended to be 8 mg/kg each time, with a single maximum dose of 800 mg, every 8 hours if necessary Can be repeated 1 time up to 4 times
.

For patients with ICANS without CRS, tocilizumab treatment is not recommended because it may lead to increased IL-6 concentrations and induce severe ICANS
.

Foreign studies have reported that the use of IL-6 antibody siltuximab (siltuximab) at 11 mg/kg each time can directly bind to IL-6 without causing an increase in the concentration of IL-6 in peripheral blood or CSF
.

4 Anti-epileptic therapy For patients receiving CAR-T cell therapy, especially those with a history of epileptic seizures, tumors involving the central nervous system, or abnormal brain MRI and EEG, CAR-T cell therapy can be initiated when CAR-T cell therapy is initiated.
Levetiracetam 750 mg orally every 12 hours is routinely used to prevent epilepsy
.

If epileptic seizures occur, classic antiepileptic drugs (carbamazepine, sodium valproate, phenytoin, etc.
) can be used orally, or new antiepileptic drugs (lamotrigine, gabapentin, levetiracetam, orca) can be used.
zepine and topiramate, etc.
)
.

For convulsive status epilepticus, the first choice for initial treatment is intravenous diazepam 10 mg, which can be repeated once within 10 to 20 minutes as appropriate, or intramuscular injection of 10 mg midazolam
.

If the treatment effect is not good, sodium valproate 15~45 mg/kg (<6 mg·kg⁻¹·h⁻¹) can be injected intravenously for 5 minutes, followed by 1~2 mg·kg⁻¹·h ⁻¹ Intravenous pump
.

If intractable status epilepticus occurs, intravenous infusion of anesthetics (propofol, pentobarbital, thiopental, and midazolam, etc.
) can be selected
.

For non-convulsive status epilepticus, diazepam 10 mg is usually given intravenously.
If status epilepticus is not terminated after 10 minutes of treatment, the same dose can be repeated once
.

If the attack is not controlled, intravenous sodium valproate is administered
.

If the epileptic seizure lasts for more than 60 minutes, it is recommended to start the application of anesthetic drugs, including propofol, pentobarbital, thiopental sodium, and midazolam
.

During antiepileptic treatment, it is necessary to pay close attention to the patient's respiratory and circulatory system to prevent respiratory depression
.

5.
Intracranial pressure reduction treatment For patients with grade 1 or 2 papilledema, CSF pressure <20 mmHg (272 mmH₂O), and no cerebral edema: ① raise the head of the bed 30 degrees; ② control agitation and maintain intracranial pressure Stable; 3.
Shorten the time (<30 min) of the patient's chest physical care (intratracheal suction, vibration expectoration, postural drainage, percussion on the back) as much as possible to avoid further increase in intracranial pressure
.

For patients with grade 3-5 papilledema, with any signs of cerebral edema on imaging, or CSF pressure ≥20 mmHg (272 mmH₂O), active treatment should be given, including: (1) Hyperventilation, PaCO₂ maintained at 28-30 mmHg, no more than 24 hours
.

②Dehydration treatment: 20% mannitol is recommended first, the initial dose is 0.
25-1 g/kg; the maintenance dose is 0.
25-0.
5 g/kg every 3-6 hours, and electrolytes, internal environment, volume status and plasma are monitored every 6 hours.
The treatment goal is generally to maintain the plasma osmotic pressure at 300-320 mOsm/L.
For elderly patients and patients with easily impaired renal function, the treatment goal can be 290-300 mOsm/L
.

Dehydration treatment can also consider the use of hypertonic saline (recommended 3%), the recommended initial dose of 3% hypertonic saline is 250 ml, the maintenance dose is 50 to 75 ml per hour, and electrolytes are monitored every 4 hours, if serum sodium levels ≥ 155 mmol/L, hypertonic saline was discontinued
.

Furosemide combined with mannitol can help improve the efficacy of lowering intracranial pressure and can be used for patients with poor efficacy of mannitol alone
.

In case of renal insufficiency, glycerol fructose can also be used, but glycerol fructose has the phenomenon of short-term intracranial pressure rebound, so caution should be used when using it
.

During dehydration treatment, the vital signs of patients should be closely monitored to prevent renal failure, electrolyte imbalance, hypovolemia and hypotension, and the recurrence of cerebral edema should be guarded against
.

③ If the ommaya capsule is installed, the CSF can be directly extracted until the CSF pressure is <20 mmHg (272 mmH₂O)
.

④If the above treatment effect is not good, please ask a neurosurgeon to evaluate whether surgical treatment is feasible
.

Prognosis Generally, ICANS has a good prognosis, but a small number of patients may progress to severe cases such as acute cerebral edema
.

In the treatment of CD19-targeted CAR-T cells, the incidence of fatal nervous system toxicity is about 3%, which cannot be ignored
.

In conclusion, the current treatment methods for ICANS are limited, and early diagnosis and early prevention are important means of managing ICANS
.

This article is excerpted from the Leukemia and Lymphoma Group of the Hematology Branch of the Chinese Medical Association, and the Hematopoietic Stem Cell Transplantation and Cellular Immunotherapy Group of the Hematology and Oncology Professional Committee of the Chinese Anti-Cancer Association.
Chinese expert consensus on the management of nervous system side effects related to chimeric antigen receptor T cell therapy (2022 edition) [J] .
Chinese Journal of Hematology, 2022, 43(2) : 96-101.
DOI: 10.
3760/cma.
j.
issn.
0253-2727.
2022.
02.
002.
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