Cytokine release syndrome (CRS)

Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever
and multiple organ dysfunction that is associated with chimeric antigen receptor (CAR)-T cell
therapy, therapeutic antibodies, and haploidentical allogeneic transplantation. Immune effector cell-
associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome that can occur in some
patients who are treated with immunotherapy and may or may not accompany CRS.

CRS occurs in patients treated with various types of immunotherapy or haploidentical allogeneic
hematopoietic cell transplantation (HCT).

Treatments that can cause CRS include: ● Chimeric antigen receptor (CAR)-T cell therapy –
Significant CRS occurs in one-quarter to one-half of patients treated with CAR-T cell therapy for
relapsed/refractory acute lymphoblastic leukemia/lymphoma (ALL/LBL), but less severe
manifestations are present in nearly all such patients [1]. The incidence is lower in patients treated
with CAR-T therapy for non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and
multiple myeloma (MM) ● Bispecific antibody therapy (eg, blinatumomab) – CRS is less common
after treatment with blinatumomab and generally only occurs with the first treatment.
●Haploidentical HCT –significant CRS was reported in 12 percent, but a milder CRS was reported in
75 percent ● Other immune therapies –infrequently following treatment with anti-thymocyte
globulin (ATG) and conventional monoclonal antibodies, including rituximab, obinutuzumab,
alemtuzumab, brentuximab, nivolumab, and others● Severe infections – A CRS-like syndrome
("cytokine storm") can develop in association with a severe viral infection, including COVID-19 or
influenza

CRS occurs most often following targeted cellular immunotherapy for B cell ALL/LBL, NHL, CLL, and
MM. CRS is less common following immunotherapy with bispecific antibodies and in the treatment
of solid tumors. CRS-like syndrome in association with viral infection or treatment with nonprotein-
based drugs, such as oxaliplatin and lenalidomide, should be referred to as cytokine storm rather
than CRS, per se

CRS is a supraphysiologic response to immune therapy that activates or engages T cells and/or other
immune effector cells. The systemic reaction is associated with increased levels of inflammatory
cytokines and activation of T lymphocytes, macrophages, and endothelial cells. However, the
contributions of the individual cellular components and cytokines to the cause and severity of CRS
are not well defined.

CRS severity has been associated with the disease burden (antigen load) of acute lymphoblastic
leukemia/lymphoma in patients treated with chimeric antigen receptor (CAR)-T cell therapy . The
dose of CAR-T cells may also affect the severity of CRS, but a dose-toxicity relationship is not well
defined within the dose ranges that are currently used; this may be because the infusion dose does
not accurately predict the final expansion and persistence of the CAR-T lymphocytes . Other
contributing factors include the molecular design of the CAR (eg, CD28 versus 4-1BB as the
costimulatory domain), the nature and intensity of lymphodepletion prior to cell infusion, and the
degree of T cell activation and overall condition ("fitness") of the cellular product . CRS can develop
in the absence of tumor if the target antigen is expressed on normal cells, as in the severe CRS that
occurred in healthy volunteers after treatment with a CD28 superagonist (TGN1412). For
haploidentical hematopoietic cell transplantation, the source of the graft (ie, peripheral blood versus
bone marrow) may influence the risk of CRS,
Cytokines contribute importantly to the pathophysiology and clinical manifestations of CRS . In the
setting of T cell-engaging immunotherapies, CRS is triggered by release of interferon gamma (IFN-g)
by activated T cells or tumor cells. IFN-g activates macrophages, which produce excessive interleukin
(IL)-6, tumor necrosis factor alpha (TNF-a), and IL-10. IL-6 binds to the soluble form of the IL-6
receptor (IL-6R) that has been cleaved from the cell surface by metalloproteinases, and the IL-6/IL-
6R complex binds to gp130 and activates cell types that ordinarily do not express membrane-bound
IL-6R. IL-1, IL-5, IL-8, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are also
consistently elevated in CRS and may also contribute to the pathophysiology of CRS.

Cytokines are thought to contribute to many of the clinical manifestations of CRS . Examples include
IL-6, which is associated with vascular leakage, activation of the complement and coagulation
cascades, disseminated intravascular coagulation (DIC), and cardiomyopathy; IFN-g, which is
associated with fever, chills, headache, dizziness, and fatigue; and TNF-a, which can cause flu-like
symptoms with fever, malaise, watery diarrhea, vascular leakage, cardiomyopathy, lung injury, and
production of acute phase proteins. The pathophysiologic centrality of IL-6 to CRS is indicated by the
often rapid abrogation of the syndrome by interruption of IL-6 signaling with the IL-6R antagonist,
tocilizumab. Various cell types contribute to CRS. T cell activation is an essential component of CRS,
monocyte/macrophages amplify and expand the repertoire of cytokines and the inflammatory
response, and endothelial cells contribute to capillary leakage, hypertension, and coagulopathy

Time course — The onset and duration of CRS is variable and depends on the cause of the syndrome.

CRS typically begins within 1 to 14 days (median, 2 to 3 days) after chimeric antigen receptor (CAR)-T
cell therapy, within 1 to 3 days after haploidentical hematopoietic cell transplantation (HCT), and
may occur within minutes to hours after infusion of conventional therapeutic or bispecific
antibodies. More severe manifestations typically present earlier. The duration of CRS is variable, but
it typically resolves within a few days to two to three weeks after CAR-T infusion and within days
after other causes

Clinical manifestations — Clinical manifestations of CRS can range from mild, flu-like symptoms to a
severe life-threatening systemic inflammatory response syndrome (SIRS).

By definition, fever must be present at the onset of CRS. With mild CRS, fever may be accompanied
by fatigue, headache, rash, diarrhea, arthralgia, and myalgia. The syndrome may progress with fever
to 40.5°C (105°F) or higher. In more severe CRS, patients may have hypotension and uncontrolled
SIRS with circulatory collapse, vascular leakage, peripheral and/or pulmonary edema, renal failure,
cardiac dysfunction, and multiorgan system failure.

Neuropsychiatric findings may develop, including aphasia, altered level of consciousness, impaired
cognitive skills, motor weakness, seizures, and cerebral edema . In most cases, neurologic toxicity
occurs two to four days after the onset of severe CRS, may be progressive, and can occur after the
resolution of CRS symptoms. Neurologic toxicity associated with immunotherapy is referred to as
immune effector cell-associated neurotoxicity syndrome (ICANS) or cytokine release encephalopathy
syndrome (CRES).

Laboratory — Laboratory findings reflect the systemic inflammatory response, but the abnormalities
are highly variable and are influenced by the type of immune therapy, status of the underlying
malignancy, and aspects of management. Leukocytosis may be present as a response to the systemic
inflammatory response and/or in association with prior use of steroids. Conversely, there may be
leukopenia, neutropenia, or thrombocytopenia as a result of lymphodepleting chemotherapy, the
underlying malignancy, and/or subsequent treatment. Abnormalities of renal or liver function tests
are common.

Nonspecific markers of inflammation (eg, C-reactive protein [CRP], ferritin) are universally elevated
in CRS; when measured, inflammatory cytokines (eg, interferon gamma, interleukin [IL]-6, IL-10,
soluble IL-2R alpha) are also elevated . In general, the degree of elevation of cytokines and markers
of inflammation correlate with the severity of the clinical syndrome. Dramatic elevation of IL-6 is a
supportive finding for the diagnosis of CRS. Importantly, CRP is not specific for CRS and changes in
CRP may lag behind clinical changes by ≥12 hours. CRP generally falls quickly after administration of
tocilizumab and is not a reliable biomarker in that setting.

Laboratory findings may also reflect manifestations of tumor lysis syndrome (eg, hyperuricemia,
hyperkalemia, hyperphosphatemia, hypocalcemia) and/or macrophage activation syndrome

The evaluation should promptly establish the presence and severity of CRS and identify other
conditions that may contribute to the clinical presentation. The evaluation of suspected CRS includes
history, physical examination, laboratory tests, and imaging. Other studies may also be required,
depending on the nature and severity of the clinical presentation. The history should report the
nature and time course of CRS-associated clinical findings, including fever, dyspnea, fatigue,
headache, confusion, rash, arthralgia, myalgias, and baseline neurologic function. The underlying
malignancy, disease status (eg, remission, relapse, treatment-refractory), and disease burden should
be noted. The type, dose, and schedule of immunotherapy and use of any preventive measures (eg,
steroids) must be documented Physical examination should document blood pressure, temperature,
and examination of the skin, heart, and lungs to assess manifestations of the systemic inflammatory
reaction syndrome. A neurologic examination should document anxiety, tremor, aphasia, delirium,
or other findings that may be related to an associated immune effector cell-associated neurotoxicity
syndrome (ICANS) or can be manifestations of the systemic inflammatory response.

It is critically important to exclude potential infections during the initial evaluation, because patients
are typically immunosuppressed or neutropenic from lymphodepleting chemotherapy. Neutropenic
patients should be empirically treated with broad-spectrum antibiotic coverage while cultures are
pending,

Laboratory studies should include:CBC) with differential count,(PT), PTT), fibrinogen, fibrin D-dimer,
Serum electrolytes, kidney and liver function, uric acid, lactate, lactate dehydrogenase (LDH)●
Markers of inflammation – C-reactive protein (CRP), ferritin; cytokines (eg, interferon gamma,
interleukin 6), Chest radiograph● Cardiac evaluation to evaluate dyspnea, edema, or hypotension
due to reduced cardiac output or excess fluid accumulation. brain natriuretic peptide (BNP),
electrocardiogram (EKG), echocardiogram, and/or cardiac telemetry ● Computed tomography (CT).
● Bronchoscopy/bronchoalveolar lavage (BAL) can be helpful for evaluation of a pulmonary infection
or hemorrhage but is generally reserved for patients who require intubation. BAL can usually be
performed safely even in a patient with thrombocytopenia and/or coagulopathy. When possible, the
area of lung with the greatest degree of radiographic abnormalities should be lavaged

CRS should be suspected in a patient with fever, which may be accompanied by tachypnea,
tachycardia, hypotension, hypoxia, or other findings after receiving immune therapy. CRS is most
commonly seen after treatment with antigen-specific chimeric antigen receptor (CAR)-T cell therapy,
but it also occurs following treatment with a therapeutic antibody (eg, blinatumomab) and after
haploidentical allogeneic hematopoietic cell transplantation. A high index of suspicion is necessary
The diagnosis of CRS requires fever (≥38.0°C), with or without variable degrees of hypotension,
hypoxia, and/or other end-organ dysfunction that develops hours to days after treatment with
immune therapy .The temporal relationship to the triggering immune therapy is important for
establishing the diagnosis of CRS.

DIFFERENTIAL DIAGNOSIS

CRS is manifest as an initial fever and a constellation of nonspecific clinical findings that may also be
caused by infection/sepsis, disease progression, heart failure, pulmonary thromboembolism,
hemophagocytic lymphohistiocytosis/macrophage activation syndrome, or other processes.

Sepsis — Infection/sepsis can present with fever, hypotension, respiratory distress, and/or
radiographic pulmonary opacities. Infections cannot be definitively distinguished from CRS based on
routine initial laboratory testing and chest radiography. The evaluation for infection should include
peripheral blood cultures and other studies that are informed by the clinical presentation, such as
stains and cultures of sputum; nasal swab for viral polymerase chain reaction; other serum and urine
tests for bacterial, fungal, and viral infections; and/or other specialized studies (eg, flexible
bronchoscopy with bronchoalveolar lavage). Empiric antibiotic therapy is often initiated while results
of laboratory studies are processed.

Tumor progression — Progression of the underlying malignancy may cause tumor-associated fever
and other clinical, metabolic, and imaging abnormalities that resemble those of CRS. Tumor lysis
syndrome (TLS) is an oncologic emergency with metabolic disorders (eg, release of potassium,
phosphate, uric acid) and renal dysfunction that may be caused by rapid tumor growth or treatment
with lymphodepleting therapy. TLS may also result from a response to treatment with chimeric
antigen receptor (CAR)-T cell therapy or a therapeutic antibody. Tumor progression is documented
by progressive changes in blood counts, bone marrow examination, or tumor masses.

Heart failure — Heart failure can be a consequence of the systemic inflammatory syndrome of CRS
or it may be caused by other conditions (eg, anthracycline-associated cardiomyopathy, ischemic
heart disease, myocarditis, pericardial effusion). Clinical evaluation, measurement of brain
natriuretic peptide (BNP), echocardiography, and/or computed tomography (CT)

Thromboembolism — Clinical features of pulmonary embolism (PE)/deep vein thrombosis (DVT),

such as dyspnea, hypoxia, hypotension, peripheral edema, leg swelling, or hemoptysis may resemble
CRS. PE should be suspected in patients with evidence of DVT affecting an extremity or central
venous catheter, and in patients with hypoxemia that is out of proportion to the extent of
radiographic opacities.

Allergic reaction — Allergic reactions including severe drug reactions can cause fever, rash, capillary
leak, and dyspnea. Evaluation of the patient suspected of a severe drug allergy, such as drug reaction
with eosinophilia and systemic symptoms (DRESS),

Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) — HLH and

MAS share many clinical and laboratory features with CRS. Both CRS and HLH/MAS have activation
of macrophages and the reticuloendothelial system that is initiated by T cell-mediated inflammation.
Indeed, most patients with moderate to severe CRS have laboratory features that meet criteria for
HLH/MAS, although patients with CRS may or may not have hepatosplenomegaly,
lymphadenopathy, or evidence of hemophagocytosis. We consider that the clinical findings that
occur after immune therapy should be designated CRS, rather than HLH/MAS.

ASTCT Consensus Grading for CRS:

● Grade 1 – Temperature ≥38°C (see note below) and no hypotension and no hypoxia. Patients may
have malaise, myalgias, or arthralgias, but the severity of these constitutional symptoms does not
affect the grade of CRS.
●Grade 2 – Temperature ≥38°C plus hypotension that does not require vasopressors and/or hypoxia
that requires low-flow nasal cannula (≤6 L/minute or blow-by oxygenation
●Grade 3 – Temperature ≥38°C plus hypotension that requires one vasopressor (with or without
vasopressin) and/or hypoxia requiring high-flow nasal cannula (≥6 L/minute), facemask, non-
rebreather mask, or Venturi mask that is not attributable to any other cause.
● Grade 4 – Temperature ≥38°C plus hypotension that requires multiple vasopressors (excluding
vasopressin) and/or hypoxia requiring positive pressure (eg, continuous positive airway pressure
[CPAP], bilevel positive airway pressure [BiPAP], intubation and mechanical ventilation).

The following should be noted with regard to grading CRS ●Fever must not be attributable to any
other cause. In patients who have CRS and then receive antipyretic or anticytokine therapy (eg,
tocilizumab, steroids), fever is no longer required to grade subsequent CRS toxicity; in such a case,
CRS grading is driven by the management of hypotension and/or hypoxia.●CRS grade is determined
by the more severe event (ie, hypotension or hypoxia).●Hypotension is not graded based on use of
vasopressin alone, if vasopressin is not being used in response to worsening hypotension. Some
critical care practitioners administer vasopressin simultaneously with other vasopressors to
capitalize on its vasoconstrictive effects, mitigate capillary leak, or minimize norepinephrine dose
requirements; such use of vasopressin is not considered to be in response to escalating toxicity. Also,
the use of the inotrope milrinone, which may be used to aid in cardiac contractility, does not affect
the grade of CRS.● Hypoxia is defined by a requirement for supplemental oxygen to correct a deficit
in oxygenation rather than a specific level of oxygen saturation.●Intubation of a patient for reasons
other than hypoxia (eg, airway protection or to enable a procedure), alone, is not a criterion for
grade 4 CRS.

Grading for other causes of CRS — CRS caused by other types of immune intervention (eg, bispecific
antibodies, haploidentical allogeneic transplantation) should be graded according to the NCI CTCAE
v5.0 as follows:●Grade 1 – Fever, with or without constitutional symptoms.●Grade 2 – Hypotension
responding to fluids. Hypoxia responding to <40 percent FiO2.●Grade 3 – Hypotension managed
with one pressor. Hypoxia requiring ≥40 percent FiO2.●Grade 4 – Life-threatening consequences;
urgent intervention needed.

Key principles — The following principles are important for management of CRS:●Grading differs
according to cause of CRS – The grading systems to assess the severity of CRS differ according to the
cause of the syndrome (ie, the type of immunotherapy). ●Management of severe CRS depends on
the cause – Management of severe CRS varies according to the type of immunotherapy that was
administered, For chimeric antigen receptor (CAR)-T cell therapy, details of management depend on
the specific agent

Control CRS without extinguishing the immunotherapeutic benefit – The goal of management is to
prevent life-threatening toxicity from the CRS while sustaining the antitumor effects of the
immunotherapy, if possible. It is generally not necessary to extinguish all evidence of CRS, as this
may adversely affect the clinical outcome of the underlying cancer. As an example, high dose
steroids may deplete or even eradicate CAR-T cells and abrogate their clinical benefit; in that setting,
alternative approaches may be preferred.
●Concurrent disorders – CRS may be present along with other serious medical conditions (eg,
infection/sepsis, tumor progression, heart failure). It is important to promptly diagnose both CRS
and coexisting disorders to provide timely, specific, and life-saving treatment.

Mild CRS — The definition of mild CRS, which generally refers to fever with or without mild
associated findings, depends on the specific causal agent and the grading system that is used to
score its toxicity, as described above. Regardless of the underlying cause of mild CRS, we suggest
symptomatic treatment with antihistamines, antipyretics, intravenous fluids, and close monitoring.
For patients with mild CRS, the balance of benefit and toxicity with symptomatic treatment is more
favorable than with high dose steroids, tocilizumab, or interruption of the infusion.

For patients who have mild CAR-T cell-associated CRS, suggestions for symptomatic treatment vary
with the individual CAR-T product. For patients with mild CRS that progresses or deteriorates while
receiving symptomatic treatment, we suggest treatment for severe CRS, according to the
precipitating cause

CAR-T cell-associated CRS — For CAR-T cell-associated CRS, we consider severe CRS to include
patients with grades 3 and 4 disease, and some patients with grade 2. Grading of CAR-T cell-
associated CRS is based on the interventions that are required to manage the patient rather than
specific laboratory values; as a result, there is some overlap between grades 2 and 3. Whether a
patient with grade 2 CRS has severe disease versus milder disease should be judged on a case-by-
case basis. For severe CRS (grades 3 and 4) caused by CAR-T cell therapy, we suggest initial
treatment with tocilizumab plus a corticosteroid rather than either agent alone. Treatment with
tocilizumab plus a steroid appears to achieve more rapid and complete control of CRS than either
agent alone, and use of the suggested doses and duration of therapy provide an acceptable balance
of control of CRS manifestations versus toxicity.

Some experts favor initial treatment of less severe CAR-T cell-associated CRS (eg, grade 2) with
tocilizumab alone because of concern that steroids might deplete or eradicate the infused CAR-T
cells. At present, the risk of depleting CAR-T cells and abrogating the clinical benefit is unproven, and
we consider that treatment with the doses and brief duration of corticosteroid treatment that are
suggested generally add benefit without undue depletion of the cells.

Tocilizumab should be administered intravenously over one hour as follows [39]:●For patients <30
kg – Tocilizumab 12 mg/kg●For patients ≥30 kg – Tocilizumab 8 mg/kg; the total tocilizumab dose
should not exceed 800 mg

Steroid therapy should be administered concurrently. We suggest treatment with hydrocortisone

100 mg every eight hours, dexamethasone 10 mg up to four times daily, or methylprednisolone 1
mg/kg/day until there is improvement in CRS.
If there is no clinical improvement in oxygenation, hypotension, fever, and other manifestations of
CRS after the first dose of tocilizumab, it may be repeated after an interval of at least eight hours.
Tocilizumab treatment should not exceed four doses in total [39].

Importantly, for patients who have delirium or other neurologic findings consistent with ICANS
without active CRS, initial treatment with steroids is preferred, as tocilizumab does not appear to be
effective for the neurologic syndrome.

Antibody-associated CRS — Severe CRS caused by blinatumomab or other therapeutic antibodies,

refers to grades 3 and 4 .For severe antibody-associated CRS, we suggest interrupting the infusion
plus treating with a corticosteroid rather than either approach alone. This offers a favorable balance
of rapid improvement and acceptable toxicity, whereas continuing the infusion risks further
worsening of the syndrome. There are only limited data, but tocilizumab appears to be less effective
than steroids in this setting. We suggest the following for blinatumomab-associated CRS Grade 4 –
Discontinue blinatumomab permanently. Administer dexamethasone 8 mg (or 5 mg/m2 if <45 kg;
maximum: 8 mg) intravenously or orally every eight hours for up to three days, then taper over four
days.●Grade 3 – Interrupt blinatumomab therapy. Administer dexamethasone 8 mg (or 5 mg/m2 if
<45 kg; maximum: 8 mg) intravenously or orally every eight hours for up to three days, then taper
over four days. Upon resolution, resume blinatumomab dosing at 9 mcg daily (or 5 mcg/m2/day if
<45 kg). Increase dose to 28 mcg daily (or 15 mcg/m2/day if <45 kg) after seven days if toxicity does
not recur.

The clinical and laboratory status should be reassessed regularly to determine if the response is
adequate. As an example, we treat with the steroid regimen until vasopressors and high-flow oxygen
are no longer needed, and then taper the steroids over several days as guided by the clinical
response. If there is no clinical improvement in oxygenation, hypotension, fever, and other CRS
manifestations within 24 to 72 hours, we suggest management for persistent or worsening CRS
CRS generally occurs only with the initial dose of blinatumomab. Blinatumomab can usually be
resumed with dose adjustment

Haploidentical HCT-associated — Severe CRS caused by haploidentical allogeneic hematopoietic cell

transplantation (HCT) refers to grades 3 and 4 For severe CRS associated with haploidentical HCT,
we suggest treatment with a corticosteroid, based on a favorable balance of benefit and toxicity and
widespread experience with steroids in this setting

MONITORING AND RESOLUTION We consider that CRS has resolved when there is sustained
resolution of fever and there is no longer a need for oxygen supplementation to relieve hypoxia nor
vasopressors to maintain blood pressure. It is important to note that normalization of temperature
alone does not define resolution of CRS, because treatments for CRS (eg, tocilizumab, steroids,
antipyretics) may lead to rapid resolution of fever while other severe manifestations of CRS including
hypotension or hypoxia persist.

Monitoring should reflect the severity of illness:● Patients with severe CRS and some cases of grade
2 CRS may require management in an intensive care setting. As the patient improves, the intensity of
the monitoring and setting can decrease, but the patient should not be discharged from the hospital
until clinically stable. Laboratory tests should be used to monitor the patient's hematologic,
coagulation, metabolic, and oxygenation status. However, it is important to note that C-reactive
protein (CRP) cannot be used as an indicator of the severity of inflammation after treatment with
tocilizumab, because blockade of the interleukin 6 signaling pathway rapidly decreases the level of
CRP.

PERSISTENT OR WORSENING CRS

For a patient with a persistent or worsening clinical condition after initial treatment of CRS, we
suggest re-evaluation for other contributing conditions. It is particularly important to reassess the
patient for coexisting infectious, cardiac, thromboembolic, and other complications. For patients
who do not improve within 8 to 24 hours after initial treatment, subsequent management is
informed by the severity of the patient's clinical condition and the treatment that was initially
administered. ●For all patients who were previously treated with a single dose of tocilizumab, we
suggest repeating the same dose of tocilizumab ≥8 hours later (up to a total of four doses) and
adding a corticosteroid The number of tocilizumab treatments needed to control severe CRS may
vary with the causative immune therapy. In the authors' experience, the optimal clinical response
may require one or rarely two doses of tocilizumab for patients treated with tisagenlecleucel, but up
to three to four doses for patients treated with axicabtagene ciloleucel.●For patients with
persistent, severe CRS of any cause, who were previously treated with steroids alone, we suggest
adding tocilizumab● For patients with severe CRS (generally grade 3 to 4) who fail to improve after
repetitive treatment with both tocilizumab and steroids, we generally add a high dose corticosteroid
(eg, solumedrol 2 mg/kg up to 1 gram daily for three days), recognizing that this may ablate the CAR-
T cells in the setting of unacceptable toxicity. There is very limited experience with other agents, but
options include the following •Monoclonal antibodies against interleukin (IL)-6 (eg, siltuximab,
clazakizumab); however, the benefit from these agents after treatment with tocilizumab (which
directed against the IL-6 receptor) is unproven.•Anakinra (blockade of IL-1RA).Etanercept (blockade
of TNF alpha).•Other possible treatments for persistent or worsening CRS include alemtuzumab,
anti-thymocyte globulin (ATG), cyclophosphamide, ruxolitinib, or ibrutinib.

In considering prevention strategies, it should be recognized that blinatumomab is an off-the-shelf

medication that can be stopped and restarted with dose adjustments, if needed, in response to
toxicity. In contrast, chimeric antigen receptor (CAR)-T cell therapy is a uniquely manufactured
"living" drug that expands several-fold in vivo after infusion, and certain prevention strategies (eg,
steroids) may interfere with expansion of the CAR-T cell clones and adversely impact the clinical
benefit. Approaches that may lessen the incidence and/or severity of CRS include:●CAR-T cells –
Because disease (antigen) burden is a risk factor, especially with acute lymphoblastic
leukemia/lymphoblastic lymphoma, tumor debulking may reduce the incidence of CRS. Debulking
chemotherapy or reducing the CAR-T cell dose may lessen the frequency and/or severity of CRS .
Treatment with tocilizumab (eg, on day +1) or early intervention (eg, at time of first fever or early
cytokine profiles) has been suggested, but this is unproven and it remains possible that early
blocking of IL-6 will interrupt the cytokine feedback loop that is part of enhanced T cell proliferation
However, early intervention with tocilizumab may be associated with increased risk of neurologic
toxicity. ●Blinatumomab – The initial dose of blinatumomab can be reduced to 9 mg/day, with
subsequent doses adjusted based on presence and severity of CRS [45]. Other approaches include
pretreatment cytoreduction with cyclophosphamide and/or dexamethasone.

ICANS (NEUROLOGIC SYNDROME)

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome that

occurs in patients treated with immunotherapy (eg, CAR-T and blinatumomab). ICANS has also been
called cytokine release encephalopathy syndrome (CRES). Clinical findings can be progressive and
may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness,
seizures, and cerebral edema [36]. ICANS may occur independently of CRS. In most cases, neurologic
toxicity occurs two to four days after the onset of CRS and may occur after the resolution of CRS
symptoms. Both syndromes may be considered as overlapping off-target toxicities that result from
excessive immune activation.The median onset of neurologic events with ICANS is four to five days
after CAR-T infusion. In general, mild clinical findings are self-limited and resolve within days,
whereas more severe symptoms may require four or more weeks to resolve and can result in death .
The tempo of progression to severe neurotoxicity may be hours or days. The severity of
neurotoxicity is roughly correlated with severity of CRS, and both are correlated with enhanced
expansion of CAR-T cells Treatment of ICANS varies with the severity of the presentation.In general,
a patient with grade 1 ICANS may be drowsy but can awaken spontaneously and when prompted.
The patient may exhibit a delay in response, disorientation to time or place, mild inattention,
difficulty counting numbers backward, or impaired handwriting. More severe neurologic findings (eg,
expressive aphasia, depressed level of consciousness, seizures, stupor, coma) are considered at least
grade 2 and warrant immediate treatment. The mainstay of treatment for ICANS is steroids, as
described above. We suggest treatment for all patients with grade ≥2 ICANS.