CRS (Cytokine Release Syndrome) CRS is an exaggerated systemic inflammatory response triggered by treatments such as Bispecific Antibodies (BsAb), which activate T cells and cause the release of inflammatory cytokines.

CRS symptoms range from mild flu-like symptoms to severe multiorgan failure.

Symptoms: Fever, hypotension, hypoxia, tachycardia, organ dysfunction.

Physical Examination - Temperature, blood pressure, pulse oximetry or arterial blood gas (or mixed venous blood gas/O2 saturation), skin, heart, and lung examination

Laboratory Tests - Complete blood count with differential diagnosis; Coagulation (PT/PTT, fibrinogen, fibrin D-dimer); Chemistry (serum electrolytes, kidney and liver function, uric acid, lactate, LDH; C-reactive protein and ferritin (inflammation); Microbiological tests, especially in neutropenic patients (blood and urine cultures); cardiac markers are clinically indicated. Do not await laboratory results.

Laboratory findings: Cytopenias, elevated creatinine, elevated liver enzymes, irregular coagulation parameters, elevated C-Reactive Protein

• Management of CRS (see Management Section below) does not require laboratory testing and should not be delayed pending laboratory results.

Management by grade:

• Grade 1: Support only (antipyretic, fluid support, close monitoring).

• Grade 2: Low-dose oxygen, IV fluids, low-dose vasopressors if necessary. Tocilizumab may be initiated.

• Grade ≥3: High-dose oxygen, intensive care support, vasopressor requirement.

Medical Treatment:

• First choice: Tocilizumab (anti-IL-6 monoclonal antibody)

• If no response: Corticosteroids (e.g., dexamethasone, methylprednisolone) are added.

• Other support: Antibiotic prophylaxis/treatment, electrolyte balance, close monitoring of organ functions.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS):

Neurological toxicity caused by the inflammatory effects of cytokines released after BsAb treatment results in disruption of the blood-brain barrier and accumulation of inflammatory cytokines in the central nervous system.

ICANS is a diagnosis of exclusion after other possibilities have been excluded. Neurological toxicity develops after immune activation.

Flu-like symptoms: Fever (≥38.0°C/<100.4°F) (unattributable to another cause); nausea; fatigue; headache; rash; diarrhea, arthralgia, myalgia

Hypotension

Systemic inflammatory response syndrome (circulatory collapse; vascular leakage; peripheral and/or pulmonary edema; renal failure; cardiac dysfunction; multiorgan failure)

Respiratory symptoms: cough; tachypnea; hypoxia, ARDS

Rash and Urticaria (allergic reaction)

Low-grade CRS is common and high-grade is rare

Diagnosis:

• ICANS should be suspected if there are new or worsening neurological symptoms following recent immune effector cell (IEC) therapy, such as CAR-T cell therapy or BsAb therapy.

• Initial symptoms may be mild, such as loss of attention and/or slurred speech or tremors.

• Further evaluation to investigate other possible causes should include review of concomitant medications or recent use of CNS-active drugs (e.g., opiates, benzodiazepines). Investigation may include a head CT or brain MRI, and a lumbar puncture to investigate infectious causes.

Management: It may occur with or without CRS.

Treatment:

• Grade 1 (mild): Close neurological monitoring, supportive care.

• Grade ≥2: Corticosteroids (Dexamethasone or Methylprednisolone) are initiated.

• Tocilizumab is generally not effective for ICANS (because the IL-6 antibody does not cross the blood-brain barrier well).

• Seizure prophylaxis/treatment: Levetiracetam is preferred.

• Intensive care support in severe cases.