Cytokine release syndrome, or CRS, and immune effector cell-associated neurotoxicity syndrome, or ICANS, are distinct toxicity syndromes following immune effector cell therapies such as CAR-T cell therapies. Both can occur in temporal association with one another, but they are assessed according to different criteria. CRS is graded based on fever, hypotension, and hypoxia, while ICANS incorporates neurological function and findings.<\/p>\n
CRS arises from rapid cytokine release by cells involved in immune responses. It frequently begins with fever and may be accompanied by malaise, headache, chills, or fatigue. In more severe cases, hypotension, hypoxia, and signs of cardiorespiratory organ dysfunction become predominant. Clinical assessment must consider infectious causes, tumor lysis, and the course of the underlying disease as differential diagnoses.<\/p>\n
ASTCT-based CRS grading bases the classification on fever as well as the support required for hypotension or hypoxia. Laboratory values alone neither confirm nor rule out the diagnosis. After treatment with antipyretics or anti-cytokine therapy, fever is no longer required for subsequent grading; hypotension and hypoxia then determine the grade.<\/p>\n
ICANS refers to a neurological toxicity associated with immune effector cells. The ICE score comprises ten points covering orientation, naming, following simple commands, writing, and attention. For overall grading, in addition to this test, level of consciousness, seizures, motor findings, and elevated intracranial pressure or cerebral edema are assessed.<\/p>\n
The ICANS grade corresponds to the most severe event that cannot be better explained by another cause. ICANS is explicitly not understood as a toxicity directly mediated by CAR-T cells. A low ICE score therefore does not describe the full neurological picture; a seizure or severe impairment of consciousness can determine the classification independently of individual test items.<\/p>\n
CRS and ICANS are not different names for the same side effect. CRS grading looks at fever, circulatory support, and oxygen support. ICANS uses the ICE score and neurological criteria. Concurrent hypotension therefore does not automatically increase the ICANS grade, and impaired writing does not determine the CRS grade.<\/p>\n
The existing terms adverse event, serious adverse event, and toxicity describe overarching reporting or safety categories. CRS and ICANS, by contrast, denote clinical syndromes with their own assessment frameworks tailored to immune effector cell therapies. Grade assignment also does not replace the assessment of whether an event must be reported as serious under GCP.<\/p>\n
The two assessment pathways answer different clinical questions but can be documented along a shared timeline. For CRS, a change in oxygen requirement or circulatory support can determine the grade. For ICANS, the ICE test reveals changes in cognition, while a single severe neurological finding can dominate the overall severity grade. The EBMT\/EHA handbook notes that tremor and myoclonus associated with immune effector cell therapy can be graded according to CTCAE but are not factored into ICANS grading. This illustrates that a complete safety record may contain several classifications in parallel. The protocol requirements must specify, for each symptom, which assessment instrument it is assigned to.<\/p>\n
The ASTCT consensus effort aimed to harmonize definitions and grading across studies and clinical care. For CRS, the presence of fever is assessed while taking other causes into account; at higher grades, the type of circulatory or respiratory support required is decisive. For ICANS, assessment in adults is performed using the ICE score together with supplementary neurological criteria. This functional separation supports comparable reporting, even when both syndromes are observed in the same patient during the treatment period.<\/p>\n
A documented temperature, the exact timing of vasopressor administration, and the type of oxygen support are therefore just as informative for CRS as the recorded ICE score is for ICANS. A generic note such as “neurotoxicity” or “cytokine reaction” is not sufficient for retrospective grading.<\/p>\n
In CAR-T trials, vital signs, oxygen and vasopressor requirements, and neurological examinations must be available promptly and in a structured format. The eCRF design should separate ICE components, level of consciousness, seizure activity, and motor signs from the CRS parameters. Only this way can it be determined which finding triggered which grade and whether a change is due to treatment, disease course, or a documentation gap.<\/p>\n
Full-service CROs such as Mediconomics support the safety sections of the trial protocol, site training materials, and the design of syndrome-specific eCRFs. They coordinate medical monitoring, pharmacovigilance, and data management so that CRS and ICANS grades, differential diagnostics, interventions, and reporting pathways are documented separately and consistently over time for the safety analysis.<\/p>\n
What is the ICE score used for?<\/strong><\/p>\n The ICE score captures cognitive and language-related functions as part of the ICANS assessment. It alone is not sufficient, since level of consciousness, seizures, motor findings, and signs of elevated intracranial pressure are also taken into account.<\/p>\n Can CRS be diagnosed without laboratory values?<\/strong><\/p>\n CRS is a clinical diagnosis. Laboratory tests help monitor organ function and support differential diagnosis, but they do not establish the diagnosis on their own.<\/p>\n Do CRS and ICANS always occur simultaneously?<\/strong><\/p>\n No. ICANS can occur at the same time as CRS, shortly afterward, or later. The fact that they may coincide in time does not change the fact that both are assessed using separate scales.<\/p>\n Cytokine release syndrome, or CRS, and immune effector cell-associated neurotoxicity syndrome, or ICANS, are distinct toxicity syndromes following immune effector cell therapies such as CAR-T cell therapies. Both can occur in temporal association with one another, but they are assessed according to different criteria. CRS is graded based on fever, hypotension, and hypoxia, while ICANS […]<\/p>\n","protected":false},"author":10,"featured_media":0,"parent":0,"template":"","meta":{"_acf_changed":false,"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"glossary-cat":[30],"class_list":["post-8143","glossary","type-glossary","status-publish","hentry","glossary-cat-atmp-onkologie"],"acf":[],"related_terms":"","external_url":"","internal_reference_id":"","_links":{"self":[{"href":"https:\/\/mediconomics.com\/en\/wp-json\/wp\/v2\/glossary\/8143","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/mediconomics.com\/en\/wp-json\/wp\/v2\/glossary"}],"about":[{"href":"https:\/\/mediconomics.com\/en\/wp-json\/wp\/v2\/types\/glossary"}],"author":[{"embeddable":true,"href":"https:\/\/mediconomics.com\/en\/wp-json\/wp\/v2\/users\/10"}],"version-history":[{"count":0,"href":"https:\/\/mediconomics.com\/en\/wp-json\/wp\/v2\/glossary\/8143\/revisions"}],"wp:attachment":[{"href":"https:\/\/mediconomics.com\/en\/wp-json\/wp\/v2\/media?parent=8143"}],"wp:term":[{"taxonomy":"glossary-cat","embeddable":true,"href":"https:\/\/mediconomics.com\/en\/wp-json\/wp\/v2\/glossary-cat?post=8143"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}Regulatory References<\/h2>\n
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