Background
CRS grading
Penn grading scale | CTCAE v4.0 | 2014 Lee et al. | MDACC | |
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Grade 1 | Mild reaction: treated with supportive care such as antipyretics and antiemetics | Mild reaction; infusion interruption not indicated; intervention not indicated | Symptoms are not life-threatening and require symptomatic treatment only, e.g., fever, nausea, fatigue, headache, myalgias, and malaise | Temperature ≥ 38 °C (fever) or grade 1 organ toxicity |
Grade 2 | Moderate reaction: some signs of organ dysfunction (e.g., grade 2 creatinine or grade 3 LFTs) related to CRS and not attributable to any other condition. Hospitalization for management of CRS-related symptoms, including fevers with associated neutropenia and need for IV therapies (not including fluid resuscitation for hypotension) | Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated for ≤ 24 h | Symptoms require and respond to moderate intervention. Oxygen requirement < 40% or hypotension responsive to fluids or low-dose pressors or grade 2 organ toxicity | Systolic blood pressure < 90 mmHg (hypotension) but responds to IV fluids or low-dose vasopressors or needing oxygen(FiO2 < 40%) for SaO2 > 90% (hypoxia) or grade 2 organ toxicity |
Grade 3 | More severe reaction: hospitalization required for management of symptoms related to organ dysfunction, including grade 4 LFTs or grade 3 creatinine related to CRS and not attributable to any other conditions; this excludes management of fever or myalgias; includes hypotension treated with IV fluids (defined as multiple fluid boluses for blood pressure support) or low-dose vasopressors, coagulopathy requiring fresh frozen plasma or cryoprecipitate or fibrinogen concentrate, and hypoxia requiring supplemental oxygen (nasal cannula oxygen, high-flow oxygen, CPAP, or BiPAP). Patients admitted for management of suspected infection due to fevers and/or neutropenia may have grade 2 CRS | Prolonged reaction (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates) | Symptoms require and respond to aggressive intervention. Oxygen requirement ≥ 40% or hypotension requiring high-dose or multiple pressors or grade 3 organ toxicity or grade 4 transaminitis | Systolic blood pressure < 90 mmHg (hypotension) and needs high-dose or multiple vasopressors or needing oxygen(FiO2 ≥ 40%) for SaO2 > 90% (hypoxia) or grade 3 organ toxicity or grade 4 transaminitis |
Grade 4 | Life-threatening complications such as hypotension requiring high-dose vasopressors and a hypoxia requiring mechanical ventilation | Life-threatening consequences; pressor or ventilator support indicated | Life-threatening symptoms. Requirements for ventilator support or grade 4 oxygen toxicity (excluding transaminitis) | Life-threatening hypotension or needing ventilator support or grade 4 oxygen toxicity (excluding transaminitis) |
CRS modeling
Establishment of CRS mouse models
Macrophages and monocytes are mediators of CRS
IL-1 is the primary cytokine for CRS and CRES
Hypotension associated with CRS is induced by nitrogen oxide (NO)
Blocking CRS does not reduce CAR T functions
IL-1 mediates both CRS and CRES
New approach for clinical management of CRS and CRES
NCT no. | Trials | Conditions | Interventions | Locations |
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03533101 | Tocilizumab for Cytokine Release Syndrome Prophylaxis in Haploidentical Transplantation | •Cytokine release syndrome •Stem cell transplant complications | •Drug: tocilizumab | •Hospital Universitario Dr. Jose E Gonzalez UANL, Monterrey, Nuevo Leon, Mexico |
03275493 | Humanized CD19 CAR-T Cells With CRS Suppression Technology for r/r CD19+ Acute Lymphoblastic Leukemia | •Acute lymphoblastic leukemia •CD19 positive •Relapse •Refractory | •Biological: humanized CD19 CAR-T cells •Biological: humanized CD19 CAR-T cells with CRS suppression technology | •The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China |
02906371 | Study of the Tocilizumab Optimization Timing for CART19 Associated Cytokine Release Syndrome | •Lymphoblastic leukemia, acute, childhood | •Drug: tocilizumab •Biological: CART 19 | •Children’s Hospital of Philadelphia, Philadelphia, PA, USA |