CAR-T Toxicity and Management

(Vortragsslides all 3 Presentations)

Cytokine release syndrome after CAR-T cells

Susana Rives, Pediatric Hematology, Hospital Sant Joan de Déu de Barcelona, Spain 

Cytokine release syndrome: 

Systemic inflammatory state Supraphysiological response to activation of Immune Effector Cells, activation of T lymphocytes, macrophages, and endothelial cells, inflammatory cytokines (IL-6, IL-1 and others).

CRS symptoms usually are progressive, Fever is the hallmark, frequent flu-like symptoms +/­Tachycardia, hypotension,
Capillary leak syndrome & organ dysfunction.

ASBMT Consensus* grading for CRS after Immune Effector Cells: ✓ Organ dysfunction not contemplated ✓ Just clinical parameters ✓ Very simple to use. 

CRS incidence: see paper from Shimabukuro-Vornhagen A et al. 

Severe CRS in CAR-T cell trials for ALL: see paper from Shet VS & Gauthier J.

CRS: Risk factors for severity: 

Patient Performance status; Pre-existing endothelial activation; Type of disease (ALL, NHL, CLL, MM, other); Tumor burden

Lymphodepletion Fludarabine

In vivo CAR-T cell expansion Patient tolerance

CAR-T cell product Lymphocyte composition (apheresis product); CAR-T cell product: - costimulatory domain (41 BB/ CD28) - composition - Ratio CD8:CD4 - T-cell subsets - manufacturing process

CAR-T cell dose
CAR-T cell infusion (single /fractionated)

CRS severity correlates to tumor burden in pediatric and adult ALL (Maude et al.; Lee et al.; Park et al.)

CRS severity: CAR-T cell dose and single vs. fractionated dose (Frey N. et al. 2016; Frey N. et al. 2020)

Fractionated: Reduction of severe CRS (Grade>3) from 27% to 4% and procedure-related mortality from 20% to 0.

CRS severity: clinical predictors: Early fever below 24h, High fever over 39.5, Tachycardia; See paper Hay KA et al.

CRS therapy: 

• Supportive: antipyretics, fluids, vasopressors, respiratory and coagulation support, • Anti-cytokines: anti-lL6 Receptor (tocilizumab) • Steroids • Optimal management for refractory cases to tocilizumab and steroids not well established.

Early use or prophylactic use of tocilizumab does not compromise response and reduces severe CRS incidence. Caution: can it increase neurotoxicity? Axi-cel (ZUMA-1): prophylactic tocilizumab d2: CRS grade 3-5: 3 VS 13%; NT grade 3-5: 41 vs 28% (grade 5 in 1 pt). No increase of neurotoxicty in other studies using pre-emptive tocilizumab.

Early use of steroids: can they impact CART-cell proliferation? 

• ZUMA-1 trial (NHL, axi-cel, CAR19 CD28) ➔ preemptive steroids (cohort 4) and ➔ prophylactic use of steroids (cohort 6) • Seattle's Children trial (pediatric ALL CAR19 4188) ➔ preemptive steroid and tocilizumab: ✓ lower incidence of severe CRS ✓ no impact in CAR-T proliferation and efficacy Caution: prolonged and high cumulative dose of steroids might impact proliferation and CAR-T cell persistence and their effect might differ across CAR-T cell constructs.

CRS treatment: Future perspectives: Siltuximab (anti-lL6); Anakinra* (anti-IL 1, crosses BBB can be useful in CRS, HLH and ICANS); Dasatinib (Inhibits lymphocyte-specific kinase LCK ➔ON/OFF); ltacitinib (JAK-1 inhibitor); Ruxolitinib (JAK-2 inhibitor); Lenzilumab (Anti-GM-CSF); Switch-off CAR-T and other new CAR-T cell constructs.


CAR T Toxicity and Management - Neurotoxicity

Miguel-Angel Perales MD, Adult Bone Marrow Transplantation Service Memorial Sloan Kettering Cancer Center

Clinical Presentation

Organ Toxicities Occur Mostly in the 1st 30 days after CART infusion; Median Time to Onset Was 3 Days for CRS and 6 Days for ICANS; CRS and ICANS rates vary across trials (see paper from Shet VS & Gauthier). Comparison of Grading Scales in Recipients of CD19 CAR-T Cells Shows Grading Differences, Comparing grading systems for ICANS: 54% of concordance on ICANS grades (see paper Pennisi et al. 2020). 

ASTCT Neurotoxicity- ICE Score Consensus Grading for Adults (see paper Lee, Santomasso et al. 2019).

Risk Factors for Severity of CRS and Neurological Events (see paper Gutierrez C. et al. 2018).

ALL is associated with higher ICANS than NHL (see paper Pasquini MC et al. 2020)

CARTITUDE-1 Neurotoxicity (see paper Madduri Det al. 2020)


  • CAR-T Cell Therapy-Associated Neurologic Events Are Almost Always Reversible 
  • Serum inflammatory cytokines are increased in more severe ICANS
  • NMDA receptor agonists QA and GLUT are increased in CSF in patients with ICANS
  • Inflammatory markers are also elevated and/or enriched in CSF during ICANS 
  • Serum and CSF markers are elevated in more severe ICANS
  • Endothelial activation is seen in neurotoxicity associated with CD19 CART cells 
  • Endothelial activation is seen in neurotoxicity associated with CD19 CART cells and vascular disruption
  • Model of blood-brain barrier disruption during ICANS (see paper Juliane Gust et al. 2020)


Steroid use is associated with decreased PFS and OS (see paper Paolo Strati et al. 2021)

Severe infections are associated with higher grade CRS/ICANS and use of Toci or Steroids (see paper JM Logue et al. 2020).

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events (see paper MV Maus et al. 2020).


CAR-T Toxicity and management EBMT recommendations

Dr. Patrick Hayden, Secretary, EBMT Chronic Malignancies Working Party, St. James's Hospital. Dublin, Ireland

Target readership: Haematologists treating 8-ALL and high-grade 8-NHL Broad overview of the whole process of CAR T therapy Practical recommendations for units setting up service Emphasis on Tables and checklists
Algorithms on the management of CRS and ICANS.

First EBMT Practice Harmonisation and Guidelines Workshop - paper:  "Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE)"


  • Eligibility for CAR T cell therapy
  • Minimum required laboratory and radiology work-up
  • How to perform apheresis
  • Requirement for bridging therapy
  • Lymphodepletion conditioning
  • CAR T infusion
  • Management of short term toxicities
  • Management of medium-term complications
  • Long-tern1 follow-up and Late Effects

Future: EBMT-EHA CART recommendations currently being prepared Goal of journal submission in May 2021