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Clinical case of the month - Approach to Cytokine Release Syndrome and Neurotoxicity with CAR T-cell Therapy


October 2019 Clinical Case of the Month

Title: Approach to Cytokine Release Syndrome and Neurotoxicity with CAR T-cell Therapy
Submitted by: Syed Ali Abutalib and Nicolaus Kröger
Physicians expert perspective: Ibrahim Yakoub-Agha
Nurses expert perspective: Michelle Kenyon and John Murray

68 year-old female was treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) x 6 cycles for stage IIIB diffuse large B cell lymphoma (DLBCL). Unfortunately, she relapsed after 4 months. Subsequently, she underwent autologous hematopoietic cell transplantation after achievement of partial response (PR) with O-GDP (obinutuzumab, gemcitabine, dexamethasone, cisplatin). She progressed again; this time only after 2 months with non-bulky generalized lymphadenopathy without B symptoms. Given her good performance status, you offered her the option of CAR (chimeric antigen receptor) T cell therapy which she readily accepted. She underwent successful leukapheresis followed by low-intensity (“bridging”) therapy with stable response (SR). CAR T cell therapy was administered following lymphodepleting regimen with fludarabine and cyclophosphamide. On day+5 after CAR T cell therapy she developed fever of 38.5°C, hypoxia requiring 3 liters/min of oxygen via nasal cannula and hypotension without need for vasopressor therapy on day +6, she also developed mild decreased in level of consciousness (awakens spontaneously) with calculated Immune effector Cell-associated Encephalopathy (ICE) score of 9 (she was unable to count backwards from 100 by 10). All symptoms resolved completely by day +10.

Which of the following statements about cytokine release syndrome (CRS) and neurotoxicity associated with CAR T cell therapy is INCORRECT?

A. Patient most likely developed CRS and neurotoxicity after CAR T cell therapy
Intensive care unit (ICU) team were most likely involved in the care of this patient
Tocilizumab was most likely administered in this patient
Systemic steroid were most likely given once neurotoxicity developed independently of severity
Electroencephalogram (EEG) monitoring must have been considered in this patient

Expert Perspective by Professor Ibrahim Yakoub-Agha

Cytokine Release Syndrome (CRS) is an abnormal acute inflammatory response following immune effector cell therapy such as chimeric antigen receptor T (CAR T) -cells, HLA-haploidentical transplantation or certain T-cell engaging monoclonal antibody (eg, blinatumomab)1.  CRS is the most common complication after CAR T-cell therapy with incidence variability anywhere from 30 to100%. However, the incidence of more severe forms of CRS (grade ≥3) ranges from 10 to 30%.2 The clinical symptoms include fever (≥ 38°C) at the start of CRS and can progress rapidly towards hypotension, hypoxia and multi-organ dysfunction (MODS) from capillary leak phenomena attributed by supraphysiologic release of inflammatory cytokines3.  It usually occurs between 1 to14 days (median, 2 to 4 days) after the CAR T-cell infusion and can last anywhere from 1 to 10 days4-5. The severity of CRS is variable and is evaluated according to a novel grading scale proposed recently by ASTCT (American Society of Transplantation and Cellular Therapy) consensus panel3.  Risk factors for CRS include tumor burden, the presence of active infection at time of the infusion, the dose of infused CAR T-cells, the type of CAR T-cell construct and the choice of lymphodepleting regimen6-9.

In the current clinical case, the patient most likely developed grade 2 CRS (fever, hypoxia and hypotension without need for vasopressor requirement) (choice A is correct). However, infection cannot be excluded and empiric broad-spectrum antimicrobial therapy, based on symptoms, physical examination, laboratory data and imaging studies should not be delayed especially in patients with neutropenia10.

Rapid access to an ICU (intensive care unit) is essential for patients with CRS of grade 2 or higher (choice B is correct). The treatment for CRS cases such as grade ≥2, in addition to symptomatic measures, consists of prompt administration of tocilizumab (monoclonal antibody against IL-6 receptor; choice C is correct) and, sometimes, corticosteroids (for grade 3 and 4 CRS)11.  It should be noted that tocilizumab should be administered no more than four times during one episode of CRS. In the current case, corticosteroid was not necessary as CRS was less than grade 3.

The neurological toxicity has recently been termed Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS)3. This is the second most common adverse event post-CAR T-cell infusion and its incidence has been reported at rates varying from 12 to 55%.  The median time of onset of the first neurologic symptoms is about 6 days (1 to 34 days) after the CAR T infusion12. The duration of symptoms is generally between 2 to 9 days; however late presentations of ICANS sometimes occur12-13.  In general, it develops either at the same time or following resolution of CRS but may occur without preceding CRS.

Any neurological symptom occurring after the CAR T-cell infusion must be considered as CAR T-related until proven otherwise. Therefore, we and the ASTCTconsensus panel recommend excluding other non-specific symptoms such as headache, tremor, myoclonus, asterixis, and hallucinations as they are usually managed symptomatically and do not generally trigger specific ICANS based interventions. The grading of ICANS requires assessment of 10-point Immune effector Cell-associated Encephalopathy (ICE) score as well as evaluation of other neurological symptoms such as decreased level of consciousness, abnormal motor system exam, seizures, which may occur with or without other encephalopathy features3.

Rapid access to neurological expertise is important. Cross-sectional imaging (CT and/or MRI scans), electroencephalography (EEG), and CSF examination may all be required in the management of these complex patients.

In the current clinical case, the patient most likely developed grade 1 ICANS (choice A is correct). While MRI scan and lumbar puncture (LP) are not mandatory at this stage (as clinically indicated to rule out differential diagnosis), EEG is to be done within few hours in this case to rule out non-clinical electrical seizures5,13. (Choice E is correct)

While corticosteroids are the treatment of choice in patients with grade > 1 ICANS, in those with grade 1 ICANS, only symptomatic measures (raised head 30°, suspended oral nutrition, replace oral drugs to intravenous) are recommended13. Steroids are not required in this case therefore choice D is incorrect answer. In our opinion, administration of tocilizumab is recommended in patients developing ICANS (any grade) if concurrent with even grade 1 CRS (fever of 38°C) since CRS is a risk factor for subsequent neurologic toxicity.  

Expert Nurses Perspective by Michelle Kenyon and John Murray

This case highlights the complex nature of nursing patients undergoing CAR T-cell therapy for refractory large B-cell lymphoma. While CRS and neurotoxicity or ICANS are widely known to be associated with CAR T-cell therapy, the rapid onset of symptoms with often debilitating impact on overall function can be alarming, especially for patients and their family.

The patients require specialist medical and nursing care in Units proficient and experienced at managing these complex and rapidly deteriorating adverse effects and complications. Nurses will be proficient at caring for allogeneic hematopoietic cell transplant recipients, competent at responding to rapidly changing clinical symptoms and complications such as sepsis, SOS/VOD, graft versus host disease (GvHD), multi-organ dysfunction (MODs). Additional training is needed to achieve competence at completing CRS and ICANS assessment tools and to understand the significance of grading and act appropriately.

As with any acutely unwell critically ill patient, safety is a priority, and must be evaluated frequently and maintained. Staffing levels on Units delivering CAR T-cell need to be sufficiently flexible to provide increasingly dependent and unwell patients with 1-1 nursing care when required.  Timely and frequent assessment, documentation, agreed reporting processes and medical care escalation criteria are crucial to optimize outcomes. It is important to note that CAR T-cell therapy patients should be woken while sleeping for routine nursing assessment and evaluated so complications especially ICE/ICANS are not missed.

  • Patients who have received CAR T-cell therapy will have 4 hourly observations (vital signs including oxygen saturation) performed routinely with frequency increased as clinically indicated and fevers treated as according to neutropenic fever/sepsis guidelines. It is important to note that fever is also the first sign of CRS.
  • Patients are assessed twice daily (12 hourly) for evidence of CRS and ICANS (completing the ICE tool) or more frequently if clinical concern and acute deterioration and grading recorded according to institutional agreed processes while informing the on-call physician immediately.

Standard nursing and supportive care needs are extremely dynamic in this setting due to rapid fluctuations in patient’s condition (minutes to hours) and function with CRS and ICANS symptoms impacting on independence with ADLs (activity of daily livings). Frequent evaluation during care delivery is required to appropriately meet the nursing needs of these patients.

Robust and regular communications both within the team and with the patient and family (especially primary caregiver) at the bedside can help to reduce patient and caregiver anxiety. However, additional support from Psychological therapy services may be appropriate for some, while referrals to physiotherapy, occupational therapy and dieticians should be considered where needed.

Recognition of the burden of care on the family is also warranted. Generally, patients are receiving CAR-T at centers far from home. Separation can contribute to social isolation and when family caregivers are present to support the patient or travelling frequently to the center, there can be additional psychological, practical and financial burden.

Given the challenges and complex nature of care required for these patients, it’s important to ensure that appropriate opportunities are available to enable staff to debrief, reflect and learn from their experiences.

Correct Answer – D


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2. Frey N, Porter D. Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy. Biol Blood Marrow Transplant. 2018.
3. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625-638.
4. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. The New England journal of medicine. 2014;371(16):1507-1517.
5. Gauthier J, Turtle CJ. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Curr Res Transl Med. 2018;66(2):50-52.
6. Maude SL, Shpall EJ, Grupp SA. Chimeric antigen receptor T-cell therapy for ALL. ASH Education Program Book. 2014;2014(1):559-564.
7. Turtle CJ, Sommermeyer D, Berger C, Hudecek M. Therapy of B cell malignancies with CD19-specific chimeric antigen receptor-modified T cells of defined subset composition. Blood. 2014.
8. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet (London, England). 2015;385(9967):517-528.
9. Frey N. Cytokine release syndrome: Who is at risk and how to treat. Best Pract Res Clin Haematol. 2017;30(4):336-340.
10. Fishman JA, Hogan JI, Maus MV. Inflammatory and Infectious Syndromes Associated with Cancer Immunotherapies. Clin Infect Dis. 2018.
11. Yakoub-Agha I, Moreau AS, Ahmad I, et al. [Management of cytokine release syndrome in adult and pediatric patients undergoing CAR-T cell therapy for hematological malignancies: Recommendation of the French Society of Bone Marrow and cellular Therapy (SFGM-TC)]. Bull Cancer. 2019;106(1S):S102-S109.
12. Rubin DB, Danish HH, Ali AB, et al. Neurological toxicities associated with chimeric antigen receptor T-cell therapy. Brain. 2019;142(5):1334-1348.
13. Cornillon J, Hadhoum N, Roth-Guepin G, et al. [Management of CAR-T cell-related encephalopathy syndrome in adult and pediatric patients: Recommendations of the French Society of Bone Marrow transplantation and cellular Therapy (SFGM-TC)]. Bull Cancer. 2019.


Syed Ali Abutalib, MD
Associate Director, Hematology and Cellular Therapy Program
Director, Clinical Apheresis Program
Cancer Treatment Centers of America, Zion, Illinois
Associate Professor, Rosalind Franklin University of Medicine and Science

Nicolaus Kröger, MD
Professor and Medical Director of the Department of Stem Cell
Transplantation at the University Hospital Hamburg-Eppendorf, Germany
University Hospital Hamburg, Hamburg, Germany

Correspondence: Nicolaus Kröger, MD

Expert Perspective

Professor Ibrahim Yakoub-Agha, MD, PhD
Head of immune cellular therapy unit
Lille University Hospital
Lille, France

Nurses Expert Perspective

Michelle Kenyon
Consultant Nurse (BMT)
King’s College Hospital NHS Foundation Trust
London, UK

John Murray
Nurse Clinician
The Christie Hospital
Manchester, UK

Future Clinical Case of the Month

If you have a suggestion for future clinical case to feature, please contact Nicolaus Kröger.