SCCM Resource Library-44-Cytokine Release Syndrome in Chimeric Antigen Receptor T-Cell Therapy: The CAR-ICU Experience

Video Transcription

Hello, I'm Heather May, pharmacist at Mayo Clinic in Rochester, and today I'm here to talk to you about cytokine release syndrome in patients receiving chimeric antigen receptor  T cell therapy, the CAR-ICU experience. And the disclosures are listed here, though I have no conflicts of interest to disclose.  Chimeric antigen receptor T cell therapy is genetically modified, usually autologous T cells that express a chimeric antigen receptor on the extracellular membrane.  When infused into a patient with cancer, they traffic to and bind their target antigen,  which triggers downstream signaling resulting in the release of cytokines, CAR T cell proliferation, and tumor cell killing.  Unfortunately, there are a few toxicities common and relatively unique to this therapy. They include immune effector cell associated neurotoxicity syndrome, commonly called ICANS,  and cytokine release syndrome, or CRS. When these toxicities are severe, patients are often admitted to the ICU for close monitoring and treatment.  We performed a historical cohort study to describe the characteristics, treatment, and outcomes of adult patients treated at 11 U.S. medical centers who are admitted to the ICU  for CRS or ICAN. This abstract focuses mainly on experiences with CRS, and I encourage you to seek out  the presentations of my co-authors Anne Rain Brown and Matthew Hensley, abstract numbers 4344 and 4506, for additional results from this study.  Cytokine release syndrome has traditionally been graded on a scale of 1 to 5, with higher numbers indicating more severe toxicity.  The study timeframe preceded the standardized grading consensus criteria for CRS and ICAN that has been established by the American Society for Transplantation and Cellular Therapy.  Therefore, different grading systems were utilized across institutions, though you can see the Lee criteria was used most commonly.  To counterbalance this variability, we recorded specific organ toxicities and organ support modalities, and I'll describe those for you today.  Of the 345 patients treated with CAR T-cell products during the study timeframe, 113 were admitted to the ICU with CRS and ICAN.  Due to the differences in toxicity patterns between CAR constructs and the fact that the vast majority of our patients were treated with the Axocell product, I'll only be reporting  the data from those treated with Axocell. Of the 105 included patients, 81 of them experienced CRS during their ICU stay.  58 patients, or 72% of these, had CRS at the time of ICU admission. 15 patients, or 19%, had concurrent ICANs at the time of ICU admission.  And 65 patients, or 80%, had concurrent ICANs or CRS at some point during their ICU stay. The median time from Axocell infusion to ICU admission was 5 days, and 23% of patients  had what we would consider advanced grade CRS at the time of ICU admission. That's grades 3 or 4.  Overall, there were 35% of these 81 patients who eventually experienced grade 3 to 5 CRS while in the ICU.  Of note, there were 21 patients who had microbiologically confirmed infection in addition to a diagnosis of CRS.  And this included 7 cases of bacteremia, 7 cases of pneumonia, 4 UTIs, and 4 viral infections, and 3 stool infections.  19 of the 81 patients with CRS required vasopressor support, and current ASTCT criteria would grade these patients as having grade 3 CRS or higher.  16% of the, I'm sorry, 16 of the 19 patients only required 1 vasopressor, while 3 patients required more than 1, which could have included vasopressin.  Of the 15 patients who required respiratory support, 4 required invasive mechanical ventilation, that's 27%.  9 required high-flow nasal cannula, so that's nasal cannula of 7 liters or more. And 2 required non-invasive mechanical ventilation.  Our current ASTCT criteria would grade those patients requiring high-flow nasal cannula as grade 3 toxicity, and those requiring invasive or non-invasive mechanical ventilation as  grade 4 toxicity. Other toxicities were defined according to the Common Terminology Criteria for Adverse Events, or CTCAE.  And in addition to those listed here, there were 4 cases of HLH, 3 individuals with cardiomyopathy, and 1 who experienced DIC.  Vaselizumab was overwhelmingly the treatment of choice for CRS. Of the 31 patients who received steroids, we noted only 12 of those had CRS alone at  the time they received their first steroid dose, whereas 19 patients had both CRS and ICANs when they first received steroids.  Filtuximab was used for patients with grade 3 and 4 CRS, and Anakinra was used in 1 patient with grade 4 CRS.  When Tocilizumab was used for CRS alone, so that's 53 patients, it was most often started at grade 2 CRS.  When steroids were used for CRS alone, they were most often started for patients who had grade 2 or grade 3 CRS.  You note that overall in-hospital death was low, 16 patients total, and the majority of deaths were attributed to infection and disease progression.  This table presents select data from univariate analysis, where several variables were observed to have a significant association with ICU or hospital mortality.  The Fisher's exact test or chi-squared test was used to evaluate the association between  two categorical variables, and the Wilcoxon rank sum test was used to evaluate the difference in continuous variables between groups.  Several interesting things to note include the association between longer time to CRS  onset and mortality risk, as well as the associations between the need for organ support or organ toxicity and the risk for death.  These are additional results from univariate analysis, where it is notable that higher exposure to steroids was associated with an increased risk for ICU and hospital mortality.  Steroid doses are in methylprednisolone equivalents when you're looking at cumulative steroid dose, and by far dexamethasone was the most commonly used steroid, though this was also  followed by methylprednisolone and hydrocortisone. The overall hospital mortality rate, only 16 out of 105 patients, precluded any adjusted or multivariable analyses.  In conclusion, we observed that 81 patients, or 77% of those admitted to the ICU, experienced CRS at some point, and 35% of those patients had grades 3 to 5 CRS.  The primary treatments included tocilizumab, steroids, and vasopressors for hemodynamic support.  We observed a low overall mortality rate in the cohort, and several variables were associated with mortality and could be explored in future research.  I'd like to recognize the other participating centers and my co-authors, and I thank you for listening today, and I welcome your feedback and questions.

Video Summary

In this video, pharmacist Heather May discusses cytokine release syndrome (CRS) in patients receiving chimeric antigen receptor T-cell therapy. CRS is a common toxicity associated with this therapy, and when severe, patients are admitted to the ICU for close monitoring and treatment. May presents the findings from a historical cohort study that describes the characteristics, treatments, and outcomes of adult patients treated at 11 U.S. medical centers who were admitted to the ICU for CRS. She discusses the use of different grading systems, specific organ toxicities and support modalities, as well as the low overall mortality rate in the cohort.

Asset Subtitle

Immunology, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Heather P. May

Methods: Multicenter historical cohort study of adults receiving CART who were admitted to the ICU with CRS from November 2017 to May 2019 in 7 US centers from the CAR-ICU initiative. Descriptive statistics were used to report demographic data and characteristics of CRS and ICU management, with continuous data reported as median (IQR).

Results: 111 patients required ICU admission during the study timeframe. CRS was the primary reason for ICU admission in 46 (41%) and 85 (77%) experienced CRS at some point during ICU stay. Overlapping CRS and immune effector cell-associated neurotoxicity syndrome was present in 66 (60%). Most had lymphoma (99%) and age was 59(18-84). SOFA score on ICU admission and maximum SOFA score during ICU stay was 4(1-21) and 6(1-23), respectively. Lee (64%), Neelapu (23%) and ASTCT (11%) criteria were used for CRS grading. Number of days from CART infusion to maximum grade CRS was 5(0-55) and from infusion to ICU admission was 5(0-54). Hypotension was present in 45 (53%) patients and 20 (24%) required vasopressors (CRS grade 3-4) for 1(1-4) day. Only 1 vasopressor was required in 16 (80%) cases. Hypoxia was present in 26 (31%) and 8 (9%) required high-flow nasal cannula, 8 (9%) BiPAP, and 3 (4%) mechanical ventilation (CRS grade 3-4). Other organ toxicities observed included arrhythmias (24%), cardiomyopathy (4%), non-cardiogenic pulmonary edema (15%) and liver injury (31%). Kidney injury was present in 11 (13%) patients and 2 required dialysis. Treatment for CRS included tocilizumab (80%), siltuximab (4%), corticosteroids (35%) and anakinra (1%). ICU and hospital LOS in patients with CRS was 1(1-21) and 23(5-80) days, respectively. Eight patients (9.4%) died in the ICU with 1 death attributed to CRS. Median overall survival was 10 months for patients with CRS.

Conclusions: One-third of patients in the ICU following CART experienced grades 3-4 CRS and treatment predominantly consisted of interleukin-6 inhibitors and corticosteroids. Other organ toxicities included arrhythmia, liver injury, kidney injury and pulmonary edema. ICU mortality remains low despite a high prevalence of CRS among critically ill patients.

Meta Tag

Content Type Presentation

Knowledge Area Immunology

Knowledge Level Advanced

Membership Level Select

Tag Oncology

Year 2021

Keywords

pharmacist

Heather May

cytokine release syndrome

chimeric antigen receptor T-cell therapy

ICU

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