CADTH Health Technology Review

Anticytokine Therapy and Corticosteroids for Cytokine Release Syndrome and for Neurotoxicity Following T-Cell Engager or CAR T-Cell Therapy

Rapid Review

What Is the Issue?

• Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common toxicities secondary to T-cell engager or chimeric antigen receptor (CAR) T-cell therapy.

• The US FDA and Health Canada approved tocilizumab, an anti-interleukin-6 receptor antagonist, for the management of severe or life-threatening cases of CRS.

• Corticosteroids also play an important role in CRS management and are the mainstay of ICANS management.

• Decision-makers are interested in understanding the use of anticytokine drugs (i.e., tocilizumab, anakinra, siltuximab) and/or corticosteroids in the management of CRS and ICANS following T-cell engager or CAR T-cell therapy.

What Did We Do?

• We identified and summarized the literature comparing the clinical effectiveness and safety of anticytokine therapy and/or corticosteroids with alternative care or treatment as usual for treating and preventing of CRS and ICANS. We also searched for evidence-based recommendations for the use of anticytokine therapy and/or corticosteroids to treat and prevent CRS and ICANS.

• A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2019 and February 26, 2024 for CRS; and between January 1, 2019 and March 4, 2024 for ICANS. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.

What Did We Find?

• This report presents evidence-based findings on 3 retrospective chart review studies, 2 prospective cohort studies, and 4 consensus guidelines.

• Limited and low-quality clinical evidence from studies with a high risk of bias suggested that early use of tocilizumab or corticosteroids, or prophylactic use of tocilizumab or anakinra may reduce the risk of a high-grade CRS without a negative impact on neurotoxicity or immunotherapy treatment outcomes.

• The included guidelines recommend the use of tocilizumab for treatment of higher-grade CRS, or for treatment of grade 1 CRS if symptoms persist for 3 days or more. Corticosteroids could be added in conjunction if there is no improvement or persistent symptoms after tocilizumab therapy.

• For the management of ICANS in the absence of concurrent CRS, supportive care is the preferred treatment option for grade 1 ICANS, while corticosteroids are recommended for the management of grade 2 to 4 ICANS. In the presence of concurrent CRS, guidelines recommend tocilizumab therapy as per management of CRS, and corticosteroids should be continued until improvement to grade 1.

• We did not identify any clinical evidence regarding the clinical efficacy and safety of anticytokine therapy and/or corticosteroids for treatment of CRS and ICANS compared with alternative treatment or treatment as usual.

• We also did not identify any guidelines for the use of prophylactic anticytokine therapy, corticosteroids, or both for the prevention of CRS and ICANS.

What Does This Mean?

• Despite limited and low-quality evidence, the findings suggest some potential benefits of prophylactic or early use of anticytokine therapy and corticosteroids for the management of immunotherapy-related toxicities. Guidelines offer guidance on the management of CRS, ICANS and other less common toxicities related to immunotherapy based on the available low-quality evidence.

• When using the clinical evidence and recommendations summarized in this report to inform decisions, decision-makers should consider that the evidence is limited and of low quality.

• To improve the certainty of findings, there is a need for more robust prospective clinical trials with larger sample sizes, and lower risk of bias.

Context and Policy Issues

What Is CAR T-Cell Therapy and T-Cell Engager Therapy?

CAR T-cell therapy is a new form of immunotherapy in which T-cells, obtained from the same individuals (autologous) or different donors (allogenic), are genetically engineered to express a specific receptor called a CAR, allowing it to recognize and kill cancer cells.¹ Currently, there are 6 CAR T products approved for use in the US and Canada.² Three products (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel) are for B-cell leukemia and lymphoma, 1 product (brexucabtagene autoleucel) for mantle cell lymphoma, and 2 products (idecabtagene vicleucel, ciltacabtagene autoleucel) for multiple myeloma.²

T-cell engager therapy involves bispecific antibodies that are engineered to redirect the immune system’ T-cells to recognize and kill cancer cells.³ Blinatumomab was the first bispecific T-cell engager approved by Health Canada for treatment of adult patients as well as pediatric patients (Notice of Compliance with Conditions) with relapsed or refractory B-cell precursor acute lymphoblastic leukemia.⁴ Health Canada recently approved teclistamab for adult patients with relapsed or refractory multiple myeloma after at least 3 lines of therapy, including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.⁵

What Are the Common T-Cell Engager- or CAR T-related Toxicities?

Introduction of CAR T-cells or T-cell engagers will trigger a systemic immune response leading to the production of inflammatory cytokines and chemokines such as interleukins (IL), tumour necrosis factors and interferons that attack cancer cells; however, they can also attack healthy cells.^3,6 The 2 most common adverse events (AEs) associated with CAR T-cell therapy and T-cell engager therapy are CRS and ICANS.^3,6 The American Society for Transplantation and Cellular Therapy (ASTCT) guidelines established a consensus grading system (grade 1 to 4) for both CRS and ICANS.⁷

CRS usually appears within 1 to 2 weeks after infusion.^6,8 The signs and symptoms of CRS can range from mild flu-like symptoms (e.g., fever, myalgia, headache, and fatigue) to life-threatening conditions (e.g., vasodilatory shock, capillary leak, hypoxia, and end-organ dysfunction).⁸ According to the ASTCT grading system, CRS severity is graded based on 3 clinical parameters, which are fever, hypotension, and hypoxia.⁷

ASTCT consensus grading for CRS:

• Grade 1: Fever (≥ 38°C).

• Grade 2: Fever with hypotension not requiring vasopressors and/or hypoxia requiring low-flow nasal cannula or blow-by.

• Grade 3: Fever with hypotension requiring a vasopressor with or without vasopressin and/or hypoxia requiring high-flow cannula, face mask, nonrebreather mask, or Venturi mask.

• Grade 4: Fever with hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation).

ICANS usually starts after the onset of CRS, and higher grades of ICANS can occur concurrently with higher grade of CRS.⁸ Symptoms of ICANS can range from encephalopathy to seizures, obtundation, and death.⁹ Atypical manifestations include transient aphasia, facial paresis, myoclonus, and hemifacial spasms.⁹ In the ASTCT grading system,⁷ the final ICANS grade is determined by the most severe events among 5 different domains: ICE (immune effector cell-associated encephalopathy) score, depressed level of consciousness, seizure, motor findings, and elevated ICP (intracranial pressure)/cerebral edema.⁷

ASTCT consensus grading for ICANS:

• Grade 1: ICE score: 7 to 9 with no depressed level of consciousness.

• Grade 2: ICE score: 3 to 6; and/or mild somnolence awaking to voice.

• Grade 3: ICE score: 0 to 2; and/or depressed level of consciousness awakening only to tactile stimulus; and/or any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on electroencephalogram (EEG) that resolve with intervention; and/or focal or local edema on neuroimaging.

• Grade 4: ICE score: 0 (patient is unarousable and unable to perform ICE); and/or stupor or coma; and/or life-threatening prolonged seizure (> 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between; and/or diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing or papilledema, sixth cranial nerve palsy, or papilledema; or Cushing triad.

What Is the Current Practice?

For most patients with lower grades of CRS or ICANS, management of toxicities relies mainly upon supportive care. In 2017, the US FDA approved tocilizumab, an IL-6 receptor antagonist, for treatment of severe or life‐threatening CAR T-cell‐induced CRS in adults and in pediatric patients 2 years of age and older.^10,11 Subsequently, the drug was also approved by Health Canada for severe or life-threatening CRS in patient populations specified for authorized CAR T-cell products.¹² However, prescribing information for individual CAR T products advises using tocilizumab at lower grades of CRS.^13-17 Depending on the persistent symptoms and severity of CRS, tocilizumab with or without systemic corticosteroids is generally administered in many centres.¹⁸ In the case of refractory CRS, several third-line drugs have been proposed, including siltuximab (an antiIL-6 antibody), anakinra (an IL-1 receptor antagonist), etanercept (anti–tumour necrosis factor), and infliximab (anti–tumour necrosis factor).^8,9

For ICANS, the therapeutic strategy is based on the grade of neurotoxicity.⁷ Corticosteroids form the mainstay of ICANS management in addition to supportive care.⁸ Grade 1 ICANS is mainly treated with supportive care. Dexamethasone is used for grade 2 and 3, and high-dose of methylprednisolone is recommended for treatment of grade 4.⁸ Anti-IL-6 therapy, such as tocilizumab, is used only in patients with concurrent CRS due to the possibility that tocilizumab may exacerbate ICANS.⁸

Why Is It Important to Do This Review?

There remains limited guidance or standardized treatment approach for the optimal management of CRS and ICANS, especially those of higher grades that are refractory to tocilizumab and steroids.¹⁹

Objective

To support decision-making about the role of anticytokine drugs (i.e., tocilizumab, anakinra, siltuximab) and corticosteroids for the treatment and prevention of CRS and ICANS, we prepared this Rapid Review to summarize and critically appraise the available studies on the clinical efficacy and safety of those drugs following T-cell engager or CAR T-cell therapy.

Research Questions

1. What is the clinical effectiveness and safety of anticytokine drugs, corticosteroids, or both for the treatment of cytokine release syndrome and for the treatment of neurotoxicity following T-cell engager therapy or CAR T-cell therapy?

2. What is the clinical effectiveness and safety of prophylactic or early use of anticytokine therapy, corticosteroids, or both for the prevention of cytokine release syndrome and neurotoxicity following T-cell engager therapy or CAR T-cell therapy?

3. What are the evidence-based guidelines for the use of anticytokine agents, corticosteroids, or both in the treatment of cytokine release syndrome and neurotoxicity following T-cell engager therapy or CAR T-cell therapy?

4. What are the evidence-based guidelines for the use of prophylactic or early of anticytokine therapy, corticosteroids, or both for the prevention of cytokine release syndrome and neurotoxicity following T-cell engager therapy or CAR T-cell therapy?

Methods

Literature Search Methods

An information specialist conducted a literature search on key resources, including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of those in Canada and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were CRS, ICANS, CAR T or T-cell therapies, and anticytokine drugs. The search was completed on February 26, 2024 for CRS, on March 4, 2024 for ICANS, and limited to English-language documents published since January 1, 2019.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria

CAR T = chimeric antigen receptor T-cell; CRS = cytokine release syndrome; ICU = intensive care unit.

Exclusion Criteria

We excluded articles that did not meet the selection criteria outlined in Table 1, or articles published before 2019. Guidelines with unclear methodology were also excluded.

Critical Appraisal of Individual Studies

One reviewer critically appraised the included publications using the following tools as a guide: The Downs and Black checklist²⁰ for nonrandomized studies, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument²¹ for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

We identified a total of 318 citations from the literature search. Following screening of titles and abstracts, we excluded 290 citations and retrieved 28 potentially relevant reports from the electronic search for full-text review. We also retrieved 6 potentially relevant publications from the grey literature search. Of these potentially relevant articles, we excluded 25 publications for various reasons, and included 9 publications that met the inclusion criteria. These comprised 5 nonrandomized studies and 4 evidence-based guidelines. Appendix 1 presents the PRISMA²² flow chart of the study selection.

Summary of Study Characteristics

Appendix 2 provides details regarding the characteristics of 5 included primary studies^23-27 and 4 evidence-based guidelines.^28-30

Included Studies for Question 1: What is the clinical effectiveness and safety of anticytokine drugs, corticosteroids, or both for the treatment of cytokine release syndrome (CRS) and for the treatment of neurotoxicity following T-cell engager therapy or CAR T-cell therapy?

We did not identify any studies comparing the clinical effectiveness and safety of anticytokine drugs, corticosteroids, or both with alternative treatment or treatment as usual for treatment of CRS and ICANS.

Included Studies for Question 2: What is the clinical effectiveness and safety of prophylactic or early use of anticytokine therapy, corticosteroids, or both for the prevention of CRS and neurotoxicity following T-cell engager therapy or CAR T-cell therapy?

Study Design

We identified 3 retrospective chart review studies^23,24,27 and 2 prospective cohort studies.^25,26 All included studies were conducted at a single institution, and were published in 2024,²³ 2023,^24-26 and 2021.²⁷

Of the included studies, the study by Scott et al. (2023)²⁵ involved prophylactic tocilizumab to prevent CRS, and the study by Strati et al. (2023)²⁶ used prophylactic anakinra to mitigate ICANS. The remaining 3 studies^23,24,27 evaluated the consequences of early management approach of tocilizumab or corticosteroids on the incidence and severity of CRS and ICANS, and CAR T-cell treatment efficacy.

Country of Origin

Four included studies^23,25-27 were conducted by authors from the US, and 1 study²⁴ was conducted by authors from Switzerland.

Patient Population

The retrospective chart review studies by Gaffney et al. (2024)²³ and by Lakomy et al. (2023)²⁴ included patients with various hematologic malignancies who underwent CAR T-cell therapy. The prospective cohort study by Scott et al. (2023)²⁵ and the retrospective chart review study by Banerjee et al. (2021)²⁷ included patients with relapsed/refractory multiple myeloma, who underwent bispecific T-cell engager therapy or CAR T-cell therapy, respectively. The prospective cohort study by Strati et al. (2023)²⁶ included patients with relapsed/refractory large B-cell lymphoma who underwent CAR T-cell therapy. Patients in all included studies were adults.

Interventions and Comparators

The retrospective chart review study by Gaffney et al. (2024)²³ compared early and standard management protocols. The early management protocol administered tocilizumab (8 mg/kg IV [IV], maximum of 800 mg/dose) when grade 1 CRS persisted for 24 hours. The standard management protocol administered the first dose of tocilizumab at 72 hours of persistent symptoms.

The retrospective chart review study by Lakomy et al. (2023)²⁴ compared early corticosteroids plus standard tocilizumab schedule with the standard tocilizumab schedule. In the early corticosteroids group, 10 mg dexamethasone was administered before each dose of tocilizumab in case of low-grade CRS.

In the prospective cohort study by Scott et al. (2023),²⁵ the cohort of 53 patients received CAR T (teclistamab) therapy at the step-up dosing at least 48 hours apart (0.06 mg/kg, 0.3 mg/kg, and 1.5 mg/kg). The authors evaluated the first 15 patients and found that the median time to CRS from the administration of the first-prime dose was 48 hours. This group of patients was considered as no prophylactic tocilizumab group. The remaining 38 patients were administered with tocilizumab (8 mg/kg IV, maximum of 800 mg/dose) over 1 hour prophylactically at 44 hours (i.e., 4 hours before the second step-up dose level of teclistamab), and this group was considered as prophylactic tocilizumab group. The outcomes were compared between the prophylactic tocilizumab group and the no prophylactic tocilizumab group, as well as between the prophylactic tocilizumab group and the cohort of the MajesTEC-1 study,³¹ a phase I/II that treated patients with relapsed/refractory multiple myeloma with teclistamab.

In the prospective cohort study by Strati et al. (2023),²⁶ anakinra was administered 6 hours before CAR T-cell infusion on day 0 at a dose of 100 mg daily (n = 10) or 100 mg every 12 hours (n = 10) for 7 days. Results in this study cohort were compared with those of a contemporaneous matched cohort treated without anakinra.

The retrospective chart review study by Banerjee et al. (2021)²⁷ divided 50 patients into 3 groups based on time-to-tocilizumab intervals. Patients in the early tocilizumab group (n = 19) received tocilizumab at most 12 hours after CRS onset, while those in the late tocilizumab group (n = 19) received tocilizumab at least 12 hours after CRS onset and the remaining 12 patients were grouped in the no tocilizumab group. Toxicity outcomes were compared between early and late tocilizumab groups, while efficacy outcomes of CAR T therapy were compared among 3 groups.

Outcomes

The outcomes reported in the included studies were:

• incidence of CRS^23-27

• incidence of ICANS^23-27

• level of care (e.g., hospital length of stay, intensive care unit [ICU] transfer)^23-25

• other AEs and mortality^23,25,27

• efficacy outcomes of immunotherapy.^23-25,27

Included Studies for Question 3: What are the evidence-based guidelines for the use of anticytokine drugs, corticosteroids, or both in the treatment of CRS and neurotoxicity following T-cell engager therapy or CAR T-cell therapy?

We identified 4 guidelines. These are the National Comprehensive Cancer Network (NCCN) guideline by Thompson et al. (2022),²⁸ the American Society of Clinical Oncology (ASCO) guideline by Santomasso et al. (2021),²⁹ the European Society for Blood and Marrow Transplantation (EBMT) and Joint Accreditation Committee of the International Society for Cell Therapy and EBMT (JACIE) guideline by Yakoub-Agha et al. (2020),³⁰ and the Society for Immunotherapy of Cancer (SITC) guideline by Maus et al. (2020).³²

Study Design

All 4 identified guidelines^28-30,32 were consensus-based whose recommendations were made from critical evaluation of evidence derived from literature review, integrated with the clinical expertise and consensus of a multidisciplinary panel of cancer specialists, clinical experts, and researchers. Due to the low level of evidence, the recommendations were usually not graded, and they represented the consensus views of the authors.

Country of Origin

The authors of the NCCN,²⁸ ASCO,²⁹ and SITC³² guidelines were from US, while those of the EBMT and JACIE guideline³⁰ were from various countries in Europe.

Patient Population

The target population in the NCCN,²⁸ EBMT and JACIE,³⁰ and SITC³² guidelines was adults and children, while that in the ASCO guideline²⁹ was restricted to adult patients only. The intended users of the guidelines^28-30,32 were health care practitioners who provide care to patients with cancer, as well as patients receiving CAR T-cell therapy, and their caregivers.

Intervention and Practice Considered

The included guidelines^28-30,32 considered various management strategies of immune-related AE associated with CAR T-cell therapy.

Outcomes

The included guidelines^28-30,32 considered all efficacy and safety outcomes of CAR T-cell therapy.

Included Studies for Question 4: What are the evidence-based guidelines for the use of prophylactic or early use of anticytokine therapy, corticosteroids, or both for the prevention of CRS and neurotoxicity following T-cell engager therapy or CAR T-cell therapy?

We did not identify any guidelines on the use of prophylactic anticytokine therapy, corticosteroids, or both for the prevention of CRS and ICANS following T-cell engager therapy or CAR T-cell therapy.

Summary of Critical Appraisal

Appendix 3 provides details regarding the strengths and limitations of included primary studies^23-27 and guidelines^28-30,32 (Table 5).

Primary Studies

The included primary studies comprised 3 retrospective chart review studies^23,24,27 and 2 prospective cohort studies.^25,26 The latter were reported as a correspondence (i.e., letter to editor).

All included studies^23-27 were explicit in term of reporting, but had several limitations related to the external and internal validity that may reduce the certainty and generalizability of the findings.

For reporting, the authors of the included studies^23-27 clearly described the objective of the study, the main outcomes to be measured, the characteristics of the patients included in the study, the interventions of interest, and the main findings. Actual P values were reported for the main outcomes in 3 retrospective chart review studies^23,24,27 but not in 2 prospective cohort studies.^25,26

For external validity, the treatment settings (i.e., hospitals) in all 5 studies^23-27 appeared to be representative of the treatment received by most of the patients with cancer undergoing immunotherapy. However, the patients may not be representative of the entire population from which they were selected, as the authors of each of the included studies^23-27 conducted the research from a single hospital with a small sample size.

For internal validity related to bias, all 5 studies^23-27 had several limitations, including risks of selection bias and missing data. Three studies^23,24,27 were of retrospective design and 2 prospective studies^25,26 indirectly compared the outcomes of its cohort with those of another cohort that underwent similar treatment. The authors of the retrospective chart review studies,^23,24,27 but not those of the prospective cohort studies,^25,26 used statistical tests appropriately for comparison of variables. All included studies^23-27 assessed the main outcome measures using accurate and reliable method. For instance, CRS and ICANS, the 2 main safety outcomes following immunotherapy, were graded according to the ASTCT criteria.⁷ Clinical responses were categorized using the International Myeloma Working Group criteria.³³

For internal validity related to confounding, the baseline characteristics of the treatment groups in all included studies^23-27 appeared to be balanced, thus reducing the risk of confounding bias. However, due to the nature of the nonrandomized studies,^23-27 residual confounding factors may exist, and failure to identify and adjust for those factors in the analyses may have an impact on the findings. The authors in all studies^23,24,27 did not report whether sample size calculations were performed, and it is unclear whether the nonsignificant differences in certain outcomes were because the studies were underpowered for those outcomes.

Guidelines

The included guidelines^28-30,32 had several strengths related to reporting. They were explicit in terms of scope and purpose (i.e., objectives, health questions and population), and had clear presentation of recommendations (i.e., specific, unambiguous, and easy to find key recommendations, with options for managing the different conditions or health issues). In terms of stakeholder involvement, the authors of all included guidelines^28-30,32 clearly defined target users and the development groups but did not report whether the views and preferences of the patients were sought. As most recommendations were based on the consensus of the authors, there were no explicit links between recommendations and the supporting evidence.^28-30,32 The methods of formulating the recommendations in all guidelines were described, but not in great details.^28-30,32 Also, the authors of all guidelines^28-30,32 considered health benefits and risks of side effects in formulating the recommendations.

However, there were also some limitations related to guideline methodology, implementation, and review. The authors of the guidelines^28-30,32 did not clearly report methods for evidence collection, criteria for selection, and methods for evidence synthesis. The authors did not report the procedures for updating the guidelines.^28-30,32 The applicability (i.e., facilitators and barriers to application, advice and/or tools on how the recommendations can be put into practice, and monitoring or auditing criteria) was unclear in the included guidelines.^28-30,32 For editorial independence, the authors of all guidelines^28-30,32 reported that all guideline development group members had no competing interest. The authors of 2 guidelines^28,30 did not report if the views of the funding body had any influence on the content of the guidelines.

Summary of Findings

Appendix 4 presents the main study findings, which are the incidence of CRS (Table 6), the incidence of ICANS (Table 7), the level of care (Table 8), other AEs and mortality (Table 9), and clinical outcomes of immunotherapies (Table 10).

Clinical effectiveness and safety of prophylactic or early use of anticytokine therapy, corticosteroids, or both for the prevention of CRS and neurotoxicity following T-cell engager therapy or CAR T-cell therapy

Two studies involved the prophylactic approach of tocilizumab²⁵ or anakinra,²⁶ 2 studies^23,27 used early treatment with tocilizumab, and 1 study²⁴ involved early use of corticosteroids.

Incidence of CRS

Prophylaxis

The study by Scott et al. (2023)²⁵ compared prophylactic tocilizumab (administered 4 hours before the second step-up dose level of CAR T-cell therapy) with no prophylactic tocilizumab and found that CRS all grades occurred in 21.1% of patients in the prophylactic group compared with 73.3% of patients in the no prophylactic group. Most of the CRS events was of grade 1 in both groups (i.e., 21.1% of patients in the prophylactic group versus 67.7% of patients in the no prophylactic group). The difference was not statistically compared. Two patients (2.6%) in the prophylactic group versus no patients (0%) in the no prophylactic group had CRS grade 2 and 3.

The study by Strati et al. (2023)²⁶ compared prophylactic anakinra (administered 6 hour before CAR T-cell infusion on day 0 at a dose of 100 mg daily (n = 10) or 100 mg every 12 hour (n = 10) for 7 days) with no prophylactic anakinra (from a contemporaneous cohort), and found that patients in both cohorts experienced similar CRS incidence for all grades, grade 2 to 4, or grade 3 and 4. Median duration of CRS after the onset was 5 days (range, 2 to 9 days) and 3 days (range, 2 to 9 days), respectively. Statistical comparison between groups was not performed.

Early Management

In the study by Gaffney et al. (2024)²³ where early management protocol (tocilizumab given if grade 1 CRS persists for 24 hour) was compared with standard management protocol (first dose of tocilizumab given at 72 hour of persistent symptoms), there were no statistically significant difference in the incidence of CRS all grades (P = 0.73) and CRS grade 3 and 4 (P = 1.0) of CRS between treatment groups.

The study by Banerjee et al. (2021)²⁷ compared early tocilizumab (administered at ≤ 12 hour after CRS onset) with late tocilizumab (administered at > 12 hour after CRS onset) groups, or with no tocilizumab group. The study found that both early and late tocilizumab groups had similar incidence of CRS grade 1 (95% versus 95%, P = 1.00) and 2 (5% versus 5%, P = 1.00). However, the median CRS duration of the early tocilizumab group was numerically lower than that in the late tocilizumab group (18.6 hours [range, 5.1 to 106.7] versus 84.7 hours [range, 20.0 to 188.0 hours]). For 7 patients (58%) in the no tocilizumab group who developed CRS (grade was not reported), the median CRS duration was 42.1 hour (range, 1.7 to 141.1 hour).

In the study by Lakomy et al. (2023),²⁴ early use of corticosteroids (10 mg dexamethasone administered before each dose of tocilizumab) was associated with statistically significant lower incidence of high-grade CRS (3 and 4) (0%) compared with standard tocilizumab schedule (10%); P = 0.0497. However, early use of corticosteroids resulted in higher incidence of CRS grade 1 (67% versus 33%; P = 0.0021).

Incidence of ICANS

Prophylaxis

The study by Scott et al. (2023)²⁵ compared prophylactic tocilizumab (administered 4 hours before the second step-up dose level of CAR T-cell therapy) with no prophylactic tocilizumab and found that the incidence of concurrent ICANS with CRS was 5.3% compared with 20%. Statistical comparison between groups was not performed.

The study by Strati et al. (2023)²⁶ compared prophylactic anakinra (administered 6 hour before CAR T-cell infusion on day 0 at a dose of 100 mg daily (n = 10) or 100 mg every 12 hour (n = 10) for 7 days) with no prophylactic anakinra (from a contemporaneous cohort), and found that patients treated with anakinra had lower incidence of ICANS of any grade (35% versus 60%), with overlapped 95% confidence intervals. The median onsets of ICANS were 7 days (range, 3 to 9 days) versus 5 days (1 to 14 days), and the median durations of ICANS were 2 days (range, 2 to 17 days) versus 3 days (1 to 24 days). Statistical comparisons for those outcomes were not performed.

Early Management

In the study by Gaffney et al. (2024)²³ where early management protocol (tocilizumab given if grade 1 CRS persists for 24 hour) was compared with standard management protocol (first dose of tocilizumab given at 72 hour of persistent symptoms), there were no statistically significant difference in the incidence of ICANS all grades (P = 1.0) and ICANS grade 3 and 4 (P = 1.0) between treatment groups.

The study by Banerjee et al. (2021)²⁷ compared early tocilizumab (administered at ≤ 12 hour after CRS onset) with late tocilizumab (administered at > 12 hour after CRS onset) or with no tocilizumab group. The study found that both early and late tocilizumab groups had similar incidence of ICANS all grades (21% versus 37%, P = 0.48). The incidence of ICANS in the no tocilizumab group was not reported.

The study by Lakomy et al. (2023)²⁴ found no statistically significant differences in any grades of ICANS (from grade 1 to 4) between early use of corticosteroids (10 mg dexamethasone administered before each dose of tocilizumab) and standard tocilizumab schedule groups.

Level of Care

Prophylaxis

The study by Scott et al. (2023)²⁵ found no patients in the prophylactic tocilizumab group readmitted to the hospital within 14 days of discharge. Results on hospital readmission in the no prophylactic tocilizumab group were not reported.

In the study by Gaffney et al. (2024),²³ there were no statistically significant differences between early management protocol and standard management protocol in terms of outpatient administration (P = 0.43), length of hospital stay (P = 0.78), and ICU transfer (P = 0.24).

In the study by Lakomy et al. (2023),²⁴ there were no statistically significant differences between early corticosteroids plus standard tocilizumab schedule and standard tocilizumab schedule in terms of length of hospital stay (P = 0.76), and ICU transfer (P = 0.37).

Other AEs and Mortality

Prophylaxis

The study by Scott et al. (2023)²⁵ made an indirect comparison between prophylactic tocilizumab cohort in their study with the cohort in the MajesTEC-1 study,³¹ which underwent standard treatment for AEs, and found that prophylactic tocilizumab did not increase the incidence of grade 3 or 4 neutropenia (42.2% versus 64.2%).

Early Management

Other AEs reported in the study by Gaffney et al. (2024),²³ included infection and cytopenia. There were no statistically significant differences between groups in terms of 90-day incidence of infection (P = 0.20) and cytopenia, including neutropenia (all grades [P = 1.0], or grade 3, 4 [P = 0.6]), anemia (all grades [P = 0.38], or grade 3, 4 [P = 0.40]), and thrombocytopenia (all grades [P = 0.68], or grade 3, 4 [P = 0.52]). The study also found no statistically significant difference between groups in treatment-related mortality (P = 0.32).

Efficacy Outcomes of CAR T-Cell Therapy

In all included studies,^23-25,27 early use or prophylaxis of tocilizumab or corticosteroids did not have negative impact on the efficacy of CAR T-cell therapy.

Prophylaxis

The study by Scott et al. (2023)²⁵ reported that the use of prophylactic tocilizumab resulted in ORR of 70%, which was comparable to that of the MajesTEC-1 study (63%).³¹

Early Management

In the study by Gaffney et al. (2024),²³ patients who received early management for CRS with tocilizumab had a statistically significantly higher overall response rate (ORR) (77% versus 56%; P = 0.0003) and complete response rate (CRR) (64% versus 33%; P = 0.01) at 30 days compared to those who were managed by standard protocol. However, there was no statistically significant difference in ORR (P = 0.14) and CRR (P = 0.29) at 90 days.

The study Banerjee et al. (2021)²⁷ found that early tocilizumab management of CRS did not have negative impact on CAR T-cell therapy efficacy regarding response rates and survival compared with late tocilizumab and no tocilizumab. In fact, the 30-day ORR of the 3 groups were 74%, 79%, and 33%, respectively. The overall difference between groups were statistically significant (P = 0.03). Likewise, the 30-day CRR were 89%, 53%, and 50%, respectively (P = 0.02). The median progression-free survival (PFS) was 35.7 months in the early tocilizumab group, 13.2 months in the late tocilizumab group, and 7.8 months in the no tocilizumab group. The median overall survival (OS) was not reached in the early tocilizumab group, 25.0 months in the late tocilizumab group, and 26.4 months in the no tocilizumab group.

In the study by Lakomy et al. (2023),²⁴ both cohorts (i.e., early corticosteroids in combination with standard tocilizumab versus standard tocilizumab) had no statistically significant difference in ORR (P = 0.79), CRR (P = 0.66), PFS (P = 0.63), and OS (P = 0.12).

Guidelines Regarding the Use of anticytokine drugs, corticosteroids, or both in the treatment of CRS and neurotoxicity following T-cell engager therapy or CAR T-cell therapy

The recommendations in all included guidelines^28-30,32 were not systematically graded due to low-quality evidence. The NCCN guideline²⁸ classified all of its recommendations by consensus as category 2A (based on lower level of evidence). The ASCO guideline²⁹ assigned the strength of its recommendations as moderate (benefits outweigh harms). The EBMT and JACIE guideline³⁰ and the SITC guideline³² did not grade their recommendations.

Three guidelines (NCCN,²⁸ ASCO,²⁹ and EBMT and JACIE³⁰) provided an algorithm outlining the management of CRS or ICANS according to the level of its severity (grade 1 to 4), which was graded based on the ASTCT criteria.⁷ The SITC guideline³² provided a set of recommendations similar to those in the other 3 guidelines,^28-30 but with less details. The following statements summarize the recommendations on the use of anticytokine drugs or corticosteroids of the included guidelines^28-30,32 for the management of CRS and ICANS. Information on additional supportive care is presented in Table 11 for CRS and Table 12 for ICANS.

Management of CRS

• Grade 1 CRS:

  • All included guidelines^28-30,32 recommend 1 dose of tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg) for patients with prolonged CRS (> 3 days), significant symptoms, comorbidities and/or they are older adults.

  • The NCCN guideline²⁸ recommends dexamethasone 10 mg IV every 24 hours for early-onset CRS (< 72 hours after infusion) for patients undergoing idecabtagene and lisocabtagene CAR T therapy.

  • The EBMT and JACIE guideline,³⁰ noted that corticosteroids are contraindicated in the absence of life-threatening complications.

• Grade 2 CRS:

  • All included guidelines^28-30,32 recommend tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg).

  • If there is no improvement or persistent symptoms, the included guidelines^28-30,32 recommend repeating tocilizumab; with no more than 3 doses in 24 hours, with a maximum of 4 doses total. Alternatively, the EBMT and JACIE guideline,³⁰ recommends that treatment could be switched to siltuximab IV 11 mg/kg, 1 dose per day.

  • If CRS does not improve after 1 to 2 doses of tocilizumab, 3 guidelines^28-30 recommend dexamethasone 10 mg IV every 6 to 24 hours depending on the product. The SITC guideline³² recommends alternative treatment with third line drugs, including anakinra, siltuximab, and high-dose methylprednisolone if CRS does not improve after 2 doses of tocilizumab (and steroids).

• Grade 3 CRS:

  • All guidelines^28-30,32 recommend tocilizumab therapy as per grade 2 if maximum dose not reached within 24-hour period. The EBMT and JACIE guideline,³⁰ recommends that treatment could be switched to siltuximab IV 11 mg/kg, 1 dose per day.

  • The included guidelines^28-30,32 recommend dexamethasone 10 to 20 mg IV given every 6 hours for 1 to 3 days. If refractory occurs, patients should be managed as per grade 4 CRS.

• Grade 4 CRS:

  • All guidelines^28-30,32 recommend tocilizumab therapy as per grade 2 if maximum dose not reached within 24-hour period.

  • The guidelines^28-30 recommend dexamethasone 10 to 20 mg IV given every 6 hours for 3 days, with progressive tapering within 3 to 7 days.

  • If refractory occurs, 3 guidelines^28-30 recommend high-dose methylprednisolone IV 1,000 mg per day or per every 12 hours for 3 days with progressive tapering. The NCCN guidelines²⁸ noted that other drugs such as anakinra, siltuximab, ruxolitinib, cyclophosphamide, IV immunoglobulin, antithymocyte globulin, or extracorporeal cytokine adsorption with continuous renal replacement therapy might be considered.

Management of ICANS

• Grade 1:

  • Without concurrent CRS: All included guidelines^28-30,32 recommend supportive care only for ICANS grade 1. The NCCN guideline²⁸ recommends dexamethasone 10 mg IV every 12 to 24 hours for 2 doses if ICANS develops within 72 hours after infusion of either lisocabtagene maraleucel or idecabtagene vicleucel for CAR T-cell therapy.

  • With concurrent CRS: Three included guidelines^28-30 recommend tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg/dose). The SITC guideline³² noted that evidence on the efficacy and safety of tocilizumab for treatment of ICANS was still limited, and that tocilizumab may worsen neurotoxicity; and, therefore, it did not include tocilizumab or other antiinterleukin-6 drugs in its recommendations.

• Grade 2:

  • Without concurrent CRS: All included guidelines^28-30,32 recommend supportive care and a dose of dexamethasone 10 mg IV, followed by reassessment of ICANS. If there is no improvement, 3 guidelines^28-30 recommend a repeat of dexamethasone every 6 to 12 hours.

  • With concurrent CRS: Three guidelines^28-30 recommend tocilizumab therapy as per management of CRS. Patients should be transfer to ICU if neurotoxicity is developed concurrently with CRS of Grade 2 or more.^28-30 The ASCO guideline²⁹ recommends that dexamethasone (10 mg IV every 6 to 12 hours) or methylprednisolone equivalent (1 mg/kg IV every 12 hours) should be initiated if refractory to tocilizumab past the first dose occurs. Corticosteroids should be continued until improvement to grade 1, and then rapidly taper as clinically appropriate.²⁹

• Grade 3:

  • Without concurrent CRS: All guidelines^28-30,32 recommend ICU care and dexamethasone or methylprednisolone therapy as per ICANS grade 2 management. The EBMT and JACIE guideline³⁰ recommends a dexamethasone dose increase to 20 mg.

  • With concurrent CRS: Three guidelines^28-30 recommend tocilizumab therapy as per management of CRS. The ASCO guideline²⁹ recommends that dexamethasone (10 mg IV every 6 to 12 hours) or methylprednisolone equivalent (1 mg/kg IV every 12 hours) should be initiated if refractory to tocilizumab past the first dose occurs, and corticosteroids should be continued until improvement to grade 1, and then rapidly taper as clinically appropriate.

• Grade 4:

  • Without concurrent CRS: Three guidelines^28-30 recommend high-dose corticosteroids (i.e., methylprednisolone IV 1,000 mg 1 to 2 times per day for 3 days. If not improving, consider 1,000 mg of methylprednisolone 2 to 3 times per day or alternate therapy. Continue corticosteroids until improvement to grade 1, and then taper as clinically appropriate.)

  • With concurrent CRS: Three guidelines^28-30 recommend tocilizumab therapy as per management of CRS in addition to methylprednisolone therapy. Continue corticosteroids until improvement to grade 1, followed by rapid tapering.

Limitations

Evidence Gaps

No evidence was found for the following 2 research questions:

• The clinical effectiveness and safety of anticytokine therapy, corticosteroids, or both for the treatment of CRS and neurotoxicity following T-cell engager therapy or CAR T-cell therapy compared with alternative treatment or usual care.

• Recommendations from evidence-based guidelines on the use of prophylactic anticytokine therapy, corticosteroids, or both for the prevention of CRS and neurotoxicity following T-cell engager therapy or CAR T-cell therapy.

Generalizability

The included clinical studies were conducted by authors in the US^23,25-27 and Switzerland.²⁴ The included guidelines were developed in US^28,29,32 and Europe.³⁰ Thus, the clinical findings of the included studies and the recommendations from the included guidelines may be generalizable to the health care context in Canada. However, as patients in all-included studies were adults, it is unclear if the treatment applies to the pediatric population. Although the target population of 3 guidelines^28,30,32 was adults and children, there were no specific recommendations for children.

Heterogeneity

There was substantial heterogeneity among the included clinical studies^23-27 in terms of protocols of anticytokine therapy and corticosteroid treatment), as well as patient population (i.e., having different underlying diagnoses and receiving different CAR T products). Therefore, it was difficult to provide a strong conclusion based on the findings of the included studies.

Certainty of Evidence

The quality of the evidence from the included studies or from the guidelines was generally low as the evidence was derived mainly from nonrandomized cohort studies or follow-up studies. All 5 included clinical studies^23-27 had a small number of patients and were from a single centre. Three studies were of retrospective design^23,24,27 and 2 studies^25,26 were of prospective cohort design that indirectly compared the results of their cohorts with those of a similar study without using any statistical methods. The findings in the included studies^23-27 should be interpreted with cautions due to methodological problems. All the recommendations in the included guidelines^28-30,32 are expert consensus that were based on low-quality evidence (i.e., without randomized evidence).

Conclusions and Implications for Decision- or Policy-Making

This review included 5 clinical studies (3 retrospective chart review studies^23,24,27 used early treatment approach and 2 prospective cohort studies^25,26 used prophylactic approach) and 4 consensus-based guidelines.^28-30,32

The prophylactic or early use of tocilizumab resulted in either lower incidence of CRS, mostly grade 1,²⁵ or no major differences in the incidence or severity of CRS between treatment groups^23,25,27 following CAR T-cell therapy. Despite no difference in the incidence of CRS between groups, it was found that the median CRS duration of the early tocilizumab group was numerically lower than those in the late tocilizumab group or in the no tocilizumab group.²⁷ Early use of corticosteroids was associated with overall higher CRS incidence, mostly grade 1, with no high-grade (3 and 4) CRS.²⁴ There was no apparent difference in the incidence, grade, and duration of CRS between prophylactic and no prophylactic anakinra groups.²⁶

With regard to ICANS, there was no difference in the incidence of all grades when comparing with prophylactic or early use of tocilizumab,^23,25,27 corticosteroids,²⁴ or anakinra²⁶ treatments with no prophylactic or no early treatments.

Early use of tocilizumab²³ or corticosteroids²⁴ following CAR T-cell therapy did not affect the length of hospital stay and incidence of ICU transfer. The incidence and severity of other AEs and/or treatment-related mortality were also not affected by early treatment^23,27 or prophylaxis with tocilizumab.²⁵

Early use of tocilizumab^23,27 or corticosteroids²⁴ did not appear to have a negative impact on treatment outcomes of CAR T-cell therapy, including response rates and survival. Similar findings were observed with prophylactic tocilizumab.²⁵

For the management of CRS, the included guidelines^28-30,32 recommend that tocilizumab can be considered for grade 1 if symptoms persist for 3 days or more. For grade 2 to 4 CRS, all guidelines^28-30,32 recommend the use of tocilizumab, while corticosteroids such as dexamethasone or methylprednisolone can be added in conjunction if there is no improvement or persistent symptoms after tocilizumab therapy. Proposed alternatives to tocilizumab are siltuximab and anakinra.

For the management of ICANS, treatment recommendations of the guidelines^28-30 were based on the absence or presence of concurrent CRS. In the absence of concurrent CRS, supportive care is the preferred treatment option for grade 1 ICANS. Corticosteroids such as dexamethasone or high-dose methylprednisolone are recommended for the management of grade 2 to 4 ICANS until improvement to grade 1, and then taper as clinically appropriate. In the presence of concurrent CRS, the guidelines^28-30 recommend tocilizumab therapy as per management of CRS. Corticosteroids should be continued until improvement to grade 1, followed by rapid tapering.

Considerations for Future Research

Prospective, randomized, and multicentre trials with large patient population are needed to validate the findings. Clinical trials should also involve the pediatric population. Future research is also needed to better understand the underlying mechanism of the disease and to develop novel therapeutic strategies for more effective prevention and management of CRS and ICANS. Future guidelines should consider the following points: recommendations should be made based on higher-quality evidence; evidence and recommendations should be graded using validated tools; recommendations should be made specific for pediatric population if children are included in the target population; methods should be reported clearer; and there must be an explicit link between evidence and recommendations.

Implications for Clinical Practice

Although the findings of this report are not conclusive, they suggest that early use of tocilizumab or corticosteroids, or prophylactic use of tocilizumab or anakinra may reduce the risk of the development of high-grade CRS without negative impact on neurotoxicity or immunotherapy treatment outcomes. However, no identified guidelines recommend prophylactic use of anticytokine therapy and/or corticosteroids for the prevention and management of CAR T-associated CRS or ICANS; therefore, no recommendations can be given. When using the clinical evidence and guidelines summarized in this report to inform decisions, decision-makers should consider that the evidence is limited and of low quality.

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Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Table 2: Characteristics of Included Primary Clinical Studies

BCMA = B-cell maturation antigen; CAR T = chimeric antigen receptor T-cell; CI = confidence interval; CRR = complete response rate; CRS = cytokine release syndrome; h = hour; ICANS = immune effector cell-associated neurotoxicity syndrome; IQR = interquartile range; NR = not reported; ORR = objective (or overall) response rate; OS = overall survival; PFS = progression-free survival; RRMM = relapse/refractory multiple myeloma.

Table 3: Characteristics of Included Guidelines

AE = adverse event; ASCO = American Society of Clinical Oncology; CAR T = chimeric antigen receptor T-cell; CRS = cytokine release syndrome; EBMT = European Society for Blood and Marrow Transplantation; IL = interleukin; JACI = Joint Accreditation Committee of the International Society for Cell Therapy and EBMT; NCCN = National Comprehensive Cancer Network; NR = not reported; PICO = population, intervention, comparator, and outcomes; SITC = Society for Immunotherapy of Cancer.

^aCategories of evidence and consensus:

      Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate;

      Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate;

      Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate;

      Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

^bSummary of The Oxford Levels of Evidence 2:

      Level 1: Systematic review or meta-analysis

      Level 2: Randomized trial or observational study with dramatic effect

      Level 3: Nonrandomized controlled cohort or follow-up study

      Level 4: Case series, case-control, or historically controlled study

      Level 5: Mechanism-based reasoning

Note that this appendix has not been copy-edited.

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 4: Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist²⁰

Table 5: Strengths and Limitations of Guidelines Using AGREE II²¹

AGREE II = Appraisal of Guidelines for Research and Evaluation II; ASCO = American Society of Clinical Oncology; EBMT = European Society for Blood and Marrow Transplantation; JACIE = Joint Accreditation Committee of the International Society for Cell Therapy and EBMT; NCCN = National Comprehensive Cancer Network; NR = not reported.

Appendix 4: Main Study Findings

Note that this appendix has not been copy-edited.

Table 6: Summary of Findings by Outcome — Incidence of CRS

CAR T = chimeric antigen receptor T-cell; CRS = cytokine release syndrome; h = hour; vs. = versus.

Table 7: Summary of Findings by Outcome — Incidence of ICANS

CAR T = chimeric antigen receptor T-cell; CI = confidence interval; CRS = cytokine release syndrome; h = hour; ICANS = immune effector cell-associated neurotoxicity syndrome; NR = not reported; vs. = versus.

Table 8: Summary of Findings by Outcome — Level of Care

CAR T = chimeric antigen receptor T-cell; CRS = cytokine release syndrome; h = hour; ICU = intensive care unit; NR = not reported; vs. = versus.

Table 9: Summary of Findings by Outcome — Other Adverse Events and Mortality

CAR T = chimeric antigen receptor T-cell; CRS = cytokine release syndrome; h = hour; NR = not reported; vs. = versus.

Table 10: Summary of Findings by Outcome — Efficacy Outcomes of Immunotherapy

CAR T = chimeric antigen receptor T-cell; CI = confidence interval; CRR = complete response rate; CRS = cytokine release syndrome; h = hour; NR = not reported; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; vs. = versus.

Table 11: Summary of Recommendations in Included Guidelines for CSR

ASCO = American Society of Clinical Oncology; ASTCT = American Society for Transplantation and Cellular Therapy; ATG = antithymocyte globulin; CRS = cytokine release syndrome; EBMT = European Society for Blood and Marrow Transplantation; G-CSF = granulocyte-colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; ICU = intensive care unit; IVIG = IV immunoglobulin; JACI = Joint Accreditation Committee of the International Society for Cell Therapy and EBMT; NCCN = National Comprehensive Cancer Network; NR = not reported.

^aGrade 1: Fever (≥ 38°C)

^bGrade 2: Fever with hypotension not requiring vasopressors and/or hypoxia requiring low-flow nasal cannula or blow-by.

^cGrade 3: Fever with hypotension requiring a vasopressor with or without vasopressin and/or hypoxia requiring high-flow cannula, face mask, nonrebreather mask, or Venturi mask.

^dGrade 4: Fever with hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation).

^eOther drugs such as anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG, ATG, or extracorporeal cytokine adsorption with continuous renal replacement therapy (CRRT) might be considered. Reported experience with these drugs is limited.

Table 12: Summary of Recommendations in Included Guidelines for ICANS

ASCO = American Society of Clinical Oncology; ASTCT = American Society for Transplantation and Cellular Therapy; ATG = antithymocyte globulin; CRS = cytokine release syndrome; CT = CT; EBMT = European Society for Blood and Marrow Transplantation; EEG = electroencephalogram; G-CSF = granulocyte-colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = immune effector cell-associated encephalopathy; ICU = intensive care unit; IVIG = IV immunoglobulin; JACI = Joint Accreditation Committee of the International Society for Cell Therapy and EBMT; LP = lumbar puncture; NCCN = National Comprehensive Cancer Network; NR = not reported.

ICANS grading according to ASTCT consensus grading scale:

^aGrade 1: ICE score: 7 to 9 with no depressed level of consciousness.

^bGrade 2: ICE score: 3 to 6; and/or mild somnolence awaking to voice.

^cGrade 3: ICE score: 0 to 2; and/or depressed level of consciousness awakening only to tactile stimulus; and/or any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention; and/or focal or local edema on neuroimaging.

^dGrade 4: ICE score: 0 (patient is unarousable and unable to perform ICE); and/or stupor or coma; and/or life-threatening prolonged seizure (> 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between; and/or diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing or papilledema, cranial nerve VI palsy, or papilledema; or Cushing triad.