CAR‑T 围治疗期重度不良反应肿瘤重症医学科救治共识

Chimeric antigen receptor (CAR) T‐cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies. The development of CAR T‐cell therapy represents a prime example for the successful bench‐to‐bedside translation of advances in immunology and cellular therapy into clinical practice. The currently available CAR T‐cell products have shown high response rates and long‐term remissions in patients with relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory lymphoma. However, CAR T‐cell therapy can induce severe life‐threatening toxicities such as cytokine release syndrome, neurotoxicity, or infection, which require rapid and aggressive medical treatment in the intensive care unit setting. In this review, the authors provide an overview of the state‐of‐the‐art in the clinical management of severe life‐threatening events in CAR T‐cell recipients. Furthermore, key challenges that have to be overcome to maximize the safety of CAR T cells are discussed.

Chimeric antigen receptor T cells are a promising new immunotherapy for haematological malignancies. Six CAR-T cells products are currently available for adult patients with refractory or relapsed high-grade B cell malignancies, but they are associated with severe life-threatening toxicities and side effects that may require admission to ICU. The aim of this short pragmatic review is to synthesize for intensivists the knowledge on CAR-T cell therapy with emphasis on CAR-T cell-induced toxicities and ICU management of complications according to international recommendations, outcomes and future issues. Question: What is the role of intensive care in the field of indications, toxicities management, and outcomes after CAR-T cell therapy. Findings: CAR-T cell therapies are developing rapidly and have an increasingly wide range of indications in haematological malignancies, as well as potential for treating solid cancers and autoimmune diseases in the near future. Despite improved survival rates, many patients present severe life-threatening toxicities that may require intensive care management, including cytokine release syndrome, immune effector cells associated neurotoxicity syndromes, immune effector cells associated haemophagocytic lymphohistiocytosis-like syndrome, infections, cardiovascular and renal specific toxicities. Meaning: This short pragmatic update reports the main toxicities after CAR-T cell therapy, the main retrospective observational studies of patients admitted to the ICU for early complications, and a summary of international recommendations for current practice in the medical intensive care unit. Question: What is the role of intensive care in the field of indications, toxicities management, and outcomes after CAR-T cell therapy. Findings: CAR-T cell therapies are developing rapidly and have an increasingly wide range of indications in haematological malignancies, as well as potential for treating solid cancers and autoimmune diseases in the near future. Despite improved survival rates, many patients present severe life-threatening toxicities that may require intensive care management, including cytokine release syndrome, immune effector cells associated neurotoxicity syndromes, immune effector cells associated haemophagocytic lymphohistiocytosis-like syndrome, infections, cardiovascular and renal specific toxicities. Meaning: This short pragmatic update reports the main toxicities after CAR-T cell therapy, the main retrospective observational studies of patients admitted to the ICU for early complications, and a summary of international recommendations for current practice in the medical intensive care unit.

Background CAR-T cell (chimeric antigen receptor T) therapy has emerged as an effective treatment of refractory hematological malignancies. Intensive care management is intrinsic to CAR-T cell therapy. We aim to describe and to assess outcomes in critically ill CAR-T cell recipients. Study design and methods Hospital-wide retrospective study. Consecutive CAR-T cell recipients requiring ICU admission from July 2017 and December 2020 were included. Results 71 patients (median age 60 years [37–68]) were admitted to the ICU 6 days [4–7] after CAR-T cell infusion. Underlying malignancies included diffuse large B cell lymphoma ( n  = 53, 75%), acute lymphoblastic leukemia (17 patients, 24%) and multiple myeloma ( n  = 1, 1.45%). Performance status (PS) was 1 [1–2]. Shock was the main reason for ICU admission ( n  = 40, 48%). Isolated cytokine release syndrome (CRS) was the most common complication ( n  = 33, 46%), while 21 patients (30%) had microbiologically documented bacterial infection (chiefly catheter-related infection). Immune effector cell-associated neurotoxicity syndrome was reported in 26 (37%) patients. At ICU admission, vasopressors were required in 18 patients (25%) and invasive mechanical ventilation in two. Overall, 49 (69%) and 40 patients (56%) received tocilizumab or steroids, respectively. Determinant of mortality were the reason for ICU admission (disease progression vs. sepsis or CRS (HR 4.02 [95%CI 1.10–14.65]), Performance status (HR 1.97/point [95%CI 1.14–3.41]) and SOFA score (HR 1.16/point [95%CI 1.01–1.33]). Conclusions Meaningful survival could be achieved in up to half the CAR-T cell recipients. The severity of organ dysfunction is a major determinant of death, especially in patients with altered performance status or disease progression.

Chimeric Antigen Receptor (CAR) T-cell therapies represents a major advancement in the treatment of refractory hematologic malignancies, with high remission rates for relapsed B-cell lymphomas and leukemias. However, it is associated with a broad spectrum of potentially life-threatening toxicities, many of which require intensive care unit (ICU) management. Key complications include Cytokine Release Syndrome (CRS) and Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS), as well as severe infections, Immune Effector Cell-associated Hematotoxicity (ICAHT), coagulopathies, and organ dysfunctions resulting from the intense inflammatory response induced by CAR T-cells. Approximately one third of patients undergoing CAR T-cell therapy require ICU admission. Among those patients, CRS is the leading indication. . ICANS and sepsis are other major causes of admission to the ICU. This review provides a comprehensive overview of ICU considerations for managing CAR T-cell-related toxicities, covering criteria for ICU admission, approaches to grading and treating complications, and interdisciplinary recommendations to optimize patient outcomes. Enhanced awareness and early intervention are critical in reducing ICU mortality and improving overall survival in patients receiving CAR T-cell therapy.

Objective: Our primary objective was to describe the baseline characteristics, main reasons for intensive care unit (ICU) admission, and interventions required in the ICU across patients who received CAR-T cell immunotherapy. The secondary objectives were to evaluate different outcomes (ICU mortality) across patients admitted to the ICU after having received CAR-T cell therapy. Materials and Methods. We performed a medical literature review, which included MEDLINE, Embase, and Cochrane Library, of studies published from the inception of the databases until 2022. We conducted a systematic review with meta-analyses of proportions of several studies, including CAR-T cell-treated patients who required ICU admission. Outcomes in the meta-analysis were evaluated using the random-effects model. Results: We included four studies and analyzed several outcomes, including baseline characteristics and ICU-related findings. CAR-T cell recipients admitted to the ICU are predominantly males (62% CI-95% (57–66)). Of the total CAR-T cell recipients, 4% CI-95% (3–5) die in the hospital, and 6% CI-95% (4–9) of those admitted to the ICU subsequently die. One of the main reasons for ICU admission is acute kidney injury (AKI) in 15% CI-95% (10–19) of cases and acute respiratory failure in 10% CI-95% (6–13) of cases. Regarding the interventions initiated in the ICU, 18% CI-95% (13–22) of the CAR-T recipients required invasive mechanical ventilation during their ICU stay, 23% CI-95% (16–30) required infusion of vasoactive drugs, and 1% CI-95% (0.1–3) required renal replacement therapy (RRT). 18% CI-95% (13–22) of the initially discharged patients were readmitted to the ICU within 30 days, and the mean length of hospital stay is 22 days CI-95% (19–25). The results paint a current state of matter in CAR-T cell recipients admitted to the ICU. Conclusions: To better understand immunotherapy-related complications from an ICU standpoint, acknowledge the deteriorating patient on the ward, reduce the ICU admission rate, advance ICU care, and improve the outcomes of these patients, a standard of care and research regarding CAR-T cell-based immunotherapies should be created. Studies that are looking from the perspective of intensive care are highly warranted because the available literature regarding this area is scarce.

Purpose: A task force of experts from 11 United States (US) centers, sought to describe practices for managing chimeric antigen receptor (CAR) T-cell toxicity in the intensive care unit (ICU). Materials and Methods: Between June-July 2019, a survey was electronically distributed to 11 centers. The survey addressed: CAR products, toxicities, targeted treatments, management practices and interventions in the ICU. Results: Most centers (82%) had experience with commercial and non-FDA approved CAR products. Criteria for ICU admission varied between centers for patients with Cytokine Release Syndrome (CRS) but were similar for Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Practices for vasopressor support, neurotoxicity and electroencephalogram monitoring, use of prophylactic anti-epileptic drugs and tocilizumab were comparable. In contrast, fluid resuscitation, respiratory support, methods of surveillance and management of cerebral edema, use of corticosteroid and other anti-cytokine therapies varied between centers. Conclusions: This survey identified areas of investigation that could improve outcomes in CAR T-cell recipients such as fluid and vasopressor selection in CRS, management of respiratory failure, and less common complications such as hemophagocytic lymphohistiocytosis, infections and stroke. The variability in specific treatments for CAR T-cell toxicities, needs to be considered when designing future outcome studies of critically ill CAR T-cell patients.

Background Chimeric antigen receptor T-cell (CAR-T) therapy is increasingly used in patients with refractory haematological malignancies but can induce severe adverse events. We aimed to describe the clinical features and outcomes of patients admitted to the intensive care unit (ICU) after CAR-T therapy. Methods This retrospective observational cohort study included consecutive adults admitted to either of two French ICUs in 2018–2022 within 3 months after CAR-T therapy. Results Among 238 patients given CAR-T therapy, 84 (35.3%) required ICU admission and were included in the study, a median of 5 [0–7] days after CAR-T infusion. Median SOFA and SAPSII scores were 3 [2–6] and 39 [30–48], respectively. Criteria for cytokine release syndrome were met in 80/84 (95.2%) patients, including 18/80 (22.5%) with grade 3–4 toxicity. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 46/84 (54.8%) patients, including 29/46 (63%) with grade 3–4 toxicity. Haemophagocytic lymphohistiocytosis was diagnosed in 15/84 (17.9%) patients. Tocilizumab was used in 73/84 (86.9%) patients, with a median of 2 [1–4] doses. Steroids were given to 55/84 (65.5%) patients, including 21/55 (38.2%) given high-dose pulse therapy. Overall, 23/84 (27.4%) patients had bacterial infections, 3/84 (3.6%) had fungal infections (1 invasive pulmonary aspergillosis and 2 Mucorales ), and 2 (2.4%) had cytomegalovirus infection. Vasopressors were required in 23/84 (27.4%), invasive mechanical ventilation in 12/84 (14.3%), and dialysis in 4/84 (4.8%) patients. Four patients died in the ICU (including 2 after ICU readmission, i.e., overall mortality was 4.8% of patients). One year after CAR-T therapy, 41/84 (48.9%) patients were alive and in complete remission, 14/84 (16.7%) were alive and in relapse, and 29/84 (34.5%) had died. These outcomes were similar to those of patients never admitted to the ICU. Conclusion ICU admission is common after CAR-T therapy and is usually performed to manage specific toxicities. Our experience is encouraging, with low ICU mortality despite a high rate of grade 3–4 toxicities, and half of patients being alive and in complete remission at one year.

Chimeric antigen receptor (CAR) T‑cells are genetically engineered to give T‑cells the ability to attack specific cancer cells, and to improve outcome of patients with refractory/relapsed aggressive B‑cell malignancies. To date, several CAR T‑cell products are approved and additional products with similar indication or extended to other malignancies are currently being evaluated. Side effects of CAR T‑cell treatment are potentially severe or even life-threatening immune-related toxicities, specifically cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Consequently, medical emergency teams (MET) are increasingly involved in the assessment and management of CAR T‑cell recipients. This article describes the principles of CAR T‑cell therapy and summarizes the main complications and subsequent therapeutic interventions aiming to provide a survival guide for METs with a proposed management algorithm.

Patients with cancer account for 15% of all admissions to critical care and so an understanding of the pathophysiology and anticipated complications of specialist treatment is essential for the intensive care clinician. The development of chimeric antigen receptor T‐cell therapy for haematological malignancies and immune checkpoint inhibitors for solid organ tumours has led to significant improvements in the prognosis of those patients whose tumours respond. This review is intended to provide the non‐specialist with an understanding of the current concepts in pathophysiology, diagnosis and management of complications due to chimeric antigen receptor T‐cell therapy and immune checkpoint inhibitors for malignant disease.

… of CAR T-cell therapy We believe that the role of intensivists is crucial at different stages of the CAR T-cell process. Once patients are assessed for CAR eligibility, ICU specialists may …

… Retrospective analysis of patients after CAR-T cell therapy, admitted to a tertiary ICU was conducted between January 2019–December 2022 using digital patient records. Our hospital …

… treated with CART who were admitted to the ICU for CART-… admitted to our medical ICU between November 2017 and … up to 60 days after ICU admission. Demographics, clinical data…

ABSTRACT Background Acute kidney injury (AKI) has been reported after CAR-T cells, but available data are limited. We sought to describe the incidence of AKI in a cohort of patients hospitalized in the intensive care unit (ICU) following CAR-T cell reinjection, identify the primary factors linked to the onset of AKI, and ascertain the key determinants associated with kidney outcomes and mortality. Methods We retrospectively analyzed 119 patients hospitalized in ICU after CAR-T cell therapy between 2017 and 2023. Factors associated with AKI, mortality, and kidney sequelae were identified using multivariate analyses. Results Of the 119 patients, 41 patients fulfilled diagnostic criteria of AKI (34%). By multivariate analysis, grade ≥3 cytokine release syndrome (CRS) [OR = 1.20 CI95% (1.01–1.43)] and elevated lactate dehydrogenase (LDH) levels at admission [OR = 1.44 CI95% (1.04–1.99)] were significantly associated with the occurrence of AKI during ICU stay. AKI KDIGO ≥2 was an independent risk factor for hospital mortality [OR = 1.50 (1.22–1.85), P < 0.001]. Nine out of 12 (75%) and 6/9 (67%) patients who had experienced AKI and survived had chronic kidney disease (CKD) at 6 months and 1 year, respectively. We did not identify any specific factor associated with kidney recovery. Conclusion AKI may occur in ICU patients receiving CAR-T cell therapy, especially those who experience CRS and exhibit elevated LDH levels. Early recognition of AKI is of utmost importance as it substantially compromises survival in these patients. Future studies should aim to elucidate the underlying pathophysiological mechanisms of AKI in this context and pinpoint predictive factors for long-term risks of CKD.

Aim: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of re-lapsed or refractory hematologic malignancies, offering durable responses in selected patients while introducing unique immune-mediated toxicities that can rapidly become life-threatening and require intensive care management. This narrative review provides an evidence-based, practical overview of CAR T-cell therapy, focusing on the recognition and management of its major complications in clinical and critical care settings. Current evidence on CAR T-cell biology, clinical indications, toxicity grading, diagnostic evaluation, and intensive care management is synthesized, with particular emphasis on cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Effective management depends on early recognition, standardized grading, close multidisciplinary collaboration, prompt initiation of immunomodulatory therapy, and timely organ support when indicated. Although the use of CAR T-cell therapy is expanding globally, published clinical experience from Türkiye remains limited, highlighting the need for specialized treatment centers, standardized national protocols, multidisciplinary expertise, and prospective outcome registries. This review provides a practical framework for intensivists caring for patients receiving CAR T-cell therapy, particularly in newly established programs and resource-limited settings, and emphasizes strategies to optimize clinical outcomes through early diagnosis and timely intervention.

… ICUs … ICU within 30 days after receiving CAR-T cell therapy. CRS and ICANS were diagnosed and graded according to the American Society for Transplantation and Cellular Therapy (…

Abstract Chimeric antigen receptor (CAR) T-cells belong to the class of immune effector cell (IEC) therapies, which have been associated with striking clinical outcomes, particularly among patients with relapsed/refractory hematologic malignancies. Yet, they have also been associated with unique toxicities, which may lead to very rapid and life-threatening cardiorespiratory, neurological, and multiorgan dysfunction. Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are well-described complications associated with CAR and other immunotherapies. The constellation of signs and symptoms of CAR-associated toxicities may require critical care recognition and intervention that is independent of CRS- and ICANS-specific treatment. Prompt recognition and supportive management by trained critical care staff of CAR-associated toxicities, including, but not limited to, hypotension and shock, acute respiratory distress syndrome (ARDS and pediatric ARDS), acute kidney injury, arrhythmias, coagulopathy, status epilepticus, and intracranial hypertension, may be lifesaving and/or preserve long-term organ function.

An amendment to this paper has been published and can be accessed via the original article.

BackgroundAnti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions.DiscussionThe Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale.ConclusionWe show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.

During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.

Severe cytokine release syndrome (CRS) and neurotoxicity following chimeric antigen receptor T cell (CAR-T) therapy can be life-threatening in some cases, and management of those toxicities is still a great challenge for physicians. Researchers hope to understand the pathophysiology of CRS and neurotoxicity, and identify predictive biomarkers that can forecast those toxicities in advance. Some risk factors for severe CRS and/or neurotoxicity including patient and treatment characteristics have been identified in multiple clinical trials of CAR-T cell therapy. Moreover, several groups have identified some predictive biomarkers that are able to determine beforehand which patients may suffer severe CRS and/or neurotoxicity during CAR-T cell therapy, facilitating testing of early intervention strategies for those toxicities. However, further studies are needed to better understand the biology and related risk factors for CRS and/or neurotoxicity, and determine if those identified predictors can be extrapolated to other series. Herein, we review the pathophysiology of CRS and neurotoxicity, and summarize the progress of predictive biomarkers to improve CAR-T cell therapy in cancer.

Chimeric antigen receptor (CAR) T-cell therapy has yielded impressive outcomes and transformed treatment algorithms for hematological malignancies. To date, five CAR T-cell products have been approved by the US Food and Drug Administration (FDA). Nevertheless, some significant toxicities pose great challenges to the development of CAR T-cell therapy, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Understanding the mechanisms underlying these toxicities and establishing prevention and treatment strategies are important. In this review, we summarize the mechanisms underlying CRS and ICANS and provide potential treatment and prevention strategies.

Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL)1. Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells)2–4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6)2,5. CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden2–4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity2–9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2–3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell–derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions. Blocking IL-1 and iNOS prevents CAR T cell–induced cytokine release syndrome.

Genetically modified T cells that express a chimeric antigen receptor (CAR) are opening a new frontier in cancer immunotherapy. CAR T cells currently are in clinical trials for many cancer types. Cytokine release syndrome (CRS) and neurotoxicities (CAR-related encephalopathy syndrome, CRES) are major adverse events limiting wide deployment of the CAR T cell treatment. Major efforts are ongoing to characterize the pathogenesis and etiology of CRS and CRES. Mouse models have been established to facilitate the study of pathogenesis of the major toxicities of CAR T cells. Myeloid cells including macrophages and monocytes, not the CAR T cells, were found to be the major cells mediating CRS and CRES by releasing IL-1 and IL-6 among other cytokines. Blocking IL-1 or depletion of monocytes abolished both CRS and CRES, whereas IL-6 blocker can ameliorate CRS but not CRES. Therefore, both IL-1 and IL-6 are major cytokines for CRS, though IL-1 is responsible for CRES. It was also demonstrated in the mouse models that blocking CRS does not interfere with the CAR T cell antitumor functions. We summarized new developments in the grading, modeling, and possible new therapeutic approaches for CRS and CRES in this review.

… CAR T cells have similar treatment-related toxicities, the most significant of which have been cytokine release syndrome (… approach that is impossible for CAR T cells. Each autologous …

Abstract Chimeric antigen receptor T cell (CART) therapy represents a novel and a paradigm-shifting approach to treating cancer. Recent clinical successes have widened the applicability of CD19 CART cells for the treatment of relapsed/refractory B-cell NHL, namely tisagenleclucel and axicabtagene ciloleucel. Tisagenleclucel is also approved for relapsed and/or refractory B-ALL up to age 25. CART therapy is associated with unique and potentially life-threatening toxicities, notably cytokine release syndrome (CRS). A better understanding of the pathogenesis of CRS is crucial to ensure proper management. In this review, CRS definitions, profiles, risk factors and grading systems are discussed. Finally, current and novel investigational approaches and therapies for CRS are summarized.

Summary Anti-CD19 chimeric antigen receptor (CAR) T cell therapy represents a breakthrough for the treatment of B cell malignancies. Yet, it can lead to severe adverse events, including cytokine release syndrome (CRS), which may require urgent clinical management. Whether interpatient variability in CAR T cell subsets contributes to CRS is unclear. Here, we show that CD4+ CAR T cells are the main drivers of CRS. Using an immunocompetent model of anti-CD19 CAR T cell therapy, we report that CD4+, but not CD8+, CAR T cells elicit physiological CRS-like manifestations associated with the release of inflammatory cytokines. In CAR T cell-treated patients, CRS occurrence and severity are significantly associated with high absolute values of CD4+ CAR T cells in the blood. CRS in mice occurs independently of CAR T cell-derived interferon γ (IFN-γ) but requires elevated tumor burden. Thus, adjusting the CD4:CD8 CAR T cell ratio to patient tumor load may help mitigate CAR T cell-associated toxicities.

T-cells engineered to express CD19-specific chimeric antigen receptors (CD19 CAR-T cells) can achieve high response rates in patients with refractory/relapsed (R/R) CD19+ hematologic malignancies. Nonetheless, the efficacy of CD19-specific CAR-T cell therapy can be offset by significant toxicities, such as cytokine release syndrome (CRS) and neurotoxicity. In this report of our presentation at the 2018 Second French International Symposium on CAR-T cells (CAR-T day), we describe the clinical presentations of CRS and neurotoxicity in a cohort of 133 adults treated with CD19 CAR-T cells at Fred Hutchinson Cancer Research Center, and provide insights into the mechanisms contributing to these toxicities.

… Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-… This syndrome is a systemic immune storm that involves the mass cytokines releasing by …

Chimeric antigen receptor T cells (CAR T) are a new and exciting immunotherapeutic approach to manage cancer, with impressive efficacy but potentially life threatening inflammatory toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Patients with severe CRS may develop capillary leak syndrome and disseminated intravascular coagulation, with a cytokine signature similar to macrophage activation syndrome/hemophagocytic lymphohistiocytosis. Moderate to severe CRS is managed with the interleukin-6 receptor antagonist tocilizumab with or without corticosteroids, with questions remaining regarding the optimal management of non-responders. ICANS is an inflammatory neurotoxicity typically occurring after CRS, characterized by impaired blood brain barrier integrity. Symptoms of encephalopathy range from mild confusion and aphasia to somnolence, obtundation, and in some cases seizures and cerebral edema. ICANS is currently managed with corticosteroids, however the optimal dose and duration remain to be determined. Little information is available to guide the management of patients with steroid-refractory ICANS. Numerous cytokine targeted therapies have been proposed to manage these inflammatory toxicities, but little clinical data is available. Management of inflammatory toxicities of CAR T often requires multidisciplinary management and intensive care, where allergists and immunologists may encounter patients with these unique toxicities.

Purpose: T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown long-term relapse-free survival in patients with B-cell leukemia and lymphoma. However, cytokine release syndrome (CRS) represents a serious, potentially life-threatening side effect often associated with CAR T-cell therapy. CRS manifests as a rapid (hyper)immune reaction driven by excessive inflammatory cytokine release, including IFNγ and IL6. Experimental Design: Many cytokines implicated in CRS are known to signal through the JAK-STAT pathway. Here we study the effect of blocking JAK pathway signaling on CAR T-cell proliferation, antitumor activity, and cytokine levels in in vitro and in vivo models. Results: We report that itacitinib, a potent, selective JAK1 inhibitor, was able to significantly and dose-dependently reduce levels of multiple cytokines implicated in CRS in several in vitro and in vivo models. Importantly, we also report that at clinically relevant doses that mimic human JAK1 pharmacologic inhibition, itacitinib did not significantly inhibit proliferation or antitumor killing capacity of three different human CAR T-cell constructs (GD2, EGFR, and CD19). Finally, in an in vivo model, antitumor activity of CD19-CAR T cells adoptively transferred into CD19+ tumor-bearing immunodeficient animals was unabated by oral itacitinib treatment. Conclusions: Together, these data suggest that itacitinib has potential as a prophylactic agent for the prevention of CAR T cell–induced CRS, and a phase II clinical trial of itacitinib for prevention of CRS induced by CAR T-cell therapy has been initiated (NCT04071366).

Cytokine release syndrome (CRS) is a common and potentially severe toxicity of chimeric antigen receptor (CAR) T cell therapy, characterized by activation of the host myeloid compartment and systemic inflammation. Although downstream effectors such as interleukin-6 (IL-6) and IL-1β are well-characterized, the upstream signals that initiate CRS remain incompletely understood. By selectively disrupting tumor necrosis factor (TNF) signaling in a mouse model of CRS, we show that CAR T cell-derived TNF promotes the accumulation of pro-inflammatory monocyte-derived macrophages at the tumor site and the induction of host-derived cytokines including IL-6 and IL-1β. We further show that TNF is a determinant of CRS severity in humanized xenochimeras, governing the overall disease course including eventual lethality. Our findings thus identify TNF as an upstream regulator of CRS acting at least in part via the host macrophage compartment.

ABSTRACT Introduction: Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated remarkable anti-tumor activity in B-cell malignancies and is under investigation in other hematologic malignancies and solid tumors. While highly efficacious, post-infusion T cell activity often results in massive cytokine release precipitating cytokine release syndrome (CRS), the signature toxicity of CAR T cells. This toxicity is characterized by systemic immune activation resulting in fever, hypotension, respiratory insufficiency and capillary leak. Either in conjunction with or in the absence of CRS, a subset of patients may also develop mild to severe neurotoxicity. Although the precise pathogenesis of CRS and neurotoxicity aren’t fully elucidated, risk factors and mitigation strategies have been reported. Areas covered: This manuscript provides an in-depth overview of the pathogenesis, clinical characteristics, current toxicity management strategies, and future perspectives pertaining to CRS and neurotoxicity. Expert Opinion: As CAR T cell based therapies gain popularity in the management of various malignancies, the complimentary toxicities of CRS and neurotoxicity pose a clinical challenge in practice. Risk adaptive modeling incorporating disease profile, patient demographics, lymphodepletion, cell dosing, CAR T construct, and potentially cytokine gene polymorphisms may be instructive to assess individualized risk and optimal CRS/neurotoxicity management.

Abstract Immune-based therapies such as chimeric antigen receptor (CAR)-T-cell therapy have revolutionized the landscape of cancer treatment in recent years. Although this class of therapy has demonstrated impressive clinical efficacy against cancers that were once thought to be incurable, its success is in part limited by unique toxicities which can be severe or even fatal. Cytokine release syndrome (CRS) is the most commonly observed toxicity and occurs as a result of non-antigen specific immune activation. Similar to macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), CRS is associated with elevated levels of several cytokines including interleukin-6 (IL-6) that serve as a driver for host immune dysregulation. As a direct anti-cytokine drug, tocilizumab has been a cornerstone in the treatment of CAR-T-associated CRS through its ability to dampen CRS without compromising CAR-T-cell function. However, optimal timing of administration is yet unknown. Here, we review the use of tocilizumab in the management of CAR-T-associated CRS, emphasizing on the clinical efficacy across various CAR constructs and its role in current CRS management algorithms. We also discuss alternative therapies that may be considered for refractory CRS therapy and the use of tocilizumab in the current COVID-19 global pandemic.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape for hematological malignancies. However, cytokine release syndrome (CRS) remains a common and potentially severe toxicity, significantly affecting patient safety and requiring intensive clinical management. This review provides a focused synthesis on the role of cytokines in CRS after CAR T cell therapy, integrating recent mechanistic insights with clinical implications. We delineate the cellular and molecular pathways involving key cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF), describing their sources, downstream signaling events, and effects on target tissues. By bridging basic cytokine biology with clinical aspects and therapeutic strategies, this review aims to provide a comprehensive framework for understanding the role of cytokines in CRS pathophysiology, ultimately supporting the development of safer and more effective CAR T cell therapies.

Chimeric antigen receptor T (CAR T) cell therapy has demonstrated efficacy in the treatment of haematologic malignancies. However, the accompanying adverse events, the most common of which is cytokine release syndrome (CRS), substantially limit its wide application. Due to its unique physiological characteristics, CRS in CAR T-cell treatment for B-cell non-Hodgkin lymphoma (B-NHL) may exhibit some special features. Although existing guidelines had greatly promoted the recognition and management of CRS, many recommendations are not fully applicable to B-NHL. Therefore, it is imperative to identify responses that are specific to CRS observed following CAR T treatment for B-NHL. Based on underlying biological processes and known pathophysiological mechanisms, we tentatively propose a new model to illustrate the occurrence and evolution of CAR T-cell-therapy-related CRS in B-NHL. In this model, tumour burden and bone marrow suppression are considered determinants of CRS. Novel phenomena after CAR T-cell infusion (such as local inflammatory response) are further identified. The proposed model will help us better understand the basic biology of CRS and recognize and manage it more rationally.

Chimeric antigen receptor (CAR) T cells have demonstrated remarkable anti-tumor efficacy against hematological malignancies, such as leukemia and lymphoma. However, patients treated with CAR-T cells frequently experience cytokine release syndrome (CRS), one of the most life-threatening adverse events of the therapy induced by systemic concentrations of pro-inflammatory cytokines throughout the body. Immunosuppressants such as tocilizumab are currently administered to treat the onset and progression of CRS symptoms. In order to reduce the risk of CRS, newly designed next-generation CAR-T treatments are being developed for both hematopoietic malignancies and solid tumors. In this review, we discuss six classes of interesting approaches that control cytokine production of CAR-T cell therapy: adaptor-based strategies, orthogonal cytokine–receptor pairs, regulation of macrophage cytokine activity, autonomous neutralization of key cytokines, kill switches and methods of reversible suppression of CARs. With these strategies, future CAR-T cell therapies will be designed to preemptively inhibit CRS, minimize the patients’ suffering, and maximize the number of benefiting patients.

Chimeric antigen receptor T-cell (CAR T-cell) therapy represents a paradigm shift in treating refractory hematological malignancies. Despite its transformative potential, clinical application is frequently complicated by severe, potentially life-threatening toxicities, with cytokine release syndrome (CRS) being the most prominent. This comprehensive review synthesizes current therapeutic strategies for CRS, integrating recent advancements in multidisciplinary care models, refined risk stratification, and evolving prophylactic protocols. Furthermore, this paper contextualizes CRS management within the broader landscape of CAR T-cell-related adverse event (AE) mitigation, highlighting established best practices and exploring future directions aimed at enhancing the safety profile and optimizing the therapeutic index of CAR T-cell therapies.

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell–associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.

Objectives We aim to assess the pooled incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) in clinical trials and real-world studies of chimeric antigen receptor (CAR) T-cell therapy for hematologic malignancy and compare the incidences among different agents. Methods The PubMed, Embase, and Web of Science databases were searched for clinical trials and real-world studies. An inverse-variance weighting model was used to calculate pooled incidences and subgroup analyses. Multivariable analysis was conducted using binomial-normal modeling. Results Seventy-five trials comprising 3,184 patients were included. The overall pooled incidence was 26.9% (95% CI, 21.7–32.7%) for all-grade and 10.5% (95% CI, 8.1–13.6%) for high-grade ICANS. In subgroup analysis, cohorts with anti-CD19 drugs had significantly higher ICANS incidences than cohorts with other agents. The multivariable analysis demonstrated higher odds of ICANS in anti-CD19 drug studies for high-grade (OR, 4.6) compared to anti-BCMA drug studies. In 12 real-world studies, studies used axicabtagene ciloleucel with CD28 (54.0% all-grade, 26.4% high-grade) exhibited significantly higher rates of all-grade and high-grade ICANS than studies using tisagenlecleucel with 4-1BB (17.2% all-grade, 6.1% high-grade). Conclusions The overall incidences of ICANS with CAR T-cell therapy were 26.9% for all-grade and 10.5% for high-grade. Compared with other agents, patients with anti-CD19 drugs had a significantly increased risk of developing high-grade ICANS. Therefore, careful monitoring of ICANS should be considered for patients undergoing CAR T-cell therapy.

Abstract Chimeric antigen receptor T‐cell (CAR‐T) treatment has revolutionized the landscape of cancer therapy with significant efficacy on hematologic malignancy, especially in relapsed and refractory B cell malignancies. However, unexpected serious toxicities such as cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) still hamper its broad application. Clinical trials using CAR‐T cells targeting specific antigens on tumor cell surface have provided valuable information about the characteristics of ICANS. With unclear mechanism of ICANS after CAR‐T treatment, unremitting efforts have been devoted to further exploration. Clinical findings from patients with ICANS strongly indicated existence of overactivated peripheral immune response followed by endothelial activation‐induced blood–brain barrier (BBB) dysfunction, which triggers subsequent central nervous system (CNS) inflammation and neurotoxicity. Several animal models have been built but failed to fully replicate the whole spectrum of ICANS in human. Hopefully, novel and powerful technologies like single‐cell analysis may help decipher the precise cellular response within CNS from a different perspective when ICANS happens. Moreover, multidisciplinary cooperation among the subjects of immunology, hematology, and neurology will facilitate better understanding about the complex immune interaction between the peripheral, protective barriers, and CNS in ICANS. This review elaborates recent findings about ICANS after CAR‐T treatment from bed to bench, and discusses the potential cellular and molecular mechanisms that may promote effective management in the future. This article is categorized under: Cancer > Biomedical Engineering Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology

Chimeric antigen receptor (CAR) T-cell therapy is one of the most innovative therapies for haematological malignancies to emerge in a generation. Clinical studies have shown that a single dose of CAR T-cells can deliver durable clinical remissions for some patients with B-cell cancers where conventional therapies have failed. A significant complication of CAR therapy is the immune effector cell-associated neurotoxicity syndrome (ICANS). This syndrome presents a continuum from mild tremor to cerebral oedema and in a minority of cases, death. Management of ICANS is mainly supportive, with a focus on seizure prevention and attenuation of the immune system, often using corticosteroids. Parallel investigation to exclude other central nervous system pathologies (infection, disease progression) is critical. In this review, we discuss current paradigms around CAR T-cell therapy, with a focus on appropriate investigation and management of ICANS.

Chimeric antigen receptor (CAR) T-cell systemic immunotherapy has revolutionized how clinicians treat several refractory and relapsed hematologic malignancies. Due to its peculiar mechanism of action, CAR T-cell-based therapy has enlarged the spectrum of neurological toxicities. CAR T-cell-associated neurotoxicity—initially defined as CAR T-cell-related encephalopathy syndrome (CRES) and currently coined within the acronym ICANS (immune effector cell-associated neurotoxicity syndrome)—is perhaps the most concerning toxicity of CAR T-cell therapy. Importantly, hematologic malignancies (especially lymphoid malignancies) may originate in or spread to the central nervous system (CNS) in the form of parenchymal and/or meningeal disease. Due to the emergence of deadly and neurological adverse events, such as fatal brain edema in some patients included in early CAR T-cell trials, safety concerns for those with CNS primary or secondary infiltration arose and contributed to the routine exclusion of individuals with pre-existing or active CNS involvement from pivotal trials. However, based primarily on the lack of evidence, it remains unknown whether CNS involvement increases the risk and/or severity of CAR T-cell-related neurotoxicity. Given the limited treatment options available for patients once they relapse with CNS involvement, it is of high interest to explore the role of novel clinical strategies including CAR T cells to treat leukemias/lymphomas and myeloma with CNS involvement. The purpose of this review was to summarize currently available neurological safety data of CAR T-cell-based immunotherapy from the clinical trials and real-world experiences in adult patients with CNS disease due to lymphoma, leukemia, or myeloma. Increasing evidence supports that CNS involvement in hematologic disease should no longer be considered per se as an absolute contraindication to CAR T-cell-based therapy. While the incidence may be high, severity does not appear to be impacted significantly by pre-existing CNS status. Close monitoring by trained neurologists is recommended.

Introduction Treatment with CD19 chimeric antigen receptor (CAR) T cells is an innovative therapeutic approach for patients with relapsed/refractory diffuse large B cell lymphoma (r/rDLBCL) and B-lineage acute lymphoblastic leukemia (r/rALL). However, convincing therapeutic response rates can be accompanied by cytokine release syndrome (CRS) and severe neurotoxicity termed immune effector cell-associated neurotoxicity syndrome (ICANS). Methods Single center, prospective observational study of fifteen consecutive r/r DLBCL patients treated with Tisagenlecleucel within 1 year at Hannover Medical School. Extensive neurological work-up prior to CAR T cell infusion included clinical examination, cognitive testing (Montreal-Cognitive-Assessment), brain MRI, electroencephalogram, electroneurography, and analysis of cerebrospinal fluid. After CAR T cell infusion, patients were neurologically examined for 10 consecutive days. Afterwards, all patients were assessed at least once a week. Results ICANS occurred in 4/15 patients (27%) within 6 days (4–6 days) after CAR T cell infusion. Patients with ICANS grade 2 (n = 3) exhibited similar neurological symptoms including apraxia, expressive aphasia, disorientation, and hallucinations, while brain MRI was inconspicuous in either case. Treatment with dexamethasone rapidly resolved the clinical symptoms in all three patients. Regarding baseline parameters prior to CAR T cell treatment, patients with and without ICANS did not differ. Conclusions In our cohort, ICANS occurred in only every fourth patient and rather low grade neurotoxicity was found during daily examination. Our results demonstrate that a structured neurological baseline examination and close monitoring are helpful to detect CAR T cell related neurotoxicity already at an early stage and to potentially prevent higher grade neurotoxicity.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for hematologic malignancies. However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant and potentially lethal complication, affecting approximately 27% to 65% of patients and challenging the therapeutic risk-benefit profile. This review synthesizes recent advances in the epidemiology, pathophysiology, diagnosis, and management of ICANS. Incidence varies significantly by product design, with anti-CD19 therapies and CD28-containing constructs demonstrating markedly higher toxicity rates compared to other targets and 4-1BB-based designs. The pathophysiological mechanism centers on blood-brain barrier disruption driven by systemic cytokine release and direct cellular injury. Monocytes and macrophages act as principal effectors, releasing interleukin-1 and granulocyte-macrophage colony-stimulating factor, which trigger endothelial activation and neuroinflammation. Clinical manifestations typically appear within the first week post-infusion, ranging from mild language disturbances to life-threatening cerebral edema. Current management has evolved from reactive symptom control to proactive strategies. Severity-based algorithms guide the use of corticosteroids and intensive care support, while emerging prophylactic approaches, particularly interleukin-1 receptor blockade with anakinra, show promise in reducing severe neurotoxicity without compromising anti-tumor efficacy. Furthermore, diagnostic precision is improving through the use of novel biomarkers, such as chimeric antigen receptor-positive extracellular vesicles, and machine-learning models that predict toxicity days before symptom onset. The management of ICANS is shifting towards a precision medicine paradigm. By integrating predictive biomarkers, artificial intelligence, and novel prophylactic interventions, clinicians can better stratify risk and implement early treatments. Future research focusing on next-generation constructs with engineered safety features will be essential to decouple therapeutic efficacy from neurotoxicity, ultimately optimizing outcomes for patients with advanced hematologic cancers.

Chimeric antigen receptor T-cell (CAR-T) therapy has remarkable efficacy in treating refractory hematologic malignancies. However, CAR-T therapy may induce neurotoxic effects in some patients. Common symptoms of neurotoxicity range from early signs such as headache, confusion, delirium, and aphasia to severe manifestations such as seizures, motor weakness, increased intracranial pressure, cerebral edema, and coma. Magnetic resonance imaging (MRI) can offer invaluable insight into resulting abnormalities in the structure, physiology, and function of the central nervous system. This review aims to examine the current literature on brain MRI findings of CAR-T-induced neurotoxicity, elucidating its diagnostic capabilities, clinical implications, and emerging trends in advancing imaging modalities. An improved understanding of neural correlates of CAR-T neurotoxicity is important for early detection, development of neuroprotective strategies, and optimization of CAR-T regimens to maximize therapeutic efficacy while minimizing adverse neurotoxic effects.

Background/Objectives: Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of hematologic malignancies, achieving durable remissions in cases refractory to standard therapies. A potentially life-threatening complication is immune effector cell-associated neurotoxicity syndrome (ICANS), which poses significant challenges to clinical management. ICANS encompasses a range of neuropsychiatric symptoms, including delirium, mood disorders, psychosis, seizures, and cerebral edema. The psychiatric dimensions of ICANS remain underreported, and their interplay with neurologic manifestations is poorly understood. This study reviews the psychiatric manifestations of ICANS and presents a case series illustrating its clinical complexity. Methods: A systematic literature search was conducted using PubMed and Google Scholar for studies published between 2020 and 2024. Search terms included “ICANS”, “delirium”, “CAR T-cell”, “neurotoxicity”, and “psychiatric”. The inclusion criteria included studies published in English that focused on adult patients experiencing neuropsychiatric symptoms of ICANS. Two clinical cases of ICANS with prominent psychiatric features are presented. Results: The literature review found three relevant studies, which emphasized agitation, hypoactivity, and mood disturbances as often-overlooked psychiatric symptoms linked to ICANS. The case series highlights psychiatric manifestations, including delirium, irritability, and cognitive impairment. Recovery was supported through interventions such as corticosteroid tapering, antipsychotic treatment, and multidisciplinary care. Conclusions: ICANS is a multifaceted syndrome with significant neuropsychiatric sequelae that complicate its diagnosis and management. An enhanced recognition of its psychiatric dimensions and interdisciplinary approaches are critical to improving outcomes.

… or systemic CAR T cell … neurotoxicity syndrome (ICANS) is a global neurotoxicity syndrome that has previously been well-established as a neurotoxicity syndrome associated with CAR T …

Neurological complications are an important concern in patients undergoing chimeric antigen receptor (CAR) T-cell therapy. Consensus guidelines inform the management of immune effector cell-associated neurotoxicity syndrome (ICANS). However, these guidelines are based on the early clinical experience with CD19 targeting CAR T cells in B-cell malignancies. In contrast, there are so far no published best practice recommendations on the current management of other non-classical neurological complications, which frequently develop after CAR T-cell infusion and cause clinically significant neurotoxicity. These non-classical neurological complications could be more prevalent because of additional CAR T-cell targets (eg, B cell maturation antigen [BCMA]), widened access, new indications in clinical development (including solid tumours in the CNS), and long-term follow-up. In this Review, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonisation and Guidelines Committee provides recommendations on the management of CAR T-cell associated neurological complications that occur after treatment with the licensed CD19 and BCMA CAR T cells, as well as neurological toxicities that are emerging with CAR T cells in clinical trials for solid and haematological cancers. We address movement and neurocognitive toxicity, cranial nerve palsies, tumour inflammation-associated neurotoxicity, stroke, myelopathy, peripheral neuropathy, Guillain-Barré syndrome, fludarabine-associated neurotoxicity, and provide guidance on the psychological support for patients. CNS infections were excluded. The guidelines were developed based on the currently available literature and expert opinion. Recommendations are provided when possible, and areas for further research are highlighted to provide a framework to improve patient care.

Chimeric antigen receptor T (CAR-T) cell therapy has transformed outcomes for relapsed/refractory B-cell malignancies and is increasingly reshaping the therapeutic landscape of autoimmune disorders and solid tumors, offering curative potential where options were previously limited. Its broader deployment is, however, constrained by immune-mediated toxicities, chiefly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS spans a heterogeneous spectrum from mild aphasia and tremor to seizures, cerebral edema, coma, and death, and remains difficult to predict prospectively. As CAR-T platforms expand beyond CD19 malignancies, neurotoxicity phenotypes are also broadening beyond classical ICANS. In plasma cell dyscrasias, BCMA-directed CAR-T has been associated with delayed non-ICANS neurotoxicities, including movement and neurocognitive/behavioral symptoms, cranial nerve palsies, and peripheral neuropathic presentations. In parallel, early experiences with CAR-T and related immune effector therapies in autoimmune and neuroimmunologic diseases suggest distinct inflammatory contexts and potentially different neurotoxicity patterns, underscoring the need for indication-specific monitoring and attribution frameworks. Converging data implicate a multilayered pathophysiology involving systemic cytokine surges, disruption of the blood–brain barrier, endothelial dysfunction, and context-dependent trafficking of activated CAR-T cells and other immune effectors into the CNS with baseline neurological vulnerability and the peri-infusion inflammatory milieu likely modulating individual risk. Given the frequency of these complications, an active research effort is underway to identify clinical, functional, and biological signals that could predict and improve their management. However, most biomarkers remain investigational, lacking prospective validation and straightforward clinical utility. This review synthesizes current evidence on the epidemiology, mechanisms, and monitoring of ICANS and emerging non-ICANS syndromes, and offers a fresh perspective on integrated, multimodal risk models to enable more precise stratification and timely intervention across indications.

Chimeric antigen receptor (CAR) T cell therapy represents a scientific breakthrough in the treatment of advanced hematological malignancies. It relies on cell engineering to direct the powerful cytotoxic T-cell activity toward tumor cells. Nevertheless, these highly powerful cell therapies can trigger substantial toxicities such as cytokine release syndrome (CRS) and immune cell-associated neurological syndrome (ICANS). These potentially fatal side effects are now better understood and managed in the clinic but still require intensive patient follow-up and management. Some specific mechanisms seem associated with the development of ICANS, such as cytokine surge caused by activated CAR-T cells, off-tumor targeting of CD19, and vascular leak. Therapeutic tools are being developed aiming at obtaining better control of toxicity. In this review, we focus on the current understanding of ICANS, novel findings, and current gaps.

Background Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of refractory hematological malignancies but is frequently complicated by immune effector cell-associated neurotoxicity syndrome (ICANS). Early clinical recognition remains challenging, as the commonly used Immune Effector Cell-Associated Encephalopathy (ICE) score lacks sensitivity for subtle deficits. Methods In this prospective bicentric study, 100 patients treated with CAR T-cells at Hannover Medical School and Charité - Universitätsmedizin Berlin underwent systematic neurological assessments using both ICE and the newly developed Berlin-Hannover ICANS Severity Assessment (BHISA). Examinations were performed at baseline prior to CAR T-cell infusion, on day 6–7 (±1 day) post-infusion, and during ICANS episodes. Data on the clinical course, other toxicities, comorbidities, CAR T-cell products, and ICANS treatment were collected. Results Thirty-seven patients (37%) developed ICANS, which was associated with preceding cytokine release syndrome and specific CAR T-cell products. While ICE scores clustered at maximum values both at baseline and follow-up, BHISA showed a broader distribution and higher sensitivity to subtle changes. Correlation analyses confirmed agreement between ICE and BHISA, but BHISA captured early cognitive decline more reliably. Receiver operating characteristic analyses demonstrated comparable diagnostic accuracy (BHISA: AUC = 0.783, ICE: AUC = 0,777), with consistently higher sensitivity of BHISA at matched specificity. (Specificity target = 0.7, BHISA sensitivity = 0.743, ICE sensitivity = 0.571; Specificity target = 0.8, BHISA sensitivity = 0.629, ICE sensitivity = 0.571). Conclusion BHISA may provide a more sensitive and more differentiated screening tool for ICANS than ICE by incorporating additional cognitive and motor domains, while remaining easy to use. This may enable earlier and more nuanced detection of CAR T related neurotoxicity, potentially improving patient monitoring across a heterogeneous population.

Background and Objectives Neuroimaging findings in immune effector cell-associated neurotoxicity syndrome (ICANS) have not been systematically described. We created the chimeric antigen receptor (CAR) T-cell Neurotoxicity Imaging Virtual Archive Library (CARNIVAL), a centralized imaging database for children and young adults receiving CAR T-cell therapy. Objectives of this study were to (1) characterize neuroimaging findings associated with ICANS and (2) determine whether specific ICANS-related neuroimaging findings are associated with individual neurologic symptoms. Methods We performed a multicenter retrospective cohort study of patients ≤30 years who experienced ICANS following CAR T-cell therapy for B-cell malignancies between January 1, 12, and January 31, 23, and had a brain MRI in the first 30 days after CAR T-cell infusion. Deidentified MRIs were reviewed by a central study team of pediatric neuroradiologists with experience in ICANS neuroimaging. Imaging features were categorized and correlated with CAR product and clinical characteristics including preinfusion neurologic history, and postinfusion neurologic symptoms alongside CAR T-cell toxicities using logistic regression. Results Of 864 patients treated with CD19 and/or CD22-directed CAR T-cells, 343 developed ICANS. 96 of the patients with ICANS (median age 12, 43% female) had an acute brain MRI. Of these, 36% (95% CI 27%–47%) had ICANS-related MRI abnormalities, most commonly affecting the white matter (24/35, 69%), brainstem (14/35, 40%), leptomeninges (10/35, 29%), and thalami (9/35, 26%). ICANS-related white matter abnormalities were generally bilateral, symmetric, and involved the supratentorial deep white structures, including the external and extreme capsules, corticospinal tracts, centrum semiovale, and periatrial white matter. There were no significant associations between ICANS-related MRI abnormalities and baseline clinical/demographic characteristic or specific ICANS symptoms, but higher ICANS grade was positively associated with MRI abnormalities (adjusted odds ratio 3.7, p < 0.001). Among 12 patients with ICANS-related MRI abnormalities who had follow-up imaging, 10 of 12 (83%) improved and 3 of 12 fully resolved. Discussion ICANS-related brain MRI abnormalities demonstrate unique patterns in the cerebral white matter, brainstem and thalami; their prevalence increases with ICANS clinical grade. Because our cohort is enriched for patients with severe ICANS, it likely overestimates the incidence of ICANS-related imaging abnormalities. A better understanding of neuroimaging findings is valuable for parsing pathophysiologic mechanisms of ICANS and optimizing patient outcomes.

Abstract Chimeric antigen receptor T-cell therapy (CAR-T cell therapy)-associated neurotoxicity includes a range of neurological side effects following CAR-T cell infusion. While ICANS is already a well-recognized, widely described neurological complication, the spectrum of neurological toxicities associated with CAR-T cell therapy has widened to include other, less common but emerging neurotoxicity syndromes. These have been observed with its broader use and the development of new agents. Movement and neurocognitive toxicity represent a recently described and challenging syndrome associated with BCMA-directed CAR-T cell therapies. Cranial and peripheral neuropathies, as well as myelopathy have increasingly been identified. Rare forms of cerebellar toxicity have been described with under development agents as well. Furthermore, strokes or tumor inflammation-associated syndrome (TIAN) in patients with CNS disease may elicit an emergency consultation. Finally, classical forms of acute toxic leukoencephalopathy have been described in a few patients receiving fludarabine as lymphodepleting treatment before CAR-T cell infusion. These forms of neurotoxicity vary in severity, with some cases being severe and even life-threatening in the context of CAR-T cell therapy. The present review summarizes several types of neurotoxicity associated with CAR-T cell therapy in patients with hematologic malignancies, focusing on available data on incidence, clinical presentation, prediction, diagnostics and therapeutic management.

Key Points • Data from a large cohort of CAR T-cell–treated patients question guidelines regarding diagnostic investigations in ICANS management.• Our results emphazise for the first time the role of EEG in the current guidelines but questions the need for systematic MRI and LP.

PURPOSE To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell–related toxicities, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell–associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell–associated neurotoxicity syndrome should be managed with corticosteroids and supportive care. Additional information is available at www.asco.org/supportive-care-guidelines.

Chimeric antigen receptor (CAR) T cell therapies have dramatically improved treatment outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. Despite unprecedented efficacy, treatment with CAR T cell therapies can cause a multitude of adverse effects which require monitoring and management at specialized centers and contribute to morbidity and non-relapse mortality. Such toxicities include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, neurotoxicity distinct from ICANS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, and immune effector cell-associated hematotoxicity that can lead to prolonged cytopenias and infectious complications. This review will discuss the current understanding of the underlying pathophysiologic mechanisms and provide guidelines for the grading and management of such toxicities.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of several haematological malignancies and is being investigated in patients with various solid tumours. Characteristic CAR T cell-associated toxicities such as cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are now well-recognized, and improved supportive care and management with immunosuppressive agents has made CAR T cell therapy safer and more feasible than it was when the first regulatory approvals of such treatments were granted in 2017. The increasing clinical experience with these therapies has also improved recognition of previously less well-defined toxicities, including movement disorders, immune effector cell-associated haematotoxicity (ICAHT) and immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), as well as the substantial risk of infection in patients with persistent CAR T cell-induced B cell aplasia and hypogammaglobulinaemia. A more diverse selection of immunosuppressive and supportive-care pharmacotherapies is now being utilized for toxicity management, yet no universal algorithm for their application exists. As CAR T cell products targeting new antigens are developed, additional toxicities involving damage to non-malignant tissues expressing the target antigen are a potential hurdle. Continued prospective evaluation of toxicity management strategies and the design of less-toxic CAR T cell products are both crucial for ongoing success in this field. In this Review, we discuss the evolving understanding and clinical management of CAR T cell-associated toxicities. Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of various haematological malignancies but is associated with characteristic toxicities as well as less well-defined adverse effects, many of which can be severe and potentially fatal. The increasing clinical experience with CAR T cell products has resulted in better recognition and management of these toxicities using a range of pharmacotherapies, although this is an area of continued evolution and refinement. In this Review, Brudno and Kochenderfer discuss the current understanding and clinical management of CAR T cell-associated toxicities. As clinicians have gained more experience with chimeric antigen receptor (CAR) T cell therapy, the management of cytokine-release syndrome (CRS) has improved, especially with use of the IL-6 receptor antagonist tocilizumab. In addition, monitoring and treatment of immune effector cell-associated neurotoxicity syndrome (ICANS) has improved with refinements to supportive care and glucocorticoid use. Movement disorders are an infrequent complication of B cell maturation antigen (BCMA)-directed CAR T cells, are difficult to manage and can be life-threatening. Prolonged cytopenias, secondary haemophagocytic lymphohistiocytosis and infectious complications are increasingly well recognized, and consensus guidelines have been developed for their management. New T cell malignancies have been reported after CAR T cell therapy but are exceedingly rare. Patients should be monitored for second malignancies indefinitely following CAR T cell therapy. Future directions in this field include the development of less-toxic CAR T cell products. As clinicians have gained more experience with chimeric antigen receptor (CAR) T cell therapy, the management of cytokine-release syndrome (CRS) has improved, especially with use of the IL-6 receptor antagonist tocilizumab. In addition, monitoring and treatment of immune effector cell-associated neurotoxicity syndrome (ICANS) has improved with refinements to supportive care and glucocorticoid use. Movement disorders are an infrequent complication of B cell maturation antigen (BCMA)-directed CAR T cells, are difficult to manage and can be life-threatening. Prolonged cytopenias, secondary haemophagocytic lymphohistiocytosis and infectious complications are increasingly well recognized, and consensus guidelines have been developed for their management. New T cell malignancies have been reported after CAR T cell therapy but are exceedingly rare. Patients should be monitored for second malignancies indefinitely following CAR T cell therapy. Future directions in this field include the development of less-toxic CAR T cell products.

CD19‐targeted chimeric antigen receptor (CAR)‐modified T (CAR‐T) cell immunotherapy has demonstrated impressive results in B‐cell malignancies, and CAR‐T cell therapies targeting other antigens are in development for other cancers. Cytokine release syndrome (CRS) and neurotoxicity can be life‐threatening in a subset of patients. The severity of CRS and neurotoxicity can be impacted by the disease burden, lymphodepletion regimen, and CAR‐T cell dose. Tocilizumab and corticosteroids have been used to manage these toxicities, enabling CD19 CAR‐T cells to be administered without obvious compromise in efficacy. Consensus criteria for grading and managing toxicities will facilitate the widespread application of this treatment modality.

Various grading systems are currently used for chimeric antigen receptor (CAR) T-cell-related toxicity, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). We compared the recently proposed American Society for Transplantation and Cellular Therapy (ASTCT) grading system to other grading scores in 2 populations of adults: patients (n = 53) with B-cell acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T-cells (clinicaltrials.gov #NCT01044069), and patients (n = 49) with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene-ciloleucel (axi-cel) or tisagenlecleucel after US Food and Drug Administration approval. According to ASTCT grading, 82% of patients had CRS, 87% in the B-ALL and 77% in the DLBCL groups (axi-cel: 86%, tisagenlecleucel: 54%), whereas 50% of patients experienced ICANS, 55% in the B-ALL and 45% in the DLBCL groups (axi-cel: 55%, tisagenlecleucel: 15%). All grading systems agreed on CRS and ICANS diagnosis in 99% and 91% of cases, respectively. However, when analyzed grade by grade, only 25% and 54% of patients had the same grade in each system for CRS and ICANS, respectively, as different systems score symptoms differently (upgrading or downgrading their severity), leading to inconsistent final grades. Investigation of possible management implications in DLBCL patients showed that different recommendations on tocilizumab and steroids across current guidelines potentially result in either overtreating or delaying treatment. Moreover, because these guidelines are based on single products and different grading systems, they cannot be universally applied. To avoid discrepancies in assessing and managing toxicities of different products, we propose that unified grading be used across clinical trials and in practice and that paired management guidelines with product-specific indications be developed.

… The use of etanercept or other TNF inhibitors for severe refractory CRS and/or ICANS is not recommended by consensus guidelines owing to the paucity of evidence20,24,44. This …

… We recommend that consensus panels put forth guidelines on early detection strategies for SPMs. Active surveillance should be pursued and may include physical examination, …

Purpose of Review Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, the remarkable efficacy of therapy is not without significant safety concerns. Herein, we will review the unique and potentially life-threatening toxicities associated with CAR-T cell therapy and their association with treatment efficacy. Recent Findings Currently, CAR-T cell therapy is approved for the treatment of B cell relapsed or refractory leukemia and lymphoma, and most recently, multiple myeloma (MM). In these different diseases, it has led to excellent complete and overall response rates depending on the patient population and therapy. Despite promising efficacy, CAR-T cell therapy is associated with significant side effects; the two most notable toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The treatment of CAR-T-induced toxicity is supportive; however, as higher-grade adverse events occur, toxicity-directed therapy with tocilizumab, an IL-6 receptor antibody, and steroids is standard practice. Overall, a careful risk–benefit balance exists between the efficacy and toxicities of therapies. The challenge lies in the underlying pathophysiology of CAR-T-related toxicity which relies upon the activation of CAR-T cells. Summary Some degree of toxicity is expected to achieve an effective response to therapy, and certain aspects of treatment are also associated with toxicity. As progress is made in the investigation and approval of new CARs, novel toxicity-directed therapies and toxicity-limited constructs will be the focus of attention.

Abstract By late 2018, 2 chimeric antigen receptor T (CAR T) cell products have been approved by US and European regulatory authorities. Tisagenlecleucel (Kymriah, Novartis) is indicated in the treatment of patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse, or adult patients with large B-cell lymphoma relapsed or refractory (r/r) after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel (Yescarta, Kite) is indicated for the treatment of adult patients with large B-cell lymphoma relapsed or refractory after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (ZUMA-1 trial). This review will offer a practical guide for the recognition and management of the most important toxicities related to the use of the current commercial CAR T cells, and also highlight strategies to diminish these side effects in the future.

Chimeric antigen receptor T-cell (CAR T) therapies have demonstrated potential to provide long-term remission in incurable hematologic malignancies, and novel approaches for CAR T therapy continue to be developed for treating cancer and other indications. Acute class-effect toxicities, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, remain significant concerns despite their potential reversibility. Given the complexities of balancing safety and efficacy of CAR T therapies, the US Food and Drug Administration (FDA) recently published Guidance for Industry, which included suggested definitions for dose-limiting toxicities (DLTs) for clinical trials of emerging CAR T therapies. However, the DLT definitions in the guidance do not reflect what was used in the phase 1 and/or registrational studies for the approved CAR Ts; for example, these studies defined DLTs as treatment-related, included exceptions, and/or allowed for time to resolve the adverse event. Using DLT definitions from the guidance could have prematurely stopped the early-phase studies of the now approved CAR Ts. In 2023, while designing a first-in-human, phase 1 study of a logic-gated cell therapy, an expert panel of academic cell therapists collaborated with industry partners at A2 Biotherapeutics to assess the practical implications of the FDA guidance. This led the panel to draft the revised recommendations contained herein, which integrate the permissibility of reversible events during dose-escalation for trial sponsors, investigators, health authorities, and other parties who may be involved in future CAR T therapy trials. These expert recommendations balance the safety of patients in early-phase trials with the potential long-term therapeutic opportunities for patients with terminal malignancies.

Autologous CAR-T cell therapy (CAR-T) has improved outcomes for patients with B-cell malignancies. It is associated with the well-described canonical toxicities cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which may be abrogated by corticosteroids and the anti-IL6 receptor antagonist tocilizumab. Practitioners and researchers should be aware of additional toxicities. Here we review current understanding and management of hematologic toxicities after CAR-T, including cytopenias, coagulopathies, bleeding and clotting events, hemophagocytic-lymphohistiocytosis, and tumor lysis syndrome. We pay particular attention to cytopenias, recently termed immune effector cell-associated hematological toxicity (ICAHT). While the "H" is silent, hematotoxicity is not: ICAHT has the highest cumulative incidence of all immune adverse events following CAR-T. Early cytopenia (day 0-30) is closely linked to lymphodepleting chemotherapy and CRS-related inflammatory stressors. Late ICAHT (after day 30) can present either with or without antecedent count recovery (e.g., "intermittent" vs "aplastic" phenotype), and requires careful evaluation and management strategies. Growth factor support is the mainstay of treatment, with recent evidence demonstrating safety and feasibility of early granulocyte colony-stimulating factor (G-CSF) (e.g., within week 1). In G-CSF refractory cases, autologous stem cell boosts represent a promising treatment avenue, if available. The CAR-HEMATOTOX scoring system, validated for use across lymphoid malignancies (B-NHL, multiple myeloma), enables pretherapeutic risk assessment and presents the potential for risk-adapted management. Recent expert panels have led to diagnostic scoring criteria, severity grading systems, and management strategies for both ICAHT and the recently termed immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), now clarified and defined as a distinct entity from CRS.

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving Axicabtagene ciloleucel (Axi-cel) or Tisagenlecleucel (Tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (ANC<100/µl) and prolonged (≥day 21) neutropenia in 72 and 64% of patients respectively. The median duration of severe neutropenia (ANC<500/µl) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary endpoint. In the training cohort (n=58), we observed a significant correlation with baseline thrombocytopenia (r= -0.43, P=0.001) and hyperferritinemia (r=0.54, P<0.0001) on uni- and multivariate analysis. Incidence and severity of CRS, ICANS and peak cytokine levels were not associated with the primary endpoint. We calculated the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (e.g. platelet count, hemoglobin and ANC) and baseline inflammation (e.g. C-reactive-protein, ferritin). This model was validated in two independent cohorts from Europe (n=91) and the USA (n=109), and discriminated patients with severe neutropenia ≥/<14 days (pooled validation: AUC=0.89, Sensitivity 89%, Specificity 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs. 5.5 days, P<0.001), and a higher incidence of severe thrombocytopenia (87% vs. 34%, P<0.001) and anemia (96% vs. 40%, P<0.001). The score implicates pre-CART bone marrow reserve and inflammatory state as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.

Objective: To describe the most common serious adverse effects and organ toxicities associated with emerging therapies for cancer that may necessitate admission to the ICU. Data Sources and Study Selection: PubMed and Medline search of relevant articles in English on the management of adverse effects of immunotherapy for cancer. Data extraction and Data Synthesis: Targeted immunotherapies including tyrosine kinase inhibitors, monoclonal antibodies, checkpoint inhibitors, and immune effector cell therapy have improved the outcome and quality of life of patients with cancer. However, severe and life-threatening side effects can occur. These toxicities include infusion or hypersensitivity reactions, cytokine release syndrome, pulmonary, cardiac, renal, hepatic, and neurologic toxicities, hemophagocytic lymphohistiocytosis, opportunistic infections, and endocrinopathies. Cytokine release syndrome is the most common serious toxicity after administration of monoclonal antibodies and immune effector cell therapies. Most of the adverse events from immunotherapy results from an exaggerated T-cell response directed against normal tissue, resulting in the generation of high levels of proinflammatory cytokines. Toxicities from targeted therapies are usually secondary to “on target toxicities”. Management is largely supportive and may include discontinuation of the specific agent corticosteroids and other immune-suppressing agents for severe (grade 3 or 4) immune-related adverse events like neurotoxicity and pneumonitis. Conclusions: The complexity of toxicities associated with modern targeted and immunotherapeutic agents for cancer require a multidisciplinary approach among ICU staff, oncologists, and organ specialists and adoption of standardized treatment protocols to ensure the best possible patient outcomes.

Immunotherapy with chimeric antigen-specific receptor modified T cells, known as CAR-T, is emerging as a promising approach to hematological malignancies. In this regard, CAR-T against human cluster of differentiation (CD) 19 has demonstrated antitumor efficacy in application to B cell neoplasms resistant to conventional therapy. However, activation of the immune system induces severe and specific complications which can prove life-threatening. These include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (known as ICANS) - the latter being the subject of the present review. Although the physiopathological mechanisms underlying ICANS are not well known, a number of clinical and biological factors increase the risk of developing neurotoxicity associated to CAR-T therapy. Treatment is based on close monitoring, measures of support, anticonvulsivants, corticosteroids, and early admission to intensive care. The present study offers a comprehensive review of the available literature from a multidisciplinary perspective, including recommendations from intensivists, neurologists and hematologists dedicated to the care of critically ill adults.

Background Immunotherapy has introduced a new spectrum of ICU-relevant complications in patients with cancer, including hyperinflammatory syndromes, neurotoxicity, severe pneumonitis, myocarditis, and overlapping infectious complications. Objective To review the major life-threatening complications of cancer immunotherapy from an ICU perspective, focusing on recognition, differential diagnosis, and management. Content We discuss the critical illness patterns associated with CAR-T therapy, immune checkpoint inhibitors, and bispecific T-cell engagers using a syndrome-based framework. Key topics include cytokine release syndrome and HLH/MAS, immune effector cell-associated neurotoxicity syndrome, respiratory failure related to pneumonitis and infection, cardiovascular emergencies such as myocarditis and arrhythmias, and other less common but ICU-relevant organ toxicities. We also summarize the major diagnostic conflicts in the ICU and propose general principles for organ support, immunomodulatory therapy, infection management, and multidisciplinary care. Conclusion Immunotherapy-related critical illness is increasingly relevant in modern oncologic intensive care. Because these syndromes are often clinically overlapping yet potentially reversible, optimal management requires early ICU escalation, parallel diagnostic reasoning, and integrated supportive and syndrome-directed treatment.

As the cancer population increases and immunotherapy becomes widely utilized, severe toxicities from these treatments will become more prevalent. In cancer patients, the most common immunotherapies that lead to critical illness are chimeric antigen receptor T cells, monoclonal antibodies, and immune checkpoint inhibitors. Awareness of their toxicities by the intensive care unit team is of extreme importance. A multidisciplinary approach for diagnosis and treatment is recommended. This article reviews the most common toxicities from immunotherapy and offers a therapy-specific and system-based approach for affected patients.

Immune effector cells (IEC) are a powerful and increasingly targeted tool, particularly for the control and eradication of malignant diseases. However, the infusion, expansion, and persistence of autologous or allogeneic IEC or engagement of endogenous immune cells can be associated with significant systemic multi-organ toxicities. Here we review the signs and symptoms, grading and pathophysiology of immune-related toxicities arising in the context of pediatric immunotherapies and haploidentical T cell replete Hematopoietic Cell Transplantation (HCT). Principles of management are discussed with particular focus on the intersection of these toxicities with the requirement for pediatric critical care level support.

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematological malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients with relapsed or refractory B-cell acute lymphoblastic leukemia up to the age of 25 years and/or adults with large B-cell lymphoma. Many more CAR T products as well as other immunotherapies including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurological toxicity. The assessment and grading of these toxicities have varied considerably across clinical trials and across institutions, making it difficult to compare safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement widely across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20–21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT) in Arlington, VA. Here, we report the consensus of the group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to use, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the post-approval clinical setting.

Advances in paediatric haematopoietic cell transplantation strategies using immune-effector cells (HCT-IEC) and in intensive care management have improved survival expectations for patients with malignant and non-malignant diseases. However, critical illness still complicates the clinical course for 10-35% of patients undergoing HCT-IEC because of disease-related complications or treatment-related toxicities. Given the improvement in survival for these patients in paediatric intensive care units (PICU), the European Society of Paediatric and Neonatal Intensive Care (ESPNIC), the HCT-Cancer Immunotherapy Subgroup of the Paediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, and the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT) derived expert consensus statements to guide PICU admission and early critical care management of patients following HCT-IEC. 27 statements were drafted by the steering committee and subsequently voted on by 20 expert panel members with expertise in HCT and IEC. 20 statements received strong agreement and seven received weak agreement. This consensus statement serves as a guide for intensivists, haematologists, and oncologists during the challenging process of PICU admission and critical care management of patients who have undergone HCT-IEC and can serve as a basis for prioritising future research in the field.

BACKGROUND Risk factors for invasive fungal infections (IFIs) after chimeric antigen receptor-modified T cells (CAR-T) treatment have been poorly studied. Here we are investigating the risk factors and prognosis of IFIs following CAR-T therapy. MATERIAL AND METHODS A case-control study was conducted on the medical records of CAR-T patients admitted to our center between June 2018 and December 2020. The case group (32) consisted of patients who developed IFIs within 60 days after CAR-T infusion, while the control group (298) consisted of patients who did not develop IFIs. The Cox Proportional Hazard Regression model was utilized to analyze the risk factors for the occurrence of IFIs, as well as the factors affecting the 1-year survival rate of patients. RESULT Cumulatively, 364 patients were included. Inflammatory cytokine release syndrome (CRS) grade (hazard ratio (HR) 2.34 confidential interval (CI)（1.03-5.30) P = 0.042), ventilation (HR 3.23 CI (1.20-8.71) P = 0.020) and lymphocyte deficiency duration (HR 1.06 CI (1.01-1.10) P = 0.015) were associated with IFIs. IFIs (HR 1.12 CI (0.52-2.41) P = 0.767) did not affect a patient's one-year survival, which was associated with lymphocyte deficiency (HR 1.04 CI (1.01-1.07) P = 0.004) and treatment with broad-spectrum antibacterial (HR 1.80 CI (1.03-3.11) P = 0.038) within 30 days prior to CAR-T infusion. CONCLUSION There is an increased risk of IFIs in patients with hematologic malignancies due to ventilation, high-grade CRS, and prolonged lymphocyte deficiency within 60 days after CAR-T infusion. Invasive fungal infection was not a risk factor for death within 1 year of CAR-T therapy, while broad-spectrum antibacterial therapy prior to infusion and prolonged lymphocyte deficiency were risk factors.

With immunotherapy innovations for cancer treatment, in particular chimeric antigen receptor (CAR) T cells, becoming more successful and prevalent, strategies to mitigate and manage their toxicities are required. Anti-CD19 CAR T-cell therapy has revolutionized the treatment of relapsed/refractory pediatric and adult acute lymphoblastic leukemia and refractory adult non-Hodgkin lymphoma, resulting in the expanded use of CAR T cells in multicenter trials and as US FDA-approved products. Cytokine release syndrome (CRS) and CAR-associated neurotoxicity, which can occur independently or concurrently with CRS, are two potentially life-threatening toxicities of CAR T-cell therapy. In this review, we will focus on describing the pathophysiology behind CRS, the proposed definitions of and grading systems for CRS, and innovative options for treating this potentially lethal systemic inflammatory condition.

With continued advances in targeted cancer treatment, such as chimeric antigen receptor T-cell (CAR-T) therapy, emergency departments (EDs) across the United States should be prepared to diagnose and care for patients who experience unique adverse events related to CAR-T administration. CAR-T therapy is the first genetically modified cellular therapy approved by the Food and Drug Administration for treatment of several hematologic malignancies, including leukemia, lymphoma, and myeloma. The side effect profile differs from conventional chemotherapy and consists of a spectrum of immune-mediated clinical manifestations, particularly cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and the more recently described immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome can present with nonspecific symptoms and signs and should be differentiated from other life-threatening pathologies such as sepsis and meningitis. There is limited guidance for emergency physicians and staff regarding the recognition and management of CAR-T complications, both in adult and pediatric patient care settings. This clinical review provides insight into the common and less common CAR-T toxicities, including symptomatology, diagnostic approach, and fundamental principles of complication management in adult and pediatric patients undergoing CAR-T therapy.

… of CRS can range from very mild grade 1 (low-grade fever, tachycardia) to very severe grade 4 CRS (respiratory failure requiring mechanical ventilation, hypotensive shock, multi-organ …

PURPOSE Life-threatening complications of CD-19 Chimeric antigen receptor - T (CAR-T) cells such as the cytokine release syndrome (CRS)) have been reported. Treatment is limited to IL-6 blockade and steroids although global removal of elevated soluble inflammatory factors might be more effective. METHODS Clinical course of a CRS patient treated with extracorporeal cytokine adsorption (Cytosorb®). A panel of 48 cytokines, chemokines and endothelial markers has been analyzed longitudinally. Ex vivo stimulation of endothelial cells to visualize (immunocytochemistry) and quantify (ECIS, TER) endothelial barrier effects. RESULTS Following CAR-T cell application a 65 years old male developed grade 4 CRS with refractory shock (3 vasopressors) and severe capillary leakage (+37 L/24 h resuscitation). Treatment included IL-6 blockade, methylprednisolone and additionally Cytosorb hemoperfusion. While multiple soluble inflammatory factors were elevated and most of them decreased by more than 50% following Cytosorb, markers of endothelial injury increased steadily (e.g. Angpt-2/Angpt-1) leading to profound endothelial activation and leakage in ex vivo assays. CONCLUSION This is the first reported use of cytokine adsorption for CRS showing efficacy in absorption of various cytokines but not endothelial growth factors. A randomized controlled trial to evaluate additional Cytosorb treatment in CRS is currently recruiting at our institution (NCT04048434).

… CRS indicated life-threatening symptoms requiring ventilator … -1-deficient mice from endotoxic shock [43]. Hence, TF and … CRS-related coagulopathy, thus enhancing the safety of CAR…

… similarities with septic shock but has distinct pathophysiological … injury specifically in CAR-T CRS is incomplete. Future … of lung-protective ventilation strategies, and prevention of …

Chimeric antigen receptor (CAR)-T cell therapy is effective in the treatment of refractory/relapsed (r/r) hematological malignancies (r/r B-cell lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma). In addition, it is being explored as a treatment option for solid tumors. As of 31 March 2022, seven CAR-T therapies for hematological malignancies have been approved worldwide. Although CAR-T therapy is an effective treatment for many malignancies, it also causes adverse effects. The incidence of cytokine release syndrome (CRS), the most common adverse reaction after infusion of CAR-T cells, is as high as 93%.CRS, is the leading risk factor of immune effector cell-associated neurotoxicity syndrome (ICANS), as well as cardiovascular, hematological, hepatorenal, skin, pulmonary, and gastrointestinal toxicity. Severe adverse reactions complicated by CRS severely impede the widespread application of CAR-T therapy. The CAR-T product was initially approved in 2017; however, only limited studies have investigated the adverse reactions owing to CAR-T therapy compared to that of clinically approved drugs. Thus, we aimed to elucidate the mechanisms, risk factors, diagnostic criteria, and treatment of toxicities concurrent with CRS, thereby providing a valuable reference for the safe, effective, and widespread application of CAR-T therapy.

Chimeric antigen receptor (CAR)-expressing T cells now offer an effective treatment option for people with previously refractory B cell malignancies and are under development for a wide range of other tumours. However, neurological toxicity is a common complication of CAR-T cell therapy, seen in over 50% of recipients in some cohorts. Since 2018, the term immune effector cell-associated neurotoxicity syndrome (ICANS) has been used to describe and grade neurotoxicity seen after CAR-T cells and other similar therapies. ICANS following CAR-T therapy is usually self-limiting but can necessitate admission to the intensive care unit and is rarely fatal. As CAR-T therapies enter routine clinical practice, it is important for neurologists to be aware of the nature of neurological complications. Here, we summarise the clinical manifestations, mechanisms, investigations and recommended treatment of CAR-T-related neurotoxicity, focusing on the licensed CD19 products.

ABSTRACT Introduction Chimeric antigen receptor (CAR) T-cell is among the most prevalent approaches that act by directing T-cells toward cancer; however, they need to be optimized to minimize side effects and maximize efficacy before being used as standard treatment for malignancies. Neurotoxicity associated with CAR T-cell therapy has been well-documented in recent works. Areas covered In this regard, two established syndromes exist. Immune effector cell-associated neurotoxicity syndrome (ICANS), previously called cytokine release encephalopathy syndrome (CRES), is a neuropsychiatric condition which can occur after therapy by immune effector cells (IEC) and T-lymphocytes utilizing treatments. Another syndrome is cytokine release syndrome (CRS), which may overlap with ICANS. Expert opinion ICANS clinical manifestations include cerebral edema, mild lethargy, aphasia, and seizures. Notably, ICANS is associated with changes to EEG and neuroradiological findings. Therefore, it is necessary to make a timely and accurate diagnosis of neurological complications of CAR T-cells by clinical presentations, neuroimaging, and EEG. Since neurological events by different CAR T-cell products are heterogeneous, guides should be developed according to each product. Here, we provide an updated review of general information on CAR T-cell therapies and applications, neurological syndromes associated with their use, and risk factors contributing to ICANS.

… Cerebral edema is the most serious of the ICANS … , specifically to address cerebral edema and seizures. While grade … correlates of neurotoxicity associated with CAR T-cell therapy in …

… type of seizures, motor deficits, and imaging-based or clinical findings of cerebral oedema. … at particular risk of ICANS, and they generally use commercial CAR T cell products that are …

The advent of chimeric antigen receptor (CAR)-T cells has recently changed the prognosis of relapsing/refractory diffuse large B-cell lymphomas, showing response rates as high as 60 to 80%. Common toxicities reported in the pivotal clinical trials include the cytokine release syndrome (CRS) and the Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), a stereotyped encephalopathy related to myeloid cell activation and blood–brain barrier dysfunction, presenting with a distinctive cascade of dysgraphia, aphasia, disorientation, attention deficits, vigilance impairment, motor symptoms, seizures, and diffuse brain oedema. The tremendous oncological efficacy of CAR-T cells observed in systemic B-cell malignancies is leading to their growing use in patients with primary or secondary central nervous system (CNS) lymphomas and in patients with solid tumours, including several CNS cancers. Early studies conducted in adult and paediatric patients with solid CNS tumours reported a distinct profile of neurotoxicity referred to as Tumour inflammation-associated neurotoxicity (TIAN), corresponding to local inflammation at the tumour site manifesting with focal neurological deficits or mechanical complications (e.g., obstructive hydrocephalus). The present review summarises available data on the efficacy and safety of CAR-T cells for solid and haematological CNS malignancies, emphasising known and emerging phenotypes, ongoing challenges, and future perspectives.

Axicabtagene ciloleucel (AC) is an FDA-approved anti-CD19 autologous chimeric antigen receptor T-cell (CAR-T) therapy for refractory diffuse large B cell lymphoma (DLBCL). While its efficacy in DLBCL has been promising, neurotoxicity remains a significant concern. We present a case of a 22-year-old woman with chemotherapy-refractory DLBCL who exhibited Grade IV neurotoxicity in the setting of sepsis, after undergoing AC infusion. Despite prophylactic levetiracetam given per guidelines,1,2 she experienced a precipitous mental status decline on post-infusion day 8 (D8) followed by hypoxic respiratory failure in the setting of clinical status epilepticus on D11 and nonconvulsive status epilepticus (NCSE) on D18. While neuroimaging was unremarkable, EEG demonstrated diffuse slowing and 2.5–3 Hz generalized periodic discharges consistent with NCSE. Seizures were initially refractory to lorazepam, increasing doses of levetiracetam, and phenobarbital, requiring a midazolam drip titrated to 50–70% burst suppression for resolution. Methylprednisolone and tocilizumab were used to treat neurotoxicity and cytokine release syndrome, respectively. Empiric antibiotics were used for sepsis. After cessation of sedatives on D19, mental status improved to near baseline. PET/CT just prior to discharge showed a complete response of the DLBCL (Deauville 3). She was discharged on D37 with no further seizure activity. Unfortunately, a 3-month interval PET/CT demonstrated disease progression which continued through salvage pembrolizumab eventually leading to death 1.2 years post-CAR-T infusion. This case illustrates the clinical management challenges of a complex and rare neurotoxic side effect of CAR-T cell therapy, namely NCSE following status epilepticus.

… While some ICANS patients experience mild symptoms … , seizure, coma, and diffuse cerebral edema, with a potentially fatal outcome.Notably, up to 10% of patients may exhibit seizures …

Dear Editor, Chimeric Antigen Receptor (CAR) T cell therapy is a transforma-tive treatment that is being increasingly utilized. The novel mechanism of action lends itself to unique toxic pro fi les. These toxicities manifest in two forms: cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). ICANS typically manifests as a toxic encephalopathy with a complex delirium. Seizures have been reported as rare occurrences, with very little detail regarding the clinical presenta- tion, assessment or management [1 – 5]. The electroencephalogram (EEG) is a critical diagnostic test for the assessment of seizures and nonconvulsive status epilepticus (NCSE). In ICANS, the indications and utility of the EEG remain poorly de fi ned [1]. EEG fi ndings have been reported anecdotally and in small case series [1, 6]. The most common fi nding has been that of non-speci fi c generalized slowing and generalized periodic discharges [6]. EEG is crucial for the diagnosis of episodic seizures and NCSE in ICANS, and it may assist in con fi rming and assessing the degree of encephalopathy. We present a uniform cohort of relapsed/refractory B cell lymphoma patients treated with a single FDA-approved CD-19 targeting CAR-T, axicabtagene ciloleucel (Yescarta). We conducted a retrospective review of all patients with B-cell non-Hodgkin lymphoma who received Yescarta through either clinical trial or standard of care at the Mayo Clinic in Minnesota, Arizona and Florida between June 2016 and October 2018. EEG recordings were independently reviewed in accordance with the American Clinical Neurophysiology Society ’ s Standardized Critical Care EEG Terminology [7]. The clinical course and grade of ICANS were determined

… Such diffuse rapid brain swelling was … ICANS may emerge from CRS weeks after CAR-T cell infusion. Our involvement started with “altered mental status and edema on CT of the brain.” …

Chimeric antigen receptor (CAR) T-cell therapy has transformed treatment of refractory B-cell malignancies; however, treatment puts patients at risk for side effects secondary to the amplified immune response it induces. Fulminant cerebral edema (FCE) is one of the rarest, yet most devastating side effects following CAR T-cell therapy. Due to this rarity, FCE has not been well characterized and the risk factors associated with its development are not fully understood. Here, we present a case of a 42-year-old male who passed away from FCE following CAR T-cell infusion with the primary goal to better understand which patients are at higher risk of developing FCE before and after infusion.

Chimeric antigen receptor (CAR) T-cell therapy is a novel immunotherapy that has demonstrated remarkable remission responses in refractory hematological cancers [1]. However, its high efficacy is hampered, in a subset of patients, by an exaggerated systemic hyper-inflammatory response, namely cytokine release syndrome (CRS), and neurological adverse events, namely immune effector cell-associated neurotoxicity syndrome (ICANS) [2]. Clinical manifestations of ICANS are heterogeneous, ranging from language disturbances and frontal-predominant encephalopathy to akinetic mutism and, anecdotally, fulminant diffuse cerebral edema [1–3]. The latter is characterized by rapid neurological deterioration which may lead to death within 24 h, therefore representing the most fearsome complication of CAR T-cell therapy [1, 4, 5]. Nonetheless, its underpinning biologics, incidence, risk factors, and best management strategies remain currently unclear, thus representing an urgent unmet need. Hereby, we describe a case of fatal fulminant diffuse cerebral edema related to CAR T-cell therapy and critically review the literature on this peculiar neurological presentation to shed light on its pathophysiological mechanisms. This was the only case that developed this complication among 46 patients affected by refractory large B cell lymphoma who received CAR T-cell therapy at our hospital. A 35-year-old woman, affected by chemo-refractory primary mediastinal large B cell lymphoma, received CAR T-cell therapy at the IRCCS AOU Bologna. A comprehensive neurological screening evaluation (neurological examination, EEG, nerve conduction study, brain MRI and neuropsychological tests) was unremarkable. The patient received five cycles of pembrolizumab (the first before leukapheresis and the other four as bridging therapy) and lymphodepleting chemotherapy according to the standard conditioning with fludarabine (30 mg/m2 once daily for three days) and cyclophosphamide (500 mg/m2 once daily for three days), prior administration of axicabtagene ciloleucel (Axi-cel; 2 × 106 anti-CD19 CAR T-cells/kg). Twelve hours after CAR T-cells infusion, she developed a grade 1 CRS, which resulted refractory to tocilizumab given for three doses on days + 2 and + 3 post CAR T-cells infusion, according with EBMT and ASTCT guidelines [2, 6]. Tocilizumab was started concomitantly with a slight increase of both IL-6 (34.9 pg/ml, normal value < 5.9 pg/mL) and C-reactive protein (5.05 mg/dL, normal value < 0.5 mg/ dL) plasma level. A chest computed tomography (CT) scan and several blood cultures, performed according to the internal protocol, excluded an infectious etiology. CRS did not progress to a higher grade and neurological evaluations were repeatedly unremarkable. Nonetheless, during the night between day + 3 and + 4, she developed vomiting in addition to fever and, on the following morning, she presented with non-fluent expressive aphasia and myoclonic postural tremors (ICANS grade 2), becoming Umberto Pensato, Lorenzo Muccioli, Francesca Bonifazi and Maria Guarino have contributed equally to this work.

Background: Chimeric antigen receptor-engineered (CAR) T-cell therapy remains limited by significant toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR T-cell patients remains unknown. Objectives: Our primary objective was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR T-cell therapy. Our secondary objective was to evaluate the impact of key treatment, patient, and disease-related variables on time to CRS/ICANS resolution and treatment-related mortality (TRM). Study design: We retrospectively analyzed the outcomes of 43 patients with B-cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of the anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin and performance status. Results: Indications for anakinra treatment were as follows: grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n=40), grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n=3). Anakinra treatment was feasible and was safe; anakinra discontinuation due to anakinra-related side effects was only reported in 3 patients (7%). The overall response rate (ORR) to CAR T-cell therapy was 77%. The cumulative incidence of TRM in the whole cohort at day-28 and day-60 after CAR T-cell infusion was 7% (95%CI, 2-17) and 23% (95%CI, 11-38), respectively. The cumulative incidence of TRM at day-28 after anakinra initiation was 0% and 47% (95%CI, 20-70) in the high-dose (>200mg/day administered intravenously [IV]) and low-dose (100-200mg/day administered subcutaneously or IV) anakinra patients, respectively. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in patients who received high-dose anakinra and was not reached in patients who received low-dose anakinra due to the high TRM in this group. Univariate Cox modeling suggested shorter time to CRS/ICANS resolution in high-dose anakinra patients (HR, 2.19; 95%CI, 0.94-5.12; p=0.069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin and pre-LD KPS, higher anakinra dose remained associated with lower TRM (HR = 0.41 per 1mg/kg/day increase; 95% CI, 0.17-0.96; p=0.039. The only factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin, and anakinra dose, was higher pre-LD KPS HR = 1.05 per 10% increase; 95%CI, 1.01-1.09; p=0.02). Conclusion: Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12mg/kg/day IV. We observed an ORR of 77% after CAR T-cell therapy despite anakinra treatment, suggesting limited impact of anakinra on CAR T-cell efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings.

Background: CD19 CAR T cells have demonstrated high response rates in patients (pts) with relapsed or refractory (R/R) lymphoma, but these therapies are associated with high rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), often requiring prolonged hospital stay including transfer to the intensive care unit (ICU). Real-world data and early and prophylactic corticosteroid trials with axicabtagene in R/R large cell lymphoma have reported lower rates of severe CRS to <10%, but severe ICANS remains elevated at 13-31% (Nastoupil L et al. J Clin Oncol2020; Oluwole O et al. BJH 2021). We have previously reported that elevated interleukin-1 (IL-1) in cerebrospinal fluid (CSF) was associated with ICANS (Santomasso B et al. Cancer Discov 2018), and IL-1 inhibition prevented development of severe ICANS and CRS in the in vivo preclinical model (Giavridis T et al. Nat Med 2018). Based on these data, we initiated a phase II study of IL-1 receptor inhibitor, anakinra (SOBI), in adult pts receiving commercial CD19 CAR T cells for prevention of CRS and ICANS (NCT04148430). Methods: Adult pts with R/R large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL) receiving commercially available CD19 CAR T cells were enrolled. Pts received anakinra 100mg subcutaneous every 12 hours starting either on day 2 of CAR T cell infusion or after 2 documented fevers of ≥38.5 prior to day 2, whichever was earlier. Anakinra was continued for a minimum of 10 days, and the dose could be increased to 100mg every 6 hours and continued beyond 10 days in the case of persistent or progressing CRS and ICANS. Pts received tocilizumab and/or corticosteroids after anakinra initiation for persistent or worsening CRS or ICANS. CRS and ICANS were assessed per the ASTCT consensus grading. Disease response was assessed per the Lugano criteria. The primary objective was to determine the rate of severe ICANS within the first 28 days of CAR T cell infusion. Secondary objectives included assessment of severe CRS, all grades of CRS and ICANS, disease response and serum and CSF cytokines. Results: A total of 31 pts (LBCL=27, MCL=4) were enrolled to the study. The median age of the pts at the time of T cell infusion was 62 (range, 30-77). CD19 CAR products included axicabtagene (23 pts; 74%), tisagenlecleucel (4 pts; 13%) and brexucabtagene (4 pts; 13%). 17 pts (55%) received bridging therapy prior to T cell infusion. All pts started anakinra at 100mg q12h; 25 pts started on day 2 and 6 pts prior to day 2 for grade 1 CRS. Anakinra dose was increased to 100mg q6h in 13 pts (42%). The median duration of anakinra administration was 10 days (range, 10-27). CRS of all grades was observed in 21 pts (68%) with severe CRS (grade 3-4) in 2 pts (6%) (1 with axicabtagene and 1 with brexucabtagene) (Table). Median CRS duration was 5.5 days (range, 1-21). ICANS of all grades was observed in 4 pts (13%), with severe ICANS in 2 pts (6%) (both grade 3; 1 with axicabtagene and 1 with brexucabtagene). No pt experienced grade 5 CRS or ICANS. Tocilizumab and corticosteroids were used in 9 pts (29%) and 6 pts (19%), respectively. Three pts (10%) required ICU transfer (2 with brexucabtagene and 1 with axicabtagene). In LBCL pts treated with axicabtagene (n=23), both severe CRS and ICANS were observed in 4% with tocilizumab and steroid use in 22% and 13%, respectively (Table). With a median follow-up of 104 days (range, 21-363), overall disease response rate at month 1 was 74% for all pts, with CR rate at 1 and 3 months of 58% and 52%, respectively. Conclusion: Early use of IL-1 receptor inhibitor anakinra appears to be safe and feasible, and reduces the rates of both severe CRS and ICANS with the comparable response rates in adult pts with R/R B-cell lymphoma receiving CD19 CAR T cells. The overall severe CRS and ICANS rates were 6% each with relatively low utilization of tocilizumab (29%) and corticosteroids (19%). In pts receiving axicabtagene, the rate of severe ICANS was 4%. A longer follow-up is needed to assess durability of remission, but the study provides strong support for continued investigation of IL-1 inhibition in prevention of severe ICANS. Further exploratory analysis is planned to address the impact of anakinra on changes in serum and CSF cytokines. Figure 1 Figure 1. Park: BMS: Consultancy; Servier: Consultancy; Minerva: Consultancy; Curocel: Consultancy; Autolus: Consultancy; PrecisionBio: Consultancy; Intellia: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Artiva: Consultancy; Kura Oncology: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Innate Pharma: Consultancy. Sauter: Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Palomba: Juno: Patents & Royalties; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; Wolters Kluwer: Patents & Royalties; PCYC: Consultancy; Ceramedix: Honoraria; Lygenesis: Honoraria; Magenta: Honoraria; BeiGene: Consultancy; WindMIL: Honoraria; Rheos: Honoraria; Nektar: Honoraria; Priothera: Honoraria; Pluto: Honoraria. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Dahi: Gilead sciences: Membership on an entity's Board of Directors or advisory committees; Kite pharma: Membership on an entity's Board of Directors or advisory committees. Scordo: Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; McKinsey & Company: Consultancy. Batlevi: Kite Pharma: Consultancy; TouchIME: Honoraria; Seattle Genetics: Consultancy; Juno/Celgene: Consultancy; Karyopharm: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Medscape: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; Life Sciences: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Perales: Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Equilium: Honoraria; Servier: Honoraria; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; Takeda: Honoraria; Medigene: Honoraria; Incyte: Honoraria, Other; Cidara: Honoraria; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; Sellas Life Sciences: Honoraria; NexImmune: Honoraria; Omeros: Honoraria; Novartis: Honoraria, Other. Santomasso: Janssen: Consultancy; Legend: Consultancy; Kite/Gilead: Consultancy; Celgene/BMS: Consultancy; Incyte: Consultancy; In8bio: Consultancy. Sadelain: Juno Therapeutics: Patents & Royalties; NHLBI Gene Therapy Resource Program: Other: Provision of Services (uncompensated); Minerva Biotechnologies: Patents & Royalties; Mnemo Therapeutics: Patents & Royalties; Fate Therapeutics: Other: Provision of Services (uncompensated), Patents & Royalties; Takeda Pharmaceuticals: Other: Provision of Services, Patents & Royalties; St. Jude Children's Research Hospital: Other: Provision of Services; Ceramedix: Patents & Royalties; Atara Biotherapeutics: Patents & Royalties. Brentjens: BMS: Consultancy, Patents & Royalties, Research Funding; Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; sanofi: Patents & Royalties; Caribou: Patents & Royalties. Anakinra for prevention of CRS and ICANS associated with CD19 CAR

Background: Chimeric antigen receptor-engineered (CAR) T-cell therapy remains associated with significant toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Recently, the recombinant IL-1 receptor antagonist anakinra has emerged as a promising approach after failure of tocilizumab and corticosteroids to treat CRS/ICANS (Norelli, Nat Med 2018; Giavridis, Nat Med 2018). Here, we describe the safety and efficacy of two anakinra dose regimens to treat refractory CRS and/or ICANS after CAR T-cell therapy. Methods: We retrospectively analyzed data from 26 patients with B-cell or plasma cell malignancies treated at 9 institutions with anakinra for CRS and/or ICANS after CAR T-cell therapy. Details regarding CAR T-cell product and disease type are shown in the Table. CRS/ICANS grade was determined by applying the ASTCT criteria at the time of peak symptom severity. We defined response to anakinra as an improvement in CRS and/or ICANS symptoms per the attending physician's evaluation. Results: Patients, disease, and CAR T-cell product are shown in the Table. Anakinra was administered at 100-200mg/day subcutaneously (SC) in 13 patients (pts) (50%; low-dose), or at 8mg/kg/day SC or intravenously (IV) in 13 pts (50%; high-dose). Most pts were treated with anakinra for steroid-refractory ICANS (n=23); two pts were treated for tocilizumab-refractory CRS (n=2) and one for both (n=1). All but one patient received anakinra concurrently with corticosteroids. Median peak CRS and ICANS grade by ASTCT criteria was 2 (range, 1-4), and 4 (range, 0-5), respectively. Median CRS and ICANS duration was 5 days (range, 1-10) and 15.5 days (range, 1-38), respectively. Median time from CAR T-cell infusion to anakinra initiation was 9 days (range, 5-31). The median duration of anakinra treatment was 8.5 days (range, 1-47). The median time to anakinra initiation from CRS or ICANS onset was comparable in pts receiving high-dose compared to low-dose anakinra (4 versus 4 days, respectively; p=0.8). Comparable peak CRS (median grade, 2 versus 2, p=0.9) and ICANS (median grade, 4 versus 4, p=0.2) were measured in both groups. Other toxicity-directed therapies were administered in 8 pts receiving low-dose anakinra (siltuximab, n=8; intrathecal chemotherapy, n=2, etoposide n=1). The only infectious event reported after anakinra initiation was HHV6 encephalitis (n=1). Two pts with infections confirmed prior to anakinra initiation died after anakinra treatment: CMV pneumonia (n=1), Escherichia coli bacteremia (n=1). In one patient the anakinra administration route was changed from SC to IV due to a subcutaneous hematoma; in one patient anakinra was discontinued due to elevated liver enzymes. We observed anti-tumor responses (partial or complete) to CAR T-cell therapy in 15 pts (58%; B-ALL, n=1/1; DLBCL, n=9/15; MCL, n=3/4; MM; n=1/1; PMBCL, n=1/3), including complete responses in 11 pts (42%). In high-dose anakinra pts, the ORR was 77% (complete response, 53%). CRS/ICANS improvement was observed after anakinra initiation in 73% of pts with a median duration of treatment of 3 days (range 1-7). Higher response rates were seen in pts who received high-dose compared to low-dose anakinra (100% versus 46%, respectively; p=0.005) and the non-relapse mortality rate at day 30 was significantly lower in pts treated with high-dose anakinra compared to low-dose anakinra (0% versus 69%; p=0.001%). In addition, a shorter time to anakinra initiation from CRS or ICANS onset was associated with CRS/ICANS improvement (median, 2 versus 5 days in responders versus non-responders, respectively; p=0.04). Conclusion After failure of tocilizumab and/or corticosteroids, early administration of high-dose anakinra (8mg/kg/day IV or SC) was associated with rapid resolution of CRS/ICANS symptoms after use of tocilizumab and/or corticosteroids, with a manageable toxicity profile, and with a non-relapse mortality rate at day 30 of 0%. In contrast, 38% of patients treated with low-dose anakinra died from infections. We observed complete responses to CAR T-cell therapy in pts treated with high-dose anakinra, suggesting limited impact on in vivo CAR-T cell function. In summary, high-dose anakinra is a feasible and promising approach after failure of conventional CRS and ICANS-directed therapies. Prospective trials of anakinra to prevent or treat CRS and ICANS are ongoing. Figure 1 Figure 1. Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Bailen: Gilead, Pfizer: Speakers Bureau. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Corral: Gilead: Consultancy; Novartis: Consultancy; Gileqd: Honoraria. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Maziarz: Allovir: Consultancy, Research Funding; Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Vor Pharma: Other: Data and Safety Monitoring Board; Incyte Corporation: Consultancy, Honoraria; Bristol-Myers, Squibb/Celgene,, Intellia, Kite: Honoraria; Artiva Therapeutics: Consultancy; CRISPR Therapeutics: Consultancy; Omeros: Research Funding; Intellia: Honoraria; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding; AstraZeneca: Research Funding. Hirayama: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Maloney: Kite, a Gilead Company, Juno, and Celgene: Research Funding; A2 Biotherapeutics: Consultancy; BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Juno: Patents & Royalties. Turtle: AstraZeneca: Consultancy, Research Funding; Nektar Therapeutics: Consultancy, Research Funding; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; T-CURX: Other: Scientific Advisory Board; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Asher Bio: Consultancy; Amgen: Consultancy; PACT Pharma: Consultancy; TCR2 Therapeutics: Research Funding; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; Allogene: Consultancy. 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Caroline Diorio,* Anant Vatsayan,* Aimee C. Talleur, Colleen Annesley, Jennifer J. Jaroscak, Haneen Shalabi, Amanda K. Ombrello, Michelle Hudspeth, Shannon L. Maude, Rebecca A. Gardner, and Nirali N. Shah Pediatric Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA; Division of BMT, Children’s National Hospital, Washington, DC; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN; Department of Pediatrics, Seattle Children’s Hospital, Seattle, WA; Pediatric Hematology/Oncology, Medical University of South Carolina, Charleston, SC; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.

… CAR-T toxicities and establishes anakinra as a safe and effective alternative toxicity management drug to tocilizumab. … indicate that earlier steroid intervention may delay CAR T-cell 400 …

Despite unprecedented efficacy, 1 the use of axicabtagene ciloleucel (axi-cel) for the treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL) remains associated with acute toxicity, such as grade $ 3 cytokine release syndrome (CRS) and immune effector cell – associated neurotoxicity syndrome (ICANS), occurring in 11% and 32% of patients, respectively. 2 Analysis of 44 different analytes in the serum of patients with relapsed or refractory LBCL treated with axi-cel showed that an increase in IL-6 or IL-1 may be associated with such toxicity. 3 However, in 2 murine models, whereas IL-6 blockade (typically achieved in clinical practice with the use of tocilizumab) prevented CRS only, only IL-1 blockade prevented both CRS and/or ICANS. 4,5 IL-1 blockade can be clinically achieved with the use of anakinra, an IL-1 receptor antagonist, currently approved by the US Food and Drug Administration for the treatment of patients with rheumatoid arthritis and neonatal-onset multisystem inflammatory disease. 6,7 Anakinra is also used off label for the treatment of secondary hemophagocytic lymphohistiocytosis (HLH), a condition in the spectrum of CRS

acenter for cancer and Blood disorders, children’s national Hospital, Washington, dc, USa; bdivision of Blood and marrow transplantation, center for cancer and Blood disorders, children’s national Hospital, Washington, dc, USa; cdivision of oncology, center for cancer and Blood disorders, children’s national Hospital, Washington, dc, USa; dneuroscience and Behavioral medicine center, children’s national Hospital, Washington, dc, USa; ecenter for cancer and immunology research, children’s national Hospital, Washington, dc, USa; fdivision of oncology, Johns Hopkins medical institutions campus, Baltimore, md, USa; gdivision of Pharmacy Services, children’s national Hospital, Washington, dc, USa

Chimeric antigen receptor T-cell therapy has revolutionized the treatment of hematological malignancies but is associated with significant immune-mediated toxicities, particularly cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, driven by an exaggerated inflammatory response involving cytokines such as interleukin (IL)-6, IL-1, and tumor necrosis factor-alpha. These processes contribute to endothelial dysfunction and a spectrum of cardiovascular complications, including hypotension, arrhythmias, myocardial dysfunction, and heart failure. The underlying pathophysiology involves complex interactions between immune activation and vascular injury, often progressing rapidly and necessitating early recognition. Contemporary management is shifting from reactive treatment to proactive strategies, emphasizing early risk stratification using clinical parameters, biomarkers, and imaging, alongside timely intervention with cytokine-directed therapies such as IL-6 and IL-1 inhibitors. Integration of cardiology within multidisciplinary care teams is essential for optimizing outcomes through tailored monitoring and management of cardiovascular complications. As chimeric antigen receptor T-cell therapy expands to broader and higher-risk populations, including those with pre-existing cardiovascular disease, a structured cardio-oncology approach and further prospective research are critical to improving safety and long-term outcomes.

Chimeric antigen receptor T-cell (CAR-T) therapy has significantly improved survival for adult patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL). However, there are novel toxicities after CAR-T infusion which can be associated with significant morbidity and mortality. The two primary toxicities are the cytokine release syndrome (CRS) and the immune effector cellassociated neurotoxicity syndrome (ICANS), which are managed with anti-cytokine therapy (e.g. tocilizumab) and corticosteroids per well-established guidelines [1,2]. In rare cases, CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS), which has been documented in patients with diffuse large B-cell lymphoma (DLBCL) [3] and B-ALL [4] and is associated with increased mortality [5]. At this time, the optimal treatment for patients with CAR-T-associated HLH/MAS is unknown. We present the following case of a patient with relapsed B-ALL who developed HLH/MAS after treatment with a commercial CAR-T product and was successfully managed with anakinra, interleukin-6 (IL-6) inhibitors, and corticosteroids. Our case highlights several key challenges surrounding the presentation, diagnosis, and management of CAR-T-associated HLH/MAS, and we discuss the biological rationale and a review of the literature on CAR-T-associated HLH/MAS and the role of anti-cytokine therapy. A 23-year-old woman with relapsed/refractory Philadelphia chromosome-negative B-ALL was admitted to our hospital for planned administration of CAR-T therapy. The patient was diagnosed with B-ALL with normal cytogenetics at age 21 and was initially treated with the CALGB 10403 regimen, but developed peripheral blasts during maintenance therapy. She was subsequently treated with blinatumomab, 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP) maintenance therapy, augmented hyper-CVAD, and FLAG-IDA, with multiple disease relapses. On admission, the patient was pancytopenic with 92% peripheral blasts and >90% bone marrow involvement by B-ALL. She was started on dexamethasone and inotuzumab as cytoreductive therapy for 2 doses, and a follow-up bone marrow biopsy demonstrated persistent 50–60% marrow involvement by B-ALL. The decision was made to proceed with the commercial CAR-T therapy product tisagenlecleucel (KymriahR ), preceded by fludarabine and cyclophosphamide lymphodepletion. At the time of tisagenlecleucel infusion, the patient was afebrile, hemodynamically within normal limits, and had a baseline ferritin of 3200 ng/mL. Our institution uses the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading for CRS and ICANS [1]. The patient developed Grade 1 CRS on Dþ 1, 14 h after CAR-T infusion, with a fever of 39.7 C, without any hypotension or hypoxia. She had no evidence of ICANS at that time. Per the CRS management guidelines by Neelapu et al. we initiated empiric antipyretics and antibiotics for neutropenic fever [2]. As shown in Figure 1, she continued to have daily maximum temperatures >39 C during Dþ 2 and Dþ 3 after CAR-T. Due to >48 h of persistent fevers refractory to acetaminophen, she was administered tocilizumab 8mg/kg IV once and scheduled dexamethasone 10mg IV daily on Dþ 3. She continued to have daily fevers up to 40.1 C on Dþ 4 through Dþ 6, and received tocilizumab 8mg/kg on Dþ 5 and again on Dþ 6. She did not defervesce despite these 3 doses of tocilizumab and daily IV dexamethasone, but continued to meet criteria only for Grade 1 CRS without any end-organ damage or evidence of ICANS. Of note, her ferritin had increased to 37,437mg/mL by Dþ 6. Due to her unrelenting fevers and rising ferritin, we administered siltuximab 11mg/kg IV once and anakinra 100mg subcutaneously once on

In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion. The primary endpoint was the rate of severe (grade ≥3) ICANS. Key secondary endpoints included the rates of all-grade cytokine release syndrome (CRS) and ICANS and overall disease response. Among 31 treated patients, 74% received axicabtagene ciloleucel, 13% received brexucabtagene ciloleucel and 4% received tisagenlecleucel. All-grade ICANS occurred in 19%, and severe ICANS occurred in 9.7% of patients. There were no grade 4 or 5 ICANS events. All-grade CRS occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77% with 65% complete response rate. These initial results show that prophylactic anakinra resulted in a low incidence of ICANS in patients with lymphoma receiving anti-CD19 CAR T-cell therapy and support further study of anakinra in immune-related neurotoxicity syndromes. Prophylactic subcutaneous administration of anakinra, an IL-1 receptor inhibitor, reduced severe immune effector cell-associated neurotoxicity syndrome incidence in patients with relapsed or refractory large B-cell and mantle cell lymphoma treated with anti-CD19 chimeric antigen receptor (CAR) T cells.

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017–March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36–1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

… To mitigate these toxicities, administration of corticosteroids, tocilizumab, and anakinra was decided per the individual study protocol and physician discretion. Grade, onset, duration, …

Chimeric antigen receptor T cell (CAR-T) therapy has demonstrated unprecedented clinical efficacy, leading to global approvals of anti-CD19 CAR-T cells for the treatment of relapsed B cell acute lymphoblastic leukemia and non-Hodgkin B cell lymphomas.1–4 Engagement of CAR-T cells with tumor cells causes proliferation and release of cytokines, resulting in the death of tumor cells but also causes systemic inflammatory state characterized by high fever, tachycardia, hemodynamic instability, tachypnea, hypoxia, hemophagocytic lymphohistiocytosis, neurotoxicity, and otherorgan damage.5–7 Managementofthese symptoms can be challenging and fatal in the worst cases.7,8

… CAR T-Cell related CRS and ICANS and our objective is to characterize the safety and efficacy of anakinra in … concomitant immunomodulating agents such as steroids and tocilizumab. …

The chimeric antigen receptor T (CAR-T) cell therapy significantly enhances the prognosis of various hematologic malignancies; however, the systemic expansion of CAR-T cells also gives rise to severe cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Despite the successful application of corticosteroids and tocilizumab in alleviating severe CRS in most patients, there are still individuals who experience life-threatening CRS without responding to the aforementioned therapies. In our retrospective cohort, we conducted an analysis of clinical and laboratory parameters, including inflammatory cytokines, in 17 patients from three centers who underwent therapeutic plasma exchange (TPE) for refractory CRS with or without ICANS following CAR-T products treatment. Our findings demonstrate a significant improvement in both clinical symptoms and laboratory parameters subsequent to TPE treatment. The rapid decrease in temperature and levels of inflammatory indexes indicates the remarkable scavenging efficacy of TPE against cytokine storm following CAR-T therapy. In conclusion, TPE may serve as a valuable and safe adjunct to corticosteroids and tocilizumab in the management of severe CRS resulting from CAR-T cell infusion. We eagerly await further prospective studies to validate this finding.