Critical care management of chimeric antigen receptor T‐cell therapy recipients

Introduction

Over the last decade, immuno-oncology has revolutionized the treatment of many cancers. Immuno-oncologic treatment strategies are playing an increasing role in the treatment of a growing number of malignant diseases. Chimeric antigen receptor (CAR) T cells represent one of the most promising novel therapeutic modalities for the treatment of cancer (Fig. 1).1-4

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Historic Timeline of the Development of Chimeric Antigen Receptor (CAR) T cells. ALL, acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; CRS, cytokine release syndrome; FDA, US Food and Drug Administration.

CAR T-cell therapy has demonstrated impressive and long-lasting responses in patients with acute lymphoblastic leukemia (ALL),5, 6 lymphoma,7-10 and multiple myeloma11 who otherwise would have few or no promising therapeutic options. Researchers around the world are developing innovative immune effector cell-based approaches to target other types of cancers12, 13 and nonmalignant diseases.14, 15

Currently, CAR T-cell therapy is reserved for patients with multiply relapsed disease. Because these patients generally have a poor prognosis, previously, they would have been considered poor candidates for intensive care unit (ICU) admission. However, the prognosis of critically ill patients with cancer has improved considerably and is approaching that of patients without cancer.16 Although the short-term outcome of critically ill patients with cancer is primarily driven by the acute medical condition, the longer term prognosis is predominantly determined by the prognosis of the underlying malignancy.17 Therefore, the biology of the tumor and the availability of effective treatments are key determinants of the expected remaining life expectancy and quality of life after successful intensive care management of a patient with cancer.18

The high effectiveness of CAR T-cell therapy challenges long-held beliefs and merits reassessment of the goals of care. Like no other cancer therapy, CAR T cells combine high response rates, long-term remissions, and a potential for cure with a high incidence of severe, potentially life-threatening but reversible side effects. Approximately 10% to 30% of patients will experience severe toxicities with severe organ dysfunction. A large proportion of these patients will require ICU admission and the provision of life-support measures such as perfusion-guided fluid therapy, vasoactive drugs, invasive or noninvasive mechanical ventilation, or renal replacement therapy.19, 20 However, given rapid and appropriate management, the outcome of CAR T-cell recipients who require ICU admission is relatively good.20, 21 Therefore, critical care has become an integral part of the clinical management framework for the safe and effective delivery of immune effector cell therapy to patients with cancer. Because the use of immune effector therapies such as CAR T cells will be expanding the number and spectrum of patients who have treatment-related severe toxicities, the need for critical care management will likely grow in the future.

CAR T-Cell Therapy

CAR T-cell therapy is a novel therapeutic modality that employs the patients' immune system for the treatment of cancer. CAR T cells overcome previous limitations of T-cell–based immunotherapy by redirecting the T-cell response to specific tumor antigens.22 The ability of CARs to recognize antigen in a major histocompatibility complex-independent fashion allows for more flexibility with regard to what types of antigens can be targeted. The CAR usually consists of an extracellular targeting domain, a transmembrane spacer, and intracellular signaling domains (Fig. 2). The targeting domain of the CAR is typically derived from the antigen-binding fragment of an antibody, ie, the immunoglobulin heavy and light chains that form the antibody binding site. The intracellular domain of the CAR contains the CD3 ζ-chain and provides a T-cell receptor activation signal and proliferative stimulus to the genetically modified T cells. First-generation CAR T cells, which only contained a single CD3 ζ-signaling module, suffered from a poor proliferative response and low cytotoxicity, resulting in poor antitumor efficacy.23, 24 Therefore, the resulting T-cell response was only short-lasting and was unable to induce durable tumor regressions. To improve the efficacy of first-generation CARs, second-generation CAR constructs were designed to include intracellular signaling domains from costimulatory receptors such as CD28 and 4-1BB.25, 26 The currently approved CAR T-cell therapies are all second-generation CARs that contain either a CD28 or a 4-1BB signaling domain. The design of the CAR construct affects the pharmacokinetic characteristics of CAR T cells such as the dynamics of expansion and persistence and thereby the effectiveness and likelihood of developing adverse events. Incorporation of the CD28 domain enhances the initial activation and proliferation of CAR T cells and improves effector function, whereas 4-1BB domain-containing CARs predominantly improve expansion and long-term persistence of CAR T cells.27 Current research focuses on the development of next-generation CAR designs with the aim of enhancing the efficacy and improving the safety of CAR T cells.28-30

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Structure of a Chimeric Antigen Receptor (CAR). CARs are fusion proteins consisting of an extracellular targeting domain derived from the antigen-binding site of an antibody, a transmembrane domain, and an intracellular signaling domain. The intracellular signaling domain of first-generation CARs is composed of a T-cell receptor (TCR) signaling domain (TCR ξ chain). The current US Food and Drug Administration-approved second-generation CAR T cells contain either an anti-CD19 (tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel) or an anti–B-cell maturation antigen (anti-BCMA) (idecaptagene vicleucel) single-chain variable domain for targeting. Their intracellular domain contains either a CD28 or a 4-1BB costimulatory signaling domain in addition to the TCR ξ chain. Next-generation CAR constructs incorporate additional signaling molecules that enhance CAR T-cell function or enable a better control of CAR T-cell activity.

In the initial step of CAR T-cell therapy, T cells are collected from a patient who has cancer using leukocyte apheresis and subsequently are transported to a central manufacturing facility, where they are genetically engineered to express CARs that recognize tumor-associated target antigens. After additional in vitro expansion, the CAR T-cell product is returned for administration. The time from CAR T-cell collection to patient infusion is usually approximately 3 weeks (range, 2-4 weeks).31 This period between leukapheresis and infusion, the so-called vein-to-vein time, during which the disease has to be kept stable, can be clinically challenging in patients with aggressive disease. To control the disease until CAR T cells can be infused, bridging therapy, ie, chemotherapy or radiotherapy, has to be administered to keep the disease under control until the CAR T cells can be administered.32 Bridging therapy may lead to toxicity and infections that might render the patient ineligible for further treatments, including CAR T-cell therapy.31 Accordingly, retrospective analyses have shown that patients who require bridging therapy have a worse outcome.33 To reduce the risk of CAR T-cell rejection and promote CAR T-cell proliferation, patients receive lymphodepleting chemotherapy before CAR T-cell infusion. In the ideal case, the administered CAR T cells recognize their target antigen, proliferate, and attack the tumor cells, eventually resulting in tumor remission. In some cases, CAR T cells have been demonstrated to sometimes persist in vivo for several years.10

Currently, there are 5 US Food and Drug Administration-approved commercial CAR T-cell products on the market: tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, and idecabtagene vicleucel (Table 1). The response rate of patients with relapsed/refractory B-cell ALL to CAR T-cell therapy is approximately 80% to 90%, with a median overall survival of more than one year.5 In patients who have lymphoma, the rates of overall response and complete response with CAR T-cell therapy lie in the range from 50% to 80% and from 40% to 60%, respectively. Some patients with ALL and lymphoma achieve durable responses lasting for many years.10, 34, 35

TABLE 1. US Food and Drug Administration-Approved Chimeric Antigen Receptor T-Cell Products PRODUCT TARGET COSTIMULATORY DOMAIN INDICATION TURNAROUND TIME, DAYSa Tisagenlecleucel CD19 4-1BB R/R ALL in patients aged ≤25 y; OR 22 R/R DLBCL, R/R PMBCL, R/R high-grade BCL, R/R transformed FL after ≥2 prior lines of systemic therapy Axicabtagene ciloleucel CD19 CD28 R/R DLBCL, R/R PMBCL, after ≥2 prior lines of systemic therapy 17 Brexucabtagene autoleucel CD19 CD28 R/R MCL 15 Lisocabtagene maraleucel CD19 4-1BB R/R DLBCL, R/R PMBCL, R/R high-grade BCL, R/R FL grade 3B after ≥2 lines of systemic therapy 24 Idecabtagene vicleucel BCMA 4-1BB R/R multiple myeloma, ≥4 prior lines of systemic therapy 28 Abbreviations: ALL, acute lymphoblastic leukemia; BCL, B-cell lymphoma; BMCA, B-cell maturation antigen; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; PMBCL, primary mediastinal B-cell lymphoma; R/R, relapsed/refractory. a Turnaround time is according to what was reported in a pivotal registration trial or in documents of the manufacturer. In practive, the turnaround times may vary significantly. CAR T-Cell Toxicities

The toxicity profile of CAR T-cell therapy is relatively unique. The side effects of CAR T cells can involve virtually any major organ system. Patients can experience respiratory,20 cardiovascular,36 hematologic,37, 38 renal,39, 40 neurologic,41 and gastrointestinal42 toxicities that can range from mild to life-threatening. Apart from common complications such as severe infections and sepsis, which are often observed after conventional types of cancer therapy, CAR T-cell therapy is accompanied by specific side effects that are uncommon in other cancer treatments. The most frequent serious toxicities of CAR T-cell therapy are listed in Table 2. The 2 typical and most common direct complications of CAR T-cell therapy are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These drug class–specific side effects can usually be treated effectively and carry a good prognosis, often with the complete recovery of organ function.43 The onset and severity of CRS and ICANS depend predominantly on the design of the CAR T-cell product, the treatment protocol, as well as tumor-related and patient-related factors.

TABLE 2. Common Serious Side Effects of Chimeric Antigen Receptor T-Cells COMPLICATION FREQUENCY TREATMENT OPTIONS CRS 37% - 93% Tocilizumab if no response to tocilizumab glucocorticoids ICANS 23% - 67% Glucocorticoids Sepsis 8% - 16% Empiric antibiotic therapy B-cell aplasia/hypogammglobulinemia 56% - 88% Intravenous immunoglobulins Abbreviations: CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.

The unspecific complications of CAR T-cell therapy such as infection and sepsis are generally more difficult to treat than CRS and ICANS and are associated with higher morbidity and mortality.44 Nonetheless, the limited long-term outcome data that exist suggest that, once patients get through the immediate posttreatment period, late adverse effects are comparatively rare and can be attributed primarily to subsequent treatments.45 Therefore, rapid ICU admission and full-code, aggressive management is justified for most patients.

Cytokine Release Syndrome

CRS is the most common serious toxicity of CAR T cells. It is a systemic inflammatory reaction elicited by proinflammatory cytokines released from CAR T cells that become activated after they have encountered tumor cells.46 This initial cytokine release results in bystander activation of other immune cells such as macrophages, endothelial cells, and stromal cells, triggering further release of proinflammatory cytokines and leading to a cytokine storm.47, 48 IL-6 is one of the key cytokines driving the pathophysiology of CRS, and serum levels of IL-6 correlate with the severity of CRS.34 Other cytokines involved in the pathophysiology of CRS include IL-8, IL-10, IFN-γ, and monocyte chemoattractant protein-1.

Initially, CRS typically presents with flu-like symptoms such as fever, fatigue, rigors, and myalgia. In the most severe cases, patients can develop signs consistent with an acute inflammatory reaction, ie, hypotension, capillary leak syndrome, respiratory insufficiency, and multiorgan failure. Some patients with severe CRS experience symptoms resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome. A recent survey reported a frequency of HLH-like disease of 3.48% in patients undergoing CAR T-cell therapy.49 However, in some settings, the incidence of HLH can be much higher. In one study of anti-CD19 CAR T cells involving 39 patients with ALL, 31% of patients fulfilled the criteria for macrophage activation syndrome.19 In another trial of CD22-targeted CAR T cells, 32.8% of patients developed an HLH-like syndrome.50

The onset of CRS usually occurs within a few days after the administration of CAR T cells. Infrequently, delayed CRS can occur. Tumor burden is among the most important clinical factors associated with the incidence and severity of CRS. Other risk factors for severe CRS that have been consistently identified across trials with different CAR T-cell constructs and underlying diseases include tumor type, T-cell dose, peak CAR T-cell expansion, and baseline inflammation.9, 11, 51 In the pivotal registration trials in patients with relapsed or refractory lymphoma, CRS occurred in 93% of patients receiving axicabtagene ciloleucel and in 58% of patients receiving tisagenlecleucel. Severe CRS, ie, grade ≥3, was observed in 13% of patients receiving axicabtagene ciloleucel and in 22% of patients receiving tisagenlecleucel. In patients who had multiple myeloma treated with CAR T cells directed against the B-cell maturation antigen, the incidence of CRS of any grade was 76%, but only 6% of patients had grade 3 CRS, and none had grade ≥4 CRS.11 Of note, different grading scales for CRS were used in the studies, making comparisons of toxicities across clinical trials difficult.

Immune Effector Cell-Associated Neurotoxicity Syndrome

ICANS, previously also called CAR T-cell–related encephalopathy syndrome, is the second most common side effect of CAR T cells.52 The pathophysiology of ICANS is still incompletely understood. Although there are common mechanisms, the pathogenesis of ICANS seems to be largely distinct from that of CRS. Laboratory studies suggest that endothelial activation plays an important role in the pathophysiology of ICANS.53 The endothelial activation, in turn, leads to disruption of the blood-brain barrier, followed by migration of CAR T cells and other immune cells into the central nervous system (CNS)47, 48, 53-56 and release of cytokines such as IL-1, IL-6, IL-8, monocyte chemoattractant protein-1, and interferon-γ–inducible protein 10 within the CNS. In particular, the production of IL-1 by myeloid cells seems to be a key mechanism in the pathophysiology of ICANS.47, 48 Cytokine-induced excitotoxicity caused by release of the N-methyl-D-aspartate receptor agonists glutamate and chinolinic acid may explain myoclonus and seizures observed in patients with ICANS.55 The recent finding that CD19 is also expressed on pericytes in the brain suggests that on-target, off-tumor toxicity by CD19-directed CARs could be a contributing factor to the pathophysiology of ICANS.57

The clinical presentation of ICANS is a continuum from mild tremor to cerebral edema, seizure, and, in rare cases, death. Usually, ICANS occurs later than CRS. Antecedent severe CRS seems to be a risk factor for the development of ICANS. Other risk factors for ICANS include disease burden and CAR T-cell dose. Rarely, ICANS can occur independent of CRS. Importantly, delayed onset up to several weeks after the infusion of CAR T cells has been observed in a subset of patients.

Off-Tumor and Off-Target Toxicity

Because most target antigens for CAR T cells are not perfectly tumor-specific but also are expressed by nonmalignant tissues, patients can experience on-target but off-tumor toxicities. With the current CAR T cells targeting the B-cell antigen CD19, patients develop B-cell aplasia, which can be accompanied by profound and long-lasting hypogammaglobulinemia, as an on-target toxicity due to the destruction of nonmalignant B cells.58 Pancytopenia, B-cell aplasia, and resultant hypogammaglobulinemia associated with CAR T-cell therapy predispose patients to the development of recurrent opportunistic infections. Because long-lived plasma cells do not express CD19, humoral immunity to some viruses is still preserved, and the occurrence of severe viral infections after the initial posttreatment phase is relatively rare.59

Off-target toxicity is a potential threat of immune effector therapies like CAR T cells. It can occur if the receptor construct used for targeting the immune effector cells cross-reacts with another antigen expressed by nonmalignant tissue. The antibody domains that are used in current CARs are highly specific and carry a low risk of cross-reactivity. So far, there have been no reports of off-target toxicities of CAR T cells.

Immunosuppression, Infection, and Sepsis

Because of the underlying disease, prior lines of cancer therapy, and the administration of immunosuppressive chemotherapy as part of the lymphodepleting treatment, patients undergoing CAR T-cell therapy are immunosuppressed and consequently are at a high risk of infections. Furthermore, the aforementioned on-target effects of CAR T cells, as well as CRS and its treatment, can cause additional hematologic toxicity, sometimes with long-lasting cytopenia, contributing to further immunosuppression.60, 61

Severe infections and sepsis are common early complications in CAR T-cell recipients. Fortunately, lethal infections are relatively rare.60 Bacteremia occurs in 10% to 30% of patients.20, 62 Because of the frequent presence of profound immunosuppression, CAR T-cell recipients can present with a broad range of pathogens. Given their immunosuppressed state and the high incidence of infections, all CAR T-cell recipients should receive appropriate prophylaxis and should be screened for viral infections to enable preemptive therapy if necessary.63 The infectious disease workup should include investigation for rare pathogens. The frequent overlap in symptoms between sepsis, CRS, and ICANS makes it difficult to distinguish between these differential diagnoses. Furthermore, CRS and infection are closely intertwined because CRS increases the risk for infections, and infections increase the risk for CRS.64 Physicians also have to be aware that the treatment of CRS and ICANS, in particular the administration of tocilizumab, can mask signs of infection such as fever. Therefore, a high degree of suspicion for infection should always be maintained in patients who show signs of renewed deterioration after treatment for CRS or ICANS.

Clinical Management of Patients With Serious CAR T-Cell–Related Toxicities

CAR T-cell therapy is still a nascent field in oncology. Therefore, it is not surprising that the management of CAR T-cell recipients is currently mostly empirical. In general, management of toxicities is mostly guided by study protocols, internal institutional guidelines, grading systems, or published guidelines and recommendations.65 However, these guidelines are partly conflicting, and only a few of these recommendations are based on solid clinical evidence and primarily represent expert opinion. There are few clinical studies, and the majority are observational, retrospective, and involve a small number of patients. Therefore, there is a lack of high-quality evidence, and many questions regarding the optimal clinical management of critically ill patients with cancer remain unanswered. Consequently, practices regarding the care for CAR T-cell recipients vary widely.66, 67 In addition to a better understanding of CAR T-cell function68 and further improvements in the CAR T-cell constructs themselves, several important clinical aspects require further research to improve the safety of CAR T-cell therapy (Table 3). Nonetheless, despite the remaining uncertainty regarding the optimal management of CAR T-cell recipients, a few general principles that can be deduced from the available data may serve as guideposts for treating clinicians.

TABLE 3. Ten Things We Do Not Know About the Provision of Intensive Care for Patients Who Receive Chimeric Antigen Receptor T-Cell Therapy TEN IMPORTANT OPEN QUESTIONS 1. Specific diagnostic and prognostic biomarkers for CRS and ICANS 2. The role of glucocorticoids in CRS 3. Value of prophylactic treatment for CRS/ICANS 4. Eligibility criteria for ICU admission 5. Optimal timing for ICU admission 6. Length of ICU trial 7. The role of ICU treatment for patients who deteriorate before CAR T-cell infusion 8. Optimal dose and duration of glucocorticoid therapy 9. Long-term outcome of CAR T-cell recipients requiring ICU admission 10. Generalizability of treatment recommendations across different CAR constructs Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; ICU, intensive care unit. Multidisciplinary Care for CAR T-Cell Recipients

The framework for the management of patients who receive CAR T cells is rapidly and continually evolving. There are several different models of managing CAR T-cell recipients. Some cancer centers have instituted dedicated CAR T-cell units, whereas others take care of these patients within the existing structures. In some places, CAR T-cell therapy is even administered in an ambulatory setting for selected patients. The comparable outcomes with CAR T-cell therapy in different centers and countries suggest that CAR T cells can be administered with similar efficacy and safety through various organizational models, as long as the care is provided in a coordinated fashion.

In light of the broad spectrum of organ systems that can be affected by toxicities of CAR T cells, the management of CAR T cell recipients is multidisciplinary in nature.69-74 Multidisciplinary assessment of patients before CAR T-cell administration can improve the selection of suitable candidates for CAR T-cell therapy and can help in developing individualized patient management plans by the stratification of patients according to their risk profiles for clinical deterioration (Table 4). Seamless cooperation between the different disciplines is key for achieving the best possible outcomes with a complex and resource-intensive treatment modality like CAR T-cell therapy (Fig. 3).

TABLE 4. Role of Critical Care at Different Stages of the Chimeric Antigen Receptor T-Cell Therapy Continuum Before leukapheresis Admission scenarios Infection, disease progression Background Patients eligible for CAR T-cell therapy may experience infections or progression of their malignant disease before leukapheresis Goals of therapy/admission policy Patients in remission/stable disease: Focus on acute pathology, ICU trial, in selected patients full code Patients with progressive disease: ICU treatment only in highly selected cases (eg, patient is treatment-naive to bridging regimen, acute pathology with good prognosis) Caveats Patient needs to be maintained in a stable condition for several wk to allow leukapheresis and successful generation of CAR T cells (bridge to therapy) Practical pitfalls The cause of deterioration (eg, progression, sepsis) can be initially difficult to distinguish; interventions that are severely myelosuppressive or interfere with T-cell function should be avoided; multidisciplinary evaluation of the patient and therapeutic options is key After leukapheresis, prior to CAR T-cell infusion Admission scenarios Infection/sepsis, disease progression Background Generation of CAR T cells requires 3-4 wk; during that time patients can deteriorate due to infections/sepsis or disease progression; death due to progression of the underlying disease is the main reason for failure to receive CAR T cells after successful leukapheresis occurring in up to one-half of patients Goals of therapy/admission policy Patients in remission/stable disease: Focus on acute pathology, ICU trial in selected patients full code Patients with rapidly progressive disease: ICU treatment only in highly selected cases (eg, patient is treatment-naive to bridging regimen, acute pathology with good prognosis) Caveats Patient needs to be maintained in a stable condition until successful generation and delivery of CAR T cells (bridge to therapy) Practical pitfalls Success of T-cell therapy depends on number and quality of T cells expanding and persisting after retransfusion; choice of concomitant drugs immediately before retransfusion is critical (eg, avoidance of T-cell–depleting antibodies, immunosuppressants); multidisciplinary evaluation of the patient and therapeutic options is key Early post–CAR T-cell administration (<4 wk) Admission scenarios Advanced monitoring in high-risk patients, CRS, ICANS, infection/sepsis, disease progression, HLH Background Prognosis of patients with CRS/ICANS is good; patient needs a stable remission for several weeks after T-cell retransfusion to allow for T-cell expansion/tumor control Goals of therapy/admission policy Patients in remission/stable disease: focus on acute pathology, ICU trial, patients with CRS/ICANS full code; patients with progressive disease: ICU treatment can be considered in slow progressors/patients with option of combination therapy, eg, radiotherapy of bulky disease Caveats/practical pitfalls CRS/sepsis/HLH/progression sometimes difficult to distinguish; early recognition and rapid treatments are important; therapy for CRS/ICANS (ie, anticytokines and/or steroids) theoretically can inhibit T-cell–mediated tumor control, but available data thus far do not substantiate this Late post-retransfusion (>1 mo) Admission scenarios Infection/sepsis, HLH, late ICANS, microangiopathy, disease progression Background Patients in CR/PR >3 mo have excellent prognosis Goals of therapy/admission policy If patient in PR/CR, full code should be considered Caveats Up to one-third of patients have prolonged aplasia/hypogammaglobulinemia Practical pitfalls Broad spectrum of opportunistic and rare pathogens reported Abbreviations: CAR, chimeric antigen receptor; CR, complete remission; CRS, cytokine release syndrome; HLH, hemophagocytic lymphohistiocytosis; ICANS, immune effector cell-associated neurotoxicity syndrome; ICU, intensive care unit; PR, partial remission. image

Schematic Diagram of Care Frameworks for the Management of Chimeric Antigen Receptor (CAR) T-Cell Recipients. (A) Status Quo. During different stages of their treatment, patients are cared for by different specialized teams that have little interaction, resulting in a fragmented care concept. (B) Continuous Care Model. Care for CAR T-cell recipients is delivered by multidisciplinary teams with communication and gradual transition of the focus of care, resulting in a continuous health care experience for the patient. ER, emergency room; ICU, intensive care unit.

Grading of CRS and ICANS

Grading and treatment algorithms for CAR T-cell–based therapies have coevolved. To facilitate a systematic approach to the management of CAR T-cell toxicity, several grading systems for CRS and neurotoxicity have been developed. Unfortunately, the use of heterogenous and inconsistent grading systems impede a fair comparison of toxicity across CAR-T constructs, institutions, trials, and registries and thereby make it hard to draw firm conclusions for the best approach to the management of toxicities.75-78 To harmonize current CRS and neurotoxicity grading, the American Society for Transplantation and Cellular Therapy hosted a multidisciplinary consensus conference, including clinicians, representatives of different medical societies, as well as companies involved in the development of CAR-T cells.79 They proposed a simple consensus grading system for CRS and ICANS that is easily applicable at the bedside (Fig. 4).79 In addition, they proposed a bedside screening test, the immune effector cell-associated encephalopathy (ICE) score, to help with assessing patients for ICANS.79

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Grading for Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). BiPAP indicates bilevel positive airway pressure; CPAP, continuous positive airway pressure; HFNC, high-flow nasal cannula; ICE score, immune effector cell-associated encephalopathy score; ICP, intracranial pressure; MV, mechanical ventilation.

The American Society for Transplantation and Cellular Therapy definition of consensus criteria that are more objective easier to assess have been a first step in the right direction.79 However, they also define the grade of CRS or ICANS not only according to signs and symptoms of CAR T-cell toxicity but based on the treatment of toxicity such as the use of vasopressors or oxygen supplementation. The use of those interventions may vary substantially across institutions or even between different physicians within one institution. A recent study showed that the gradings were concordant across grading systems in only 25% and 54% of patients with CRS and ICANS, respectively.80 Importantly, because the risk-management strategies depended exclusively on grading of toxicity, treatment recommendations for toxicity varied substantially, depending on the grading systems used.80

Furthermore, the current grading systems do not fully account for the complexity of patients who are treated outside of clinical trials in a real-world setting, suggesting that the risk-manage

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