Back To Search Results

CART Cell Therapy Toxicity

Editor: Hira Shaikh Updated: 4/19/2023 3:30:12 PM


Chimeric antigen receptor-T (CAR-T) cell therapy is a type of genetically modified immunotherapy that is directed at cancer cells. The method involves using an individual's own T-cells (or donor cells in allogeneic CART), transduced with gene encodes ex vivo, then introduced to the patient.[1] CAR-T has changed the treatment paradigm for hematological malignancies, such as B-cell lymphomas and multiple myeloma, and continues to be a promising approach for many other malignancies, including solid tumors.[2][3][4][5]

Clusters of differentiation-19 (CD-19), a B cell surface marker, -directed CAR-T cells show encouraging outcomes in a variety of malignancies, including pediatric and B-cell acute lymphocytic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL). The first approved CAR-T therapy targeting CD-19, tisagenlecleucel (tisa-cel, ELIANA), was initially approved by the Food and Drug Administration (FDA) for patients with ALL in 2017, and later diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (JULIET).[6][7][8] Around the same time, axicabtagene ciloleucel (axi-cel, ZUMA-1) gained approval for relapsed/refractory (R/R) DLBCL and later for R/R follicular lymphoma.[9][10] 

Since then, more agents such as lisocabtagene maraleucel (liso-cel) have made their way onto the market, demonstrating better tolerance.[11] Later, brexucabtagene autoleucel was approved for R/R mantle cell lymphoma (MCL).[12] More recently, anti-B-cell Maturation Antigen (BCMA) CAR-T, idecabtagene vicleucel (ide-cel, KarMMa), and ciltacabtagene autoleucel (cilta-cel, CARTITUDE-1) have been approved for R/R multiple myeloma.[3][4]

Despite the current success rate of CAR-T therapy, it comes with the caveat of significant toxicities. The most common adverse events (AEs) of CAR-T therapy, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain barriers to the use of CAR-T cell therapy. Other AEs, such as cytopenia,s, infections, tumor lysis syndrome (TLS), acute anaphylaxis, etc., are also challenging.[13] Now that cellular therapy is making its way to earlier lines of the treatment paradigm, these challenges have become even more relevant.[14][15]


Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care


The exact mechanism of CRS is not well understood. CRS is a systemic inflammatory response that occurs during the CAR-T activation and expansion in the human body.[16] It is thought to be related to the cytokines secreted during the tumor and immune effector cell interaction, including tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), which then activate monocytes and macrophages to release cytokines such as interleukin-1 (IL-1), and IL-6.[17] 

ICANS is thought to be related to myeloid cell activation, including granulocyte-macrophage colony-stimulating factor (GM-CSF) mediated stimulation of monocytes after CAR-T and monocyte-derived IL-1 and IL-6. [18][19]

The costimulatory domain is a component of CAR-T necessary for T cell activation and expansion of the CAR-T cells.[20] CAR-T therapies that activate 4-1BB (tisa-cel, liso-cel) costimulatory domain instead of CD28 (axi-cel) have exhibited slower expansion, thus prolonging the persistence of CAR-T cells and later CRS onset.[21][22] While this has assisted in bringing these therapies outpatient, logistics, reimbursement, and managing CAR-T therapy-related AEs are the major challenges healthcare providers face.[23]


CAR-T-related toxicity occurs with varying frequency depending on factors discussed later. CRS is the most common type of toxicity associated with CAR-T therapy, followed by ICANS.

Cytokine Release Syndrome (CRS)

CRS is considered a predominantly reversible complication of CAR-T therapy, with an incidence of occurrence in 42 to 100% of the patients. It presents with varying severity, with 0 to 46% of patients exhibiting features of severe CRS and from 0 to 9.1% of cases progressing to fatal outcomes.[24]

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Similar to CRS, ICANS presents in most patients after CAR-T infusions as a reversible complication. It occurs less frequently and is often delayed compared to CRS, with the incidence ranging between 3 and 64% and 0 to 54% of cases exhibiting signs of severe illness.[25]


Cytokine Release Syndrome (CRS)

CRS is the most common type of toxicity following CAR-T therapy. It is a multi-systemic inflammatory response caused by cytokines released following the infusion of CAR-T cells that can lead to multiorgan dysfunction. The onset of symptoms usually occurs during the first week after CAR-T cell infusion, with a typical duration of 7 to 8 days.[26][27] 

Multiple risk factors for CRS include high disease burden, a high number of administered CAR-T cells, the high peak of CAR-T cell expansion, thrombocytopenia, endothelial activation before CAR-T infusion, and lymphodepletion therapy with fludarabine and cyclophosphamide.[27] 

Studies have suggested that disease characteristics such as tumor burden, Eastern Cooperative Oncology Group (ECOG) performance status, ferritin, lactate dehydrogenase (LDH), and C reactive protein (CRP) levels prior to CAR-T can be used as predictors of the onset of CRS and ICANS, thus guiding the outcomes of CAR-T.[28][28]


CRS is thought to be related to the production of inflammatory cytokines by CAR-T, e.g., TNF-a, IFN-γ, IL-2, IL-8, IL-10, and GM-CSF following interaction with corresponding target cells.[17] Following that, inflammation recruits and provokes bystander immune cells, e.g., macrophages, monocytes, dendritic cells (DC), and other T cells. Eventually, it potentiates the immune response by releasing IL-1 and IL-6 as well as nitric oxide. This hyperactivated inflammatory response provokes the endothelium, which further releases IL-6. This destabilizes membrane stability, resulting in capillary membrane leakage, hemodynamic instability, and consumptive coagulopathy.

Clinical Features  

CRS typically presents with constitutional symptoms such as a fever, fatigue, myalgia, arthralgia, rigors, or anorexia. It can rapidly progress to tachycardia, hypotension requiring vasopressors and intensive care unit (ICU) care, tachypnea, and hypoxia. Eventually, it can lead to coagulopathy, capillary leak, respiratory failure, shock, and multiple organ failure.

 Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS)

It is a form of clinical and neuropsychiatric disease manifestation that occurs within days to 2-3 weeks following CAR-T therapy administration.[29] The risk factors for ICANS include the presence of CRS, pre-existing neurologic dysfunction, high disease burden, elevated LDH, thrombocytopenia, elevated ferritin within 72 hours after CAR-T cell administration, chimeric antigen receptor (CAR) design such as CD28 costimulatory domain, certain hinge, transmembrane CAR domains, and lymphodepletion therapy with fludarabine and cyclophosphamide.[29]


The pathophysiology behind ICANS is not well studied. Theories include CNS trafficking of CAR-T cells and endothelial disruption within the blood-brain barrier. Moreover, myeloid cell activation in the CNS with the secretion of IL-1 and IL-6 by monocytes, GM-CSF-mediated stimulation of monocytes after CART, elevated levels of IL-15, and N-methyl-D-aspartate (NMDA) receptor agonists (e.g., glutamate and quinolinic acid) have all been suggested to cause ICANS.[18][19]


Cytopenias are very frequent following CAR-T cell therapy, the most common being neutropenia. They occur in about 20-40% of patients and can last beyond 30 days after administration.[30][31] According to a systematic analysis following CD-19 CAR-T therapy, the rates of all grade anemia, thrombocytopenia, and neutropenia, were 65%, 55%, and 78%, respectively. Age, gender, disease, number of prior lines of therapy, and the target and costimulatory domain have been noted to influence the incidence of cytopenias following CAR-T therapy.[32]

Tumor Lysis Syndrome (TLS)

TLS can be a life-threatening condition leading to arrhythmias and renal failure. It usually occurs due to cell depletion following chemotherapy but can occur as a direct effect following CAR T-cell therapy.[33] It can be related to elevated levels of serum creatinine and severe CRS.[34]

Anaphylaxis and Immunogenicity 

CAR-T cells involve the addition of non-human products that renders a risk for allergic reactions. Anaphylaxis is rather uncommon and is reported only with repeated CAR-T infusions. Additionally, anti-murine antibodies against CD-19 have been detected prior to CAR-T cell infusion. Fully human-containing CAR-T cells are under clinical trials.[35]

Hypogammaglobulinema due to B-Cell Aplasia

B-cell aplasia with hypogammaglobulinemia is an expected AE associated with CAR-T therapy.[36][37] Hypogammaglobulinemia can be delayed and increases the risk of infections.[38] B-cell aplasia could last for up to 5 years, with longer aplasia usually being noticed after comprising 4-1BB as a costimulatory domain. Thus it can be used as a biomarker to assess CAR-T cell persistence.[39][38][40]


Multiple etiologies can explain recurrent infections, including underlying disease, cytotoxic treatment, neutropenia, hypogammaglobinemia, treatment for CRS and ICANS, and the CAR-T itself. In addition, patients with an absolute neutrophil count (ANC) <500 cells/mm3 receiving higher doses of CAR-T therapy administration carry a higher risk than other patients.[30]

 Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

Hemophagocytic lymphohistiocytosis (HLH) was reported in around 1% of patients receiving CAR-T cells.[41] It was unclear whether HLH/MAS represents the end point of CRS until the ASTCT grading guidelines excluded HLH/MAS from the definition of CRS, and then the diagnostic criteria were identified (see table below).[41]

Diagnostic Criteria of Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) [adapted from criteria proposed by the CARTOX Working Group]

Ferritin >10,000 ng/ml during CRS 

And two of the following:  Grade 3 liver toxicity (increase in levels of bilirubin, aspartate aminotransferase, or alanine aminotransferase)  Grade 3 kidney toxicity (oliguria or increase in serum creatinine)  Grade 3 pulmonary edema  Hemophagocytosis in the bone marrow or other organs 

Secondary Malignancies

Secondary malignancies after CAR-T are primarily related to lymphodepletion chemotherapy, including myelodysplastic syndrome, acute myeloid leukemia, etc.[42][43]

 Graft-Versus-Host Disease (GVHD)

Patients receiving allogeneic CAR-T cells from donors carry a risk of developing mild acute GVHD or slow worsening of previously existing chronic GVHD, though this has only rarely been reported.[34][44]

History and Physical

Healthcare professionals caring for patients receiving commercial CAR-T products must complete product-specific Risk Evaluation and Mitigation Strategy (REMS) training.[45][46][47] Nurses caring for these patients are educated to recognize CAR-T AEs, especially CRS and ICANS.[46] 

Every CAR-T center has institutional guidelines to evaluate the patients for related toxicities, depending on whether the CAR-T product was infused in an inpatient or outpatient setting. Generally, in an outpatient setting, patients are evaluated once daily for both CRS and ICANS-related features for at least 14 days and up to 30 days post-infusion. If the CAR-T therapy is administered inpatient, vitals are typically assessed every 4 hours; the ICE score is at least once a day, with a daily comprehensive physical exam and blood work including complete blood count (CBC) and complete metabolic panel (CMP).[41] 

If a patient is admitted with an AE such as CRS, vital signs are checked more frequently, ideally every 2-4 hours, immune effector cell-associated encephalopathy (ICE) score is evaluated at least once a day and up to every 8 hours, and blood work including CBC, CMP, and other relevant tests are done once to twice daily.[41][48]

Most centers alert neurology service for a neurological evaluation of the patient before the CAR-T administration. However, in case of a suspected or confirmed ICANS-related toxicity, a neurological exam is performed at least 4-6 hourly or more frequently if a decline in the neurological status is noted.[49] Further neurological investigations, including neuroimaging, electroencephalogram (EEG), etc., are performed if there is a concern for ICANS.[41]


Toxicities related to CAR-T cell therapy are diverse and still poorly understood. The evaluation of CAR-T-associated toxicities and their severity is based on clinical symptoms and signs, which are further aided by laboratory biomarkers and/or radiological findings.

CRS: It is a clinical diagnosis and usually presents with varying degrees of fever, tachycardia, hypotension, hypoxia, nausea, vomiting, etc. The vital signs are assessed frequently, depending on the institutional policies, with most centers mandating reevaluation every 4 hours for grades 1 and 2 and 1 to 2 hourly evaluations for grades 3 and 4 CRS.[41][48]

Useful laboratory evaluation for CRS involves performing a CBC, renal and liver function test, coagulation profile, LDH, serum ferritin, IL-6, and CRP. These biomarkers are performed serially to determine the severity and response to the treatment. Some have also postulated checking IL-5,  IL-13, TNF-a, and IFN-γ levels.[50][51] 

ICANS: Like CRS, ICANS is diagnosed based on clinical symptoms, including headache, impaired attention and consciousness, lethargy, agitation, hallucinations, tremors, aphasia, encephalopathy, and seizures.[52] As discussed in detail below, the grading and surveillance of neurotoxicity are based on the ICE criteria (which has replaced the CARTOX-10 criteria to include more objectivity in the neurotoxicity grading).[50][53][28]

Laboratory evaluation of ICANS includes biomarkers similar to CRS in addition to a lumbar puncture to analyze cerebrospinal fluid, neuroimaging, and EEG to determine the extent of damage from ICANS and rule out other organic factors and/or sinister causes, including but not limited to infections.[41]

Treatment / Management

Here, we review the toxicities caused by CAR-T cell therapy and summarize the clinical findings, grades, and management of the most relevant adverse events associated with CAR-T cell therapy.

The toxicity of CAR-T remains challenging. However, numerous safety measures have been implemented in clinical trials.[27] Standardized protocols need to be developed, including universal guidelines for managing CRS and ICANs and the safe administration of outpatient CAR-T therapy.[54] (A1)

Management of CRS and ICANS requires frequent assessment and grading several times a day in addition to monitoring inflammatory markers such as ferritin and CRP. Aggressive supportive care is the cornerstone of managing all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. IL-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. For FDA-approved CAR-T cell products, REMS requires prompt availability of at least two doses of tocilizumab per patient that can be administered within two hours of CAR-T infusion.[55] 

Corticosteroids should only be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the activity of the CAR-T cells.[56] Given the potential of corticosteroids to limit CAR-T cell proliferation and expansion, they should not be permitted starting on the first day of lymphodepletion chemotherapy, including as antiemetics.[57]

Cytokine Release Syndrome (CRS)

Grading and management of CRS are derived from the American Society for Transplantation and Cellular Therapy (ASTCT) consensus guidelines for CRS grading.[28][58][59] (B3)

Grade Clinical Presentation Management

Symtpoms require symptomatic treatment only

  • Fever, nausea, fatigue, headache, myalgia, malaise, etc., but no hypotension or hypoxia.
Supportive measures, including antipyretics, IV hydration, and infectious disease workup such as blood cultures and imaging as needed. If there is no improvement within three days and no other differential diagnosis, consider tocilizumab as below.

Symptoms require and respond to moderate intervention

  • Fever (temperature ≥38°C), and
  • Hypotension that doesn’t require vasopressors and/or 
  • Hypoxia on low-flow oxygen (O2) <40% FiO2.
  • Supportive measures, similar to grade 1 CRS, IV fluid boluses, supplemental oxygenation, and
  • Tocilizumab 8 mg/kg once (maximum dose: 800 mg [based on CAR-T cell CRS dosing]). If there is no clinical improvement in the signs and symptoms of CRS after the first dose, repeat tocilizumab every 8 hours as needed. Limit to a maximum of 3 doses in a 24-hour period and a total of 4 doses.
  • Corticosteroids (dexamethasone 10 gm every 6 hours or methylprednisolone equivalent, that is 1 mg/kg twice daily) if no improvement within 24 hours of starting tocilizumab.

Symptoms require and respond to aggressive intervention

  • Fever, and
  • Hypotension that requires one vasopressor and/or 
  • Hypoxia that necessitates high-flow O2 (high-flow nasal cannula, mask, non-invasive ventilation) ≥40% FiO2.
  • Supportive management similar to CRS grade 1 and intensive care unit (ICU) management with vasopressor support and/or supplemental oxygen, and
  • Tocilizumab 8 mg/kg once (maximum dose: 800 mg [based on CAR-T cell CRS dosing]), plus 
  • Dexamethasone 10-20 mg IV every 6 h or methylprednisolone equivalent.  

Life-threatening symptoms

  • Fever, and
  • Hypotension that requires multiple vasopressors and/or
  • Hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation).
  • Supportive management similar to CRS grade 1, ICU admission, vasopressor support, and/or supplemental O2 via the positive pressure method, and
  • Tocilizumab 8 mg/kg once (maximum dose: 800 mg [based on CAR-T cell CRS dosing]), and
  • Methylprednisolone 1000 mg/day for three days.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

The grading and proposed management of ICANS are according to and adapted from the ASTCT consensus guidelines for ICANS grading.[28][53](B3)

Grade Clinical presentation Management
  • Immune effector cell-associated encephalopathy (ICE) score 7-9.
  • Awakens spontaneously.
  • No motor findings or seizure-like activity.
  • No signs of increased intracranial pressure (ICP) or CNS edema.
Supportive management with electroencephalogram (EEG), neuroimaging, and lumbar puncture. Add tocilizumab only if concurrent CRS.
  • ICE 3-6.
  • Awakens to a voice.
  • No motor findings or seizure-like activity.
  • No signs of increased ICP or CNS edema.
  • Supportive management similar to ICANS grade 1.
  • Consider dexamethasone 10 mg every 6 hours or methylprednisolone equivalent.
  • ICE 0-2.
  • Awakens only to tactile stimuli.
  • Usually presents with a seizure that resolves rapidly, with/without interventions.
  • There is usually focal or local edema on imaging.
  • Supportive management similar to ICANS grade 1; consider transfer to ICU and airway protection. 
  • Dexamethasone 10-20 mg IV every 6 hours or methylprednisolone equivalent. If deterioration, increase steroids to that in grade 4.
  • Control seizures with antiepileptics and status with benzodiazepines.
  • ICE 0.
  • Unarousable, stuporous, or in a coma, or requires vigorous stimuli to wake.
  • Usually presents with prolonged life-threatening seizures (>5 min) or repetitive clinical or electrical seizures without returning to baseline. Additionally may have deep focal weakness, i.e., hemiparesis or paraparesis.
  • Imaging shows diffuse cerebral edema. On physical examination, usually papilledema, decerebrate/decorticate posture, cranial nerve VI palsy, or Cushing’s triad (bradycardia, hypertension, and abnormal breathing).
  • Supportive management similar to ICANS grade 1, transfer to ICU, and airway protection, e.g., by intubation and mechanical ventilation.
  • High-dose methylprednisolone (1000 mg/day).
  • Control seizures with antiepileptics.
  • Lower elevated ICP with hyperventilation, hyperosmolar therapy, and/or neurosurgical intervention.
  • If refractory, discuss agents such as siltuximab or anakinra, as detailed below.

Immune effector cell-associated encephalopathy (ICE) assessment adapted from ASTCT grading consensus guidelines:[28](B3)

ICE Parameter


Scoring point 


Orientation to the year, month, city, and hospital 


Ability to name three objects 


Follow Commands 

Ability to follow simple commands 

Writing Ability 

Ability to write a standard sentence 

Attention Ability

Ability to count backward from 100 by 10s 


CRS and ICANS Refractory to the Above Treatment

If despite the use of tocilizumab and corticosteroids, patients with CRS and ICANS continue to worsen, siltuximab, a monoclonal antibody, binds to  IL-6, thus preventing it from binding to the IL-6 receptors.[60] Another alternative is Anakinra, which is an IL-1 receptor that shows activity in CRS and ICANS that is refractory to corticosteroids and tocilizumab.[61] Given that IL-1 precedes IL-6 production, it can be used to prevent CRS and ICANS. However, further studies are still under investigation.[62](B3)


Mostly, cytopenias resolve over time. Bone marrow biopsy is recommended in patients with prolonged or delayed cytopenias to evaluate for secondary bone marrow malignancy.[63] Anemia and thrombocytopenia are managed through the replacement of erythrocytes and platelets. Granulocyte colony-stimulating factor (G-CSF) is used to manage neutropenia and should be strongly recommended in patients with prolonged neutropenia. Anecdotally, persistent refractory cytopenia after CAR-T has been treated by the infusion of autologous or allogeneic stem cells.[32][63](A1)

Tumor Lysis Syndrome

Management involves frequent hydration and the use of uric acid-lowering agents (allopurinol, rasburicase, and febuxostat) as per the standard guidelines for chemotherapy.[33][64]

Hypogammaglobulinema Due to B-Cell Aplasia

Long-term follow-up is essential to assess the need for IgG replacement.[65] In pediatric patients, intravenous immunoglobulin (IVIG) replacement is typically given.[66] In adults, antibody-secreting CD19-negative cells resembling memory plasma cells that show basic humoral immune function despite CAR-T cell treatment have been noted. Hence, in adults, IVIG is usually given at IgG levels ≥ 400 mg/dl or in patients with severe or recurrent infections, usually at a dose of 400 to 600 mg/kg every 3 to 4 weeks.[66][38] 


Patients with fevers and neutropenia should have blood cultures drawn and broad-spectrum antibiotics initiated.[52] Antimicrobial prophylaxis is majorly extrapolated from that of hematopoietic stem cell transplants (HSCT). This includes antimicrobials, such as acyclovir or valacyclovir, for herpes simplex virus (HSV), and varicella zoster (VZV), starting prior to the conditioning chemotherapy continuing up to 1-year following CAR-T therapy.[30][52] 

Trimethoprim-sulfamethoxazole or alternative agents are recommended for pneumocystis jirovecii (PJP) starting before conditioning chemotherapy and is usually continued until CD4 reaches more than 200/ml.[30][32][52] Antifungal prophylaxis should be considered in those at high risk, such as prolonged steroid exposure, or in patients within patients with prolonged (>14 days) or severe (ANC <0.5 × 10/l) neutropenia.[30](A1)

Hemophagocytic Lymphohistiocytosis

Treatment usually involves corticosteroids and tocilizumab if co-existent with CRS. In refractory cases or if independent of CRS, treatment with etoposide and intrathecal methotrexate or cytarabine has been suggested. Additionally, anakinra has also been proposed but needs further evaluation.[67]

Differential Diagnosis

Differential diagnoses for CRS are mainly related to its clinical manifestations and laboratory findings, such as fever and/or hypoxia and hypotension, elevated CRP, ferritin, and IL-6 levels.[68] These include Infection/sepsis, anaphylactic reactions/shock, heart failure, thromboembolism, malignancy relapse/refractoriness, TLS, and HLH unrelated to CAR-T toxicity.[69][70][71] 

These patients are usually required to undergo extensive evaluation and investigations to rule out other causes and often require empirical treatments until proven otherwise.

ICANS can be frequently confused with uncommon viral infections, stroke, chemotherapy-related toxicity, and the CNS involvement of malignancy.[72]


CRS: It is a reversible complication, mostly symptoms resolving within 2 to 6 weeks. Mortality can be observed in 0 to 9.1% of cases.[25][24] However, the majority of trials have reported <1% fatal outcomes.[28]

ICANS: A vast majority of cases of neurotoxicity associated with CART therapy show symptom resolution within 3-8 weeks.[73][74] With early and aggressive management, even high-grade CRS is considered reversible.


While, in most instances, CAR-T complications are reversible, occasionally, they can lead to death or irreversible organ damage.[25] Neuropsychiatric AEs such as anxiety, depression, or cognitive difficulty have been reported in long-term survivors of CAR-T, up to 37.5% in one study.[75]

Deterrence and Patient Education

Frequent monitoring, clear instructions for patients and caregivers, and a robust on-call system are essential post-CAR-T. Patients and caregivers should be provided with after-hours contact information, clear instructions for monitoring symptoms and vital signs, and when to present to the hospital.[57] 

Patients need to be provided with a product-specific wallet card identifying their reception of a CAR T-cell product and giving information about the managing oncologist. They will need to show their wallet card if and when they present for evaluation of symptoms, especially if they arrive at a hospital or emergency department (ED) outside of the CAR-T therapy programs.[46]

Caregiver support throughout the process of CAR-T and after is critical. The need for a 24-hour caregiver for at least four weeks and staying close to the center after treatment should be emphasized.[76] Caregivers should be included from the start, from informed consenting to teaching, clinic visit, and after discharge.

Enhancing Healthcare Team Outcomes

Cancer immunotherapy has greatly advanced in recent years, with CAR-T cells emerging as an innovative technology that harnesses the immune system to combat malignant diseases. An interprofessional team is needed to recognize and appropriately manage CAR-T AEs, including but not limited to neurology, critical care, and infectious diseases subspecialties. Most centers alert the neurology team for a neurological evaluation of the patient prior to the CAR-T administration. Efforts should be aimed at providing accommodation to the patients traveling far from home for CAR-T and assisting with out-of-pocket costs.[77]

Patient prerequisites that are fundamental for managing complications of HSCT post-discharge are also relevant to successful CAR-T, including socioeconomic and caregiver support and patient staying within a 1-hour transportation distance from the hospital for at least four weeks post-infusion.[46] Various centers have devised comprehensive protocols to monitor patients closely, ensure multidisciplinary coordination, and quick evaluation of the patients in either the clinic or ED for any AEs, including fever, CRS, and ICANs.[47][41]



Sermer D, Brentjens R. CAR T-cell therapy: Full speed ahead. Hematological oncology. 2019 Jun:37 Suppl 1():95-100. doi: 10.1002/hon.2591. Epub     [PubMed PMID: 31187533]


Braendstrup P, Levine BL, Ruella M. The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19. Cytotherapy. 2020 Feb:22(2):57-69. doi: 10.1016/j.jcyt.2019.12.004. Epub 2020 Feb 1     [PubMed PMID: 32014447]


Sharma P, Kanapuru B, George B, Lin X, Xu Z, Bryan WW, Pazdur R, Theoret MR. FDA Approval Summary: Idecabtagene Vicleucel for Relapsed or Refractory Multiple Myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 May 2:28(9):1759-1764. doi: 10.1158/1078-0432.CCR-21-3803. Epub     [PubMed PMID: 35046063]


Chekol Abebe E, Yibeltal Shiferaw M, Tadele Admasu F, Asmamaw Dejenie T. Ciltacabtagene autoleucel: The second anti-BCMA CAR T-cell therapeutic armamentarium of relapsed or refractory multiple myeloma. Frontiers in immunology. 2022:13():991092. doi: 10.3389/fimmu.2022.991092. Epub 2022 Sep 2     [PubMed PMID: 36119032]


Safarzadeh Kozani P, Safarzadeh Kozani P, Ahmadi Najafabadi M, Yousefi F, Mirarefin SMJ, Rahbarizadeh F. Recent Advances in Solid Tumor CAR-T Cell Therapy: Driving Tumor Cells From Hero to Zero? Frontiers in immunology. 2022:13():795164. doi: 10.3389/fimmu.2022.795164. Epub 2022 May 11     [PubMed PMID: 35634281]

Level 3 (low-level) evidence


. First-Ever CAR T-cell Therapy Approved in U.S. Cancer discovery. 2017 Oct:7(10):OF1. doi: 10.1158/2159-8290.CD-NB2017-126. Epub 2017 Sep 8     [PubMed PMID: 28887358]


Si Lim SJ, Grupp SA, DiNofia AM. Tisagenlecleucel for treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Pediatric blood & cancer. 2021 Sep:68(9):e29123. doi: 10.1002/pbc.29123. Epub 2021 Jun 1     [PubMed PMID: 34061452]


. Tisagenlecleucel Is Safe and Effective in Relapsed/Refractory Follicular Lymphoma. Cancer discovery. 2022 Mar 1:12(3):OF4. doi: 10.1158/2159-8290.CD-RW2022-004. Epub     [PubMed PMID: 34996779]


Bouchkouj N, Kasamon YL, de Claro RA, George B, Lin X, Lee S, Blumenthal GM, Bryan W, McKee AE, Pazdur R. FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-cell Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Mar 15:25(6):1702-1708. doi: 10.1158/1078-0432.CCR-18-2743. Epub 2018 Nov 9     [PubMed PMID: 30413526]


Bouchkouj N, Zimmerman M, Kasamon YL, Wang C, Dai T, Xu Z, Wang X, Theoret M, Purohit-Sheth T, George B. FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Follicular Lymphoma. The oncologist. 2022 Jul 5:27(7):587-594. doi: 10.1093/oncolo/oyac054. Epub     [PubMed PMID: 35403693]


St-Pierre F, Gordon LI. Lisocabtagene maraleucel in the treatment of relapsed/refractory large B-cell lymphoma. Future oncology (London, England). 2023 Jan:19(1):19-28. doi: 10.2217/fon-2022-0774. Epub 2023 Jan 18     [PubMed PMID: 36651471]


Deshpande A, Wang Y, Munoz J, Jain P. Brexucabtagene autoleucel: a breakthrough in the treatment of mantle cell lymphoma. Drugs of today (Barcelona, Spain : 1998). 2022 Jun:58(6):283-298. doi: 10.1358/dot.2022.58.6.3378055. Epub     [PubMed PMID: 35670706]


Logue JM, Peres LC, Hashmi H, Colin-Leitzinger CM, Shrewsbury AM, Hosoya H, Gonzalez RM, Copponex C, Kottra KH, Hovanky V, Sahaf B, Patil S, Lazaryan A, Jain MD, Baluch A, Klinkova OV, Bejanyan N, Faramand RG, Elmariah H, Khimani F, Davila ML, Mishra A, Blue BJ, Grajales-Cruz AF, Castaneda Puglianini OA, Liu HD, Nishihori T, Freeman CL, Brayer JB, Shain KH, Baz RC, Locke FL, Alsina M, Sidana S, Hansen DK. Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma. Blood advances. 2022 Dec 27:6(24):6109-6119. doi: 10.1182/bloodadvances.2022008320. Epub     [PubMed PMID: 35939783]

Level 3 (low-level) evidence


Albanyan O, Chavez J, Munoz J. The role of CAR-T cell therapy as second line in diffuse large B-cell lymphoma. Therapeutic advances in hematology. 2022:13():20406207221141511. doi: 10.1177/20406207221141511. Epub 2022 Dec 6     [PubMed PMID: 36505886]

Level 3 (low-level) evidence


Mohty R, Moustafa MA, Aljurf M, Murthy H, Kharfan-Dabaja MA. Emerging Role of Autologous CD19 CAR T-Cell Therapies in the Second-Line Setting for Large B-cell Lymphoma: A Game Changer? Hematology/oncology and stem cell therapy. 2022 Nov 7:15(3):73-80. doi: 10.56875/2589-0646.1025. Epub 2022 Nov 7     [PubMed PMID: 36395495]


Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, Pequignot E, Gonzalez VE, Chen F, Finklestein J, Barrett DM, Weiss SL, Fitzgerald JC, Berg RA, Aplenc R, Callahan C, Rheingold SR, Zheng Z, Rose-John S, White JC, Nazimuddin F, Wertheim G, Levine BL, June CH, Porter DL, Grupp SA. Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia. Cancer discovery. 2016 Jun:6(6):664-79. doi: 10.1158/2159-8290.CD-16-0040. Epub 2016 Apr 13     [PubMed PMID: 27076371]


Gauthier J, Turtle CJ. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Current research in translational medicine. 2018 May:66(2):50-52. doi: 10.1016/j.retram.2018.03.003. Epub 2018 Apr 3     [PubMed PMID: 29625831]


Taraseviciute A, Tkachev V, Ponce R, Turtle CJ, Snyder JM, Liggitt HD, Myerson D, Gonzalez-Cuyar L, Baldessari A, English C, Yu A, Zheng H, Furlan SN, Hunt DJ, Hoglund V, Finney O, Brakke H, Blazar BR, Berger C, Riddell SR, Gardner R, Kean LS, Jensen MC. Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. Cancer discovery. 2018 Jun:8(6):750-763. doi: 10.1158/2159-8290.CD-17-1368. Epub 2018 Mar 21     [PubMed PMID: 29563103]


Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, Yeung C, Liles WC, Wurfel M, Lopez JA, Chen J, Chung D, Harju-Baker S, Özpolat T, Fink KR, Riddell SR, Maloney DG, Turtle CJ. Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer discovery. 2017 Dec:7(12):1404-1419. doi: 10.1158/2159-8290.CD-17-0698. Epub 2017 Oct 12     [PubMed PMID: 29025771]


Dotti G, Gottschalk S, Savoldo B, Brenner MK. Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunological reviews. 2014 Jan:257(1):107-26. doi: 10.1111/imr.12131. Epub     [PubMed PMID: 24329793]

Level 3 (low-level) evidence


van der Stegen SJ, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nature reviews. Drug discovery. 2015 Jul:14(7):499-509. doi: 10.1038/nrd4597. Epub     [PubMed PMID: 26129802]


Zhao Z, Condomines M, van der Stegen SJC, Perna F, Kloss CC, Gunset G, Plotkin J, Sadelain M. Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. Cancer cell. 2015 Oct 12:28(4):415-428. doi: 10.1016/j.ccell.2015.09.004. Epub     [PubMed PMID: 26461090]


Manz CR, Porter DL, Bekelman JE. Innovation and Access at the Mercy of Payment Policy: The Future of Chimeric Antigen Receptor Therapies. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020 Feb 10:38(5):384-387. doi: 10.1200/JCO.19.01691. Epub 2019 Nov 1     [PubMed PMID: 31675247]


Abramson JS, Solomon SR, Arnason JE, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers PGNJ, Hernandez-Ilizaliturri FJ, Izutsu K, Morschhauser F, Lunning MA, Crotta A, Montheard S, Previtali A, Ogasawara K, Kamdar M. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2022 Dec 21:():. pii: blood.2022018730. doi: 10.1182/blood.2022018730. Epub 2022 Dec 21     [PubMed PMID: 36542826]


Xiao X, Huang S, Chen S, Wang Y, Sun Q, Xu X, Li Y. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies. Journal of experimental & clinical cancer research : CR. 2021 Nov 18:40(1):367. doi: 10.1186/s13046-021-02148-6. Epub 2021 Nov 18     [PubMed PMID: 34794490]


Owusu KA, Schiffer M, Perreault S. Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations. AACN advanced critical care. 2022 Dec 15:33(4):301-307. doi: 10.4037/aacnacc2022936. Epub     [PubMed PMID: 36477845]


Frey N, Porter D. Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019 Apr:25(4):e123-e127. doi: 10.1016/j.bbmt.2018.12.756. Epub 2018 Dec 23     [PubMed PMID: 30586620]


Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019 Apr:25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25     [PubMed PMID: 30592986]

Level 3 (low-level) evidence


Holtzman NG, Xie H, Bentzen S, Kesari V, Bukhari A, El Chaer F, Lutfi F, Siglin J, Hutnick E, Gahres N, Ruehle K, Ahmad H, Shanholtz C, Kocoglu MH, Badros AZ, Yared JA, Hardy NM, Rapoport AP, Dahiya S. Immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy for lymphoma: predictive biomarkers and clinical outcomes. Neuro-oncology. 2021 Jan 30:23(1):112-121. doi: 10.1093/neuonc/noaa183. Epub     [PubMed PMID: 32750704]

Level 2 (mid-level) evidence


Hayden PJ, Roddie C, Bader P, Basak GW, Bonig H, Bonini C, Chabannon C, Ciceri F, Corbacioglu S, Ellard R, Sanchez-Guijo F, Jäger U, Hildebrandt M, Hudecek M, Kersten MJ, Köhl U, Kuball J, Mielke S, Mohty M, Murray J, Nagler A, Rees J, Rioufol C, Saccardi R, Snowden JA, Styczynski J, Subklewe M, Thieblemont C, Topp M, Ispizua ÁU, Chen D, Vrhovac R, Gribben JG, Kröger N, Einsele H, Yakoub-Agha I. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Annals of oncology : official journal of the European Society for Medical Oncology. 2022 Mar:33(3):259-275. doi: 10.1016/j.annonc.2021.12.003. Epub 2021 Dec 16     [PubMed PMID: 34923107]


Sharma N, Reagan PM, Liesveld JL. Cytopenia after CAR-T Cell Therapy-A Brief Review of a Complex Problem. Cancers. 2022 Mar 15:14(6):. doi: 10.3390/cancers14061501. Epub 2022 Mar 15     [PubMed PMID: 35326654]


Xia Y, Zhang J, Li J, Zhang L, Li J, Fan L, Chen L. Cytopenias following anti-CD19 chimeric antigen receptor (CAR) T cell therapy: a systematic analysis for contributing factors. Annals of medicine. 2022 Dec:54(1):2951-2965. doi: 10.1080/07853890.2022.2136748. Epub     [PubMed PMID: 36382675]

Level 1 (high-level) evidence


Zhang Q, Zu C, Meng Y, Lyu Y, Hu Y, Huang H. Risk factors of tumor lysis syndrome in relapsed/refractory multiple myeloma patients undergoing BCMA CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences. 2022 Apr 25:51(2):144-150. doi: 10.3724/zdxbyxb-2022-0038. Epub     [PubMed PMID: 36161293]


Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, Hakim FT, Halverson DC, Fowler DH, Hardy NM, Mato AR, Hickstein DD, Gea-Banacloche JC, Pavletic SZ, Sportes C, Maric I, Feldman SA, Hansen BG, Wilder JS, Blacklock-Schuver B, Jena B, Bishop MR, Gress RE, Rosenberg SA. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013 Dec 12:122(25):4129-39. doi: 10.1182/blood-2013-08-519413. Epub 2013 Sep 20     [PubMed PMID: 24055823]


Miao L, Zhang Z, Ren Z, Li Y. Reactions Related to CAR-T Cell Therapy. Frontiers in immunology. 2021:12():663201. doi: 10.3389/fimmu.2021.663201. Epub 2021 Apr 28     [PubMed PMID: 33995389]


Davila ML, Kloss CC, Gunset G, Sadelain M. CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia. PloS one. 2013:8(4):e61338. doi: 10.1371/journal.pone.0061338. Epub 2013 Apr 9     [PubMed PMID: 23585892]

Level 3 (low-level) evidence


Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA, Rosenberg SA. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010 Nov 18:116(20):4099-102. doi: 10.1182/blood-2010-04-281931. Epub 2010 Jul 28     [PubMed PMID: 20668228]


Doan A, Pulsipher MA. Hypogammaglobulinemia due to CAR T-cell therapy. Pediatric blood & cancer. 2018 Apr:65(4):. doi: 10.1002/pbc.26914. Epub 2017 Dec 12     [PubMed PMID: 29230962]


Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, Roshal M, Maslak P, Davila M, Brentjens RJ, Sadelain M. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. The New England journal of medicine. 2018 Feb 1:378(5):449-459. doi: 10.1056/NEJMoa1709919. Epub     [PubMed PMID: 29385376]


Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines KM, Heitjan DF, Albelda SM, Carroll RG, Riley JL, Pastan I, June CH. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proceedings of the National Academy of Sciences of the United States of America. 2009 Mar 3:106(9):3360-5. doi: 10.1073/pnas.0813101106. Epub 2009 Feb 11     [PubMed PMID: 19211796]

Level 3 (low-level) evidence


Neelapu SS,Tummala S,Kebriaei P,Wierda W,Gutierrez C,Locke FL,Komanduri KV,Lin Y,Jain N,Daver N,Westin J,Gulbis AM,Loghin ME,de Groot JF,Adkins S,Davis SE,Rezvani K,Hwu P,Shpall EJ, Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nature reviews. Clinical oncology. 2018 Jan     [PubMed PMID: 28925994]


Gödel P, Sieg N, Heger JM, Kutsch N, Herling C, Bärmann BN, Scheid C, Borchmann P, Holtick U. Hematologic Rescue of CAR T-cell-mediated Prolonged Pancytopenia Using Autologous Peripheral Blood Hematopoietic Stem Cells in a Lymphoma Patient. HemaSphere. 2021 Mar:5(3):e545. doi: 10.1097/HS9.0000000000000545. Epub 2021 Feb 17     [PubMed PMID: 33623885]


Giri S, Bhatt VR, Verma V, Pathak R, Bociek RG, Vose JM, Armitage JO. Risk of Second Primary Malignancies in Patients With Follicular Lymphoma: A United States Population-based Study. Clinical lymphoma, myeloma & leukemia. 2017 Sep:17(9):569-574. doi: 10.1016/j.clml.2017.06.028. Epub 2017 Jun 24     [PubMed PMID: 28709798]


Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, Gea-Banacloche JC, Pavletic SZ, Hickstein DD, Lu TL, Feldman SA, Iwamoto AT, Kurlander R, Maric I, Goy A, Hansen BG, Wilder JS, Blacklock-Schuver B, Hakim FT, Rosenberg SA, Gress RE, Kochenderfer JN. Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016 Apr 1:34(10):1112-21. doi: 10.1200/JCO.2015.64.5929. Epub 2016 Jan 25     [PubMed PMID: 26811520]


Bouchkouj N, Lin X, Wang X, Przepiorka D, Xu Z, Purohit-Sheth T, Theoret M. FDA Approval Summary: Brexucabtagene Autoleucel for Treatment of Adults With Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia. The oncologist. 2022 Oct 1:27(10):892-899. doi: 10.1093/oncolo/oyac163. Epub     [PubMed PMID: 35983953]


Taylor L,Rodriguez ES,Reese A,Anderson K, Building a Program: Implications for Infrastructure, Nursing Education, and Training for CAR T-Cell Therapy. Clinical journal of oncology nursing. 2019 Apr 1;     [PubMed PMID: 30880820]


Marzal-Alfaro MB,Escudero-Vilaplana V,Revuelta-Herrero JL,Collado-Borrell R,Herranz-Alonso A,Sanjurjo-Saez M, Chimeric Antigen Receptor T Cell Therapy Management and Safety: A Practical Tool From a Multidisciplinary Team Perspective. Frontiers in oncology. 2021;     [PubMed PMID: 33777790]

Level 3 (low-level) evidence


Yáñez L, Sánchez-Escamilla M, Perales MA. CAR T Cell Toxicity: Current Management and Future Directions. HemaSphere. 2019 Apr:3(2):e186. doi: 10.1097/HS9.0000000000000186. Epub 2019 Mar 29     [PubMed PMID: 31723825]

Level 3 (low-level) evidence


Yáñez L, Alarcón A, Sánchez-Escamilla M, Perales MA. How I treat adverse effects of CAR-T cell therapy. ESMO open. 2020 Aug:4(Suppl 4):e000746. doi: 10.1136/esmoopen-2020-000746. Epub     [PubMed PMID: 32839196]


Chou CK, Turtle CJ. Assessment and management of cytokine release syndrome and neurotoxicity following CD19 CAR-T cell therapy. Expert opinion on biological therapy. 2020 Jun:20(6):653-664. doi: 10.1080/14712598.2020.1729735. Epub 2020 Feb 24     [PubMed PMID: 32067497]

Level 3 (low-level) evidence


Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014 Jul 10:124(2):188-95. doi: 10.1182/blood-2014-05-552729. Epub 2014 May 29     [PubMed PMID: 24876563]

Level 3 (low-level) evidence


Brudno JN,Kochenderfer JN, Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016 Jun 30     [PubMed PMID: 27207799]


Murthy HS, Yassine F, Iqbal M, Alotaibi S, Moustafa MA, Kharfan-Dabaja MA. Management of CAR T-cell Related Toxicities: What did the Learning Curve Teach us so Far? Hematology/oncology and stem cell therapy. 2022 Nov 7:15(3):100-111. doi: 10.56875/2589-0646.1029. Epub 2022 Nov 7     [PubMed PMID: 36395496]


Maus MV, Alexander S, Bishop MR, Brudno JN, Callahan C, Davila ML, Diamonte C, Dietrich J, Fitzgerald JC, Frigault MJ, Fry TJ, Holter-Chakrabarty JL, Komanduri KV, Lee DW, Locke FL, Maude SL, McCarthy PL, Mead E, Neelapu SS, Neilan TG, Santomasso BD, Shpall EJ, Teachey DT, Turtle CJ, Whitehead T, Grupp SA. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events. Journal for immunotherapy of cancer. 2020 Dec:8(2):. doi: 10.1136/jitc-2020-001511. Epub     [PubMed PMID: 33335028]

Level 1 (high-level) evidence


Booth JP, Kusoski CL, Kennerly-Shah JM. The pharmacist's role in chimeric antigen receptor T cell therapy. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2020 Oct:26(7):1725-1731. doi: 10.1177/1078155220948940. Epub 2020 Aug 20     [PubMed PMID: 32819199]


Haseeb F, Tholouli E, Wilson A. Chimeric antigen receptor T-cell therapy in adults: management of toxicities and implications for critical care. BJA education. 2022 Sep:22(9):330-333. doi: 10.1016/j.bjae.2022.04.001. Epub 2022 Jul 11     [PubMed PMID: 36033934]


Alexander M, Culos K, Roddy J, Shaw JR, Bachmeier C, Shigle TL, Mahmoudjafari Z. Chimeric Antigen Receptor T Cell Therapy: A Comprehensive Review of Clinical Efficacy, Toxicity, and Best Practices for Outpatient Administration. Transplantation and cellular therapy. 2021 Jul:27(7):558-570. doi: 10.1016/j.jtct.2021.01.014. Epub 2021 Jan 20     [PubMed PMID: 33910041]


Acharya UH, Dhawale T, Yun S, Jacobson CA, Chavez JC, Ramos JD, Appelbaum J, Maloney DG. Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy. Expert review of hematology. 2019 Mar:12(3):195-205. doi: 10.1080/17474086.2019.1585238. Epub 2019 Mar 18     [PubMed PMID: 30793644]


Porter D, Frey N, Wood PA, Weng Y, Grupp SA. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. Journal of hematology & oncology. 2018 Mar 2:11(1):35. doi: 10.1186/s13045-018-0571-y. Epub 2018 Mar 2     [PubMed PMID: 29499750]


Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nature reviews. Drug discovery. 2018 Jun:17(6):395-412. doi: 10.1038/nrd.2018.45. Epub 2018 May 4     [PubMed PMID: 29725131]


Strati P, Ahmed S, Kebriaei P, Nastoupil LJ, Claussen CM, Watson G, Horowitz SB, Brown ART, Do B, Rodriguez MA, Nair R, Shpall EJ, Green MR, Neelapu SS, Westin JR. Clinical efficacy of anakinra to mitigate CAR T-cell therapy-associated toxicity in large B-cell lymphoma. Blood advances. 2020 Jul 14:4(13):3123-3127. doi: 10.1182/bloodadvances.2020002328. Epub     [PubMed PMID: 32645136]

Level 3 (low-level) evidence


Lipe BC, Renaud T. Siltuximab as a primary treatment for cytokine release syndrome in a patient receiving a bispecific antibody in a clinical trial setting. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2022 Dec 4:():10781552221140320. doi: 10.1177/10781552221140320. Epub 2022 Dec 4     [PubMed PMID: 36464766]


Jain T, Olson TS, Locke FL. How I Treat Cytopenias after CAR T-cell Therapy. Blood. 2023 Feb 17:():. pii: blood.2022017415. doi: 10.1182/blood.2022017415. Epub 2023 Feb 17     [PubMed PMID: 36800563]


Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, Wasik M, Levine BL, Lacey SF, Melenhorst JJ, Porter DL, June CH. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. The New England journal of medicine. 2017 Dec 28:377(26):2545-2554. doi: 10.1056/NEJMoa1708566. Epub 2017 Dec 10     [PubMed PMID: 29226764]


Hernani R, Benzaquén A, Solano C. Toxicities following CAR-T therapy for hematological malignancies. Cancer treatment reviews. 2022 Dec:111():102479. doi: 10.1016/j.ctrv.2022.102479. Epub 2022 Oct 22     [PubMed PMID: 36308910]


Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. The New England journal of medicine. 2014 Oct 16:371(16):1507-17. doi: 10.1056/NEJMoa1407222. Epub     [PubMed PMID: 25317870]


Zu C, Wang K, Zhang Q, Hu Y, Huang H. Clinical features of hemophagocytic syndrome following BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences. 2022 Apr 25:51(2):160-166. doi: 10.3724/zdxbyxb-2022-0039. Epub     [PubMed PMID: 36161295]


Sievers S, Watson G, Johncy S, Adkins S. Recognizing and Grading CAR T-Cell Toxicities: An Advanced Practitioner Perspective. Frontiers in oncology. 2020:10():885. doi: 10.3389/fonc.2020.00885. Epub 2020 Jun 24     [PubMed PMID: 32670871]

Level 3 (low-level) evidence


Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, Zhao Y, Kalos M, June CH. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer immunology research. 2013 Jul:1(1):26-31. doi: 10.1158/2326-6066.CIR-13-0006. Epub 2013 Apr 7     [PubMed PMID: 24777247]

Level 3 (low-level) evidence


Hashmi H, Bachmeier C, Chavez JC, Song J, Hussaini M, Krivenko G, Nishihori T, Kotani H, Davila ML, Locke FL, Jain MD. Haemophagocytic lymphohistiocytosis has variable time to onset following CD19 chimeric antigen receptor T cell therapy. British journal of haematology. 2019 Oct:187(2):e35-e38. doi: 10.1111/bjh.16155. Epub 2019 Aug 13     [PubMed PMID: 31410842]


Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. The New England journal of medicine. 2011 May 12:364(19):1844-54. doi: 10.1056/NEJMra0904569. Epub     [PubMed PMID: 21561350]

Level 3 (low-level) evidence


Messmer AS, Que YA, Schankin C, Banz Y, Bacher U, Novak U, Pabst T. CAR T-cell therapy and critical care : A survival guide for medical emergency teams. Wiener klinische Wochenschrift. 2021 Dec:133(23-24):1318-1325. doi: 10.1007/s00508-021-01948-2. Epub 2021 Oct 6     [PubMed PMID: 34613477]


Tallantyre EC, Evans NA, Parry-Jones J, Morgan MPG, Jones CH, Ingram W. Neurological updates: neurological complications of CAR-T therapy. Journal of neurology. 2021 Apr:268(4):1544-1554. doi: 10.1007/s00415-020-10237-3. Epub 2020 Nov 2     [PubMed PMID: 33140239]


Hunter BD, Jacobson CA. CAR T-Cell Associated Neurotoxicity: Mechanisms, Clinicopathologic Correlates, and Future Directions. Journal of the National Cancer Institute. 2019 Jul 1:111(7):646-654. doi: 10.1093/jnci/djz017. Epub     [PubMed PMID: 30753567]

Level 3 (low-level) evidence


Ruark J, Mullane E, Cleary N, Cordeiro A, Bezerra ED, Wu V, Voutsinas J, Shaw BE, Flynn KE, Lee SJ, Turtle CJ, Maloney DG, Fann JR, Bar M. Patient-Reported Neuropsychiatric Outcomes of Long-Term Survivors after Chimeric Antigen Receptor T Cell Therapy. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020 Jan:26(1):34-43. doi: 10.1016/j.bbmt.2019.09.037. Epub 2019 Oct 9     [PubMed PMID: 31605820]


Perica K, Curran KJ, Brentjens RJ, Giralt SA. Building a CAR Garage: Preparing for the Delivery of Commercial CAR T Cell Products at Memorial Sloan Kettering Cancer Center. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018 Jun:24(6):1135-1141. doi: 10.1016/j.bbmt.2018.02.018. Epub 2018 Mar 1     [PubMed PMID: 29499327]


Hernandez I, Prasad V, Gellad WF. Total Costs of Chimeric Antigen Receptor T-Cell Immunotherapy. JAMA oncology. 2018 Jul 1:4(7):994-996. doi: 10.1001/jamaoncol.2018.0977. Epub     [PubMed PMID: 29710129]