Cytokine Release Syndrome
Cytokine release syndrome (CRS) is a potentially life-threatening condition that results from the pathologic over-activation of T cells, leading to hypersecretion of cytokines by T cells and other immune cell types. Similar in presentation to a “cytokine storm”, which can be observed across a variety of diseases and treatments, CRS has recently become more formally associated with T-cell–engaging immunotherapies, such as blinatumomab and chimeric antigen receptor T-cell (CAR-T) therapy. At the time of this review, the US Food and Drug Administration (FDA) has approved two CAR-T cell therapies: tisagenlecleucel (approved for relapsed/refractory childhood/adolescent acute lymphoblastic lymphoma and adult relapsed/refractory large B cell lymphoma) [1, 2] and axicabtagene ciloleucel (approved for relapsed/refractory diffuse large B cell lymphoma).  Other CAR-T cell therapies are undergoing clinical trials.
Onset of CRS typically occurs early in the treatment course, within the first 14 days of CAR-T cell infusion or during the first cycle of blinatumomab administration.  CRS can last several days, depending on severity and intervention strategies. 
CRS is clinically characterized by fever and malaise, which can progress rapidly to capillary leak, hypoxia, hypotension, vasodilatory shock, and death. [6, 7] Laboratory markers of systemic inflammation, such as interleukin-6 (IL-6), C-reactive protein (CRP), and ferritin are elevated in response to the hyper-activation of the immune system. While some cytokine profiles have been shown to be predictive of severe CRS,  there is no standard cytokine profile currently utilized to predict CRS severity. [9, 10]
Mild CRS after CAR-T cell infusion often resolves without anti-cytokine intervention and patients are supported with antipyretics and intravenous fluids as needed. Corticosteroids and anti-cytokine–directed therapy with the anti-IL-6 receptor antibody tocilizumab are effective in mitigating CRS. While often reserved for patients with more severe CRS, earlier intervention strategies are being explored. Tocilizumab initially received companion FDA approval for treating CRS with tisagenlecleucel  and is also part of the CRS treatment regimen for axicabtagene ciloleucel.
The terms cytokine storm and CRS have both been used to describe similar syndromes of systemic inflammation that are associated with a variety of diseases and treatments, such as graft versus host disease (GVHD) after allogeneic stem cell transplant, macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), idiopathic multicentric Castleman disease (iMCD), and as an adverse event associated with several monoclonal antibody infusions. [11, 12, 13, 14, 15, 16, 17] However, CRS has been more frequently used to describe a common toxicity in the setting of T-cell–engaging immunotherapies such as CAR-T cells and blinatumomab. [12, 18] This review will focus on systemic CRS. Its grading and treatment are independent of immune effector cell–associated neurotoxicity (ICANS). 
The CRS in CAR-T cell therapy may be biologically distinct from the form seen with blinatumomab, though they likely share many similarities both to each other as well as otto her diseases in which the immune system is hyper-activated. While some studies have suggested that the cytokines are released by the blinatumomab-activated/CAR-T cells,  resulting in a positive feedback loop of T cell activation and inflammatory cytokine release, a recent murine model study has suggested that the cytokines and factors that mediate the severity of CRS, IL-6, IL-1, and nitric oxide are not produced by the CAR-T cells but by recipient macrophages, and can be reversed by IL-1 blockade. 
Abnormal macrophage activation has also been implicated in blinatumomab-related CRS, which also responds to IL-6–directed therapy.  Further studies elucidating the key pathways involved in CRS are needed to develop additional targeted therapeutics for this potentially life-threatening syndrome, especially as the use of CAR-T cell therapies increases in both research settings and routine clinical practice.
CRS occurs in 43-100% of study patients with leukemia or lymphoma receiving CAR-T cell therapy targeted to CD19. [10, 22, 23, 24, 25, 26, 27, 28, 29] While about 60% of patients in a study of blinatumomab in B-cell acute lymphoblastic leukemia experienced pyrexia, only 2% had grade 3 CRS.  The following factors may affect the incidence and severity of CRS in CAR-T cell therapy:
Investigations to mitigate CRS without impacting efficacy are under way, with potential strategies including the following:
CRS can vary widely in severity, from a self-limited febrile illness to life-threatening hypotension and hypoxia requiring support in an intensive care setting.  In addition to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0), several grading scales have been developed for CRS in the context of CAR T cell clinical trials. [5, 26, 40] The use of these different grading scales has made it challenging to interpret toxicity across trials.
Because of these concerns and a desire for harmonization in the field, the American Society for Transplantation and Cellular Therapy (ASTCT) has developed a consensus grading scale based on the 3 clinical factors of fever, hypoxia, and hypotension.  The ASTCT scale is as follows  :
Note the following:
CRS tends to present in the first 2 weeks of CAR T-cell therapy, or the first cycle of treatment with blinatumomab. [4, 10, 23, 24] A detailed history is important, as patients will present with any or all of the following nonspecific signs and symptoms:
In addition to the above presenting manifestations of CRS, detailed questions regarding possible infectious causes for the patient’s condition are important to consider. Exposure to sick contacts, diarrhea or abdominal complaints, dysuria, or a history of a productive cough may hint at alternative diagnoses that must be considered in the differential.
Physical exam should first focus on a general assessment of the patient’s respiratory status with regard to impending respiratory failure. The use of accessory muscles of inspiration, interval development of inspiratory crackles as a result of pulmonary edema or capillary leak, and confusion as a result of hypercarbia must be considered in this assessment. After the respiratory evaluation, the other vital signs should be evaluated, and re-evaluated early and often once CRS is suspected.
Once the patient is deemed to be stable from a respiratory and circulatory perspective, the exam should focus on ruling out potential sources of infection, such as findings consistent with a new lung consolidation, skin rash/lesion suggesting cellulitis or other dermal source of infection, or the development of new abdominal tenderness or guarding.
CRS is a diagnosis of exclusion. As the syndrome’s presentation is similar to sepsis, systemic infection is at the top of the differential for CRS, especially because patients with relapsed/refractory leukemia/lymphoma are at increased risk for infection. In addition to sepsis, tumor lysis syndrome (TLS) must also be considered, as these patients are also at risk for TLS, and management of TLS requires additional laboratory studies and interventions that are distinct from those for sepsis or CRS. Lastly, progression of the underlying malignancy should be considered as a possibility if only mild symptoms are present.
The approach to evaluating a patient with CRS should accomplish three main goals: ruling out other likely diagnoses, establishing the grade/severity of CRS, and determining the clinical trajectory of the patient. If the laboratory workup is initially concerning for TLS, one should consider additional therapies and lab monitoring for TLS, if they are warranted beyond the fluid resuscitation that would otherwise accompany treatment of CRS (such as allopurinol, rasburicase, or febuxostat).
A complete infectious workup should be obtained, including blood cultures, respiratory viral pathogen analysis, urinalysis, urine culture, and chest x-ray. Laboratory assessment of kidney (blood urea nitrogen [BUN] and creatinine) and liver function tests (LFTs) should be obtained. Arterial blood gas measurement should be considered if the respiratory evaluation warrants it. Uric acid and lactate dehydrogenase (LDH) should also be tested in addition to renal function, to evaluate for possible TLS. If cytokine profiles are clinically available, they may be helpful as baseline values that can then be followed, though results will not typically return soon enough for consideration as part of the immediate work-up and evaluation. Inflammatory acute phase biomarkers such as CRP and ferritin can be measured, as they are often elevated in CRS and correlate with onset and resolution of signs and symptoms.
A patient with mild CRS (grade 1-2) related to CAR-T cells can be managed with supportive care alone, such as antipyrectics, fluids and supplemental oxygen for mild hypoxia. Patients with low-grade CRS should be closely monitored in an inpatient setting for signs of progression. The management of CRS with T cell engagers, such as blinatumomab, includes the potential to start and stop the drug. Blinatumomab is administered as a continuous infusion with administration of dexamethasone at onset of infusion and at dose escalation to prevent CRS. If mild CRS occurs with blinatumomab, it can be continued with close inpatient monitoring for progression of CRS.
Severe CRS (grade 3-4) is life-threatening and should be managed in an experienced intensive care unit setting. Concurrent broad antibiotic coverage for presumed sepsis is advised. For severe CRS, blinatumomab should be held until resolution. For adults, reinitiation of blinatumomab should be at the lower dose (9 mcg/day) and patients should be premedicated with dexamethasone. Corticosteroids are also used as a standard treatment for CRS related to blinatumomab.
In addition to supportive measures, the anti–IL-6 receptor antibody tocilizumab has been approved for use by the FDA in severe/life-threatening CRS,  and is considered standard of care for these cases. Tocilizumab is an effective treatment of CRS for the majority of patients receiving CAR-T cell therapy, and has limited intrinsic toxicity. The optimal time to introduce tocilizumab remains unclear and is the subject of active research. [33, 40]
Despite limited data, there is concern that corticosteroids could negatively impact the antitumor effects of CAR-T cell therapy, and thus their liberal use in the management of CRS associated with CAR-T cell therapy is not recommended. However, they should be administered in conjunction with tocilizumab for grade 3 or 4 CRS or in the event of tocilizumab failure or concurrent CAR-T cell–related neurotoxicity.
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Nicholas P McAndrew, MD, MSCE Clinical Instructor, Division of Hematology/Oncology, University of California, Los Angeles, David Geffen School of Medicine
Nicholas P McAndrew, MD, MSCE is a member of the following medical societies: American Society of Clinical Oncology
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Novartis, Daiichi Sankyo<br/>Serve(d) as a speaker or a member of a speakers bureau for: Novartis<br/>Research funding to my institution for a clinical trial of which I am the PI for: Novartis, Daiichi Sankyo.
Noelle Frey, MD, MSCE Assistant Professor of Medicine, University of Pennsylvania School of Medicine; Associate Director, Bone Marrow Transplant Program, Division of Hematology/Oncology, Perelman Center for Advanced Medicine, Hospital of the University of Pennsylvania
Noelle Frey, MD, MSCE is a member of the following medical societies: American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Served on Advisory Boards for Novartis; Kite; Servier.
David C Fajgenbaum, MD, MBA, MSc Research Assistant Professor of Medicine, Translational Medicine and Human Genetics, University of Pennsylvania School of Medicine; Associate Director, Patient Impact, Orphan Disease Center, Division of Medical Genetics, Hospital of the University of Pennsylvania
David C Fajgenbaum, MD, MBA, MSc is a member of the following medical societies: American Society of Hematology
Disclosure: Received research grant from: Janssen Pharmaceuticals; EUSA Pharma.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
John Heinegg Editor, eMedicine
Disclosure: Nothing to disclose.
Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences
Disclosure: Nothing to disclose.
Cytokine Release Syndrome
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