Cytokine Release Syndrome

Etiology

Alemtuzumab (Campath, MabCampath, Campath-1H, Lemtrada) (see Alemtuzumab): anti-CD52 monoclonal antibody
- Epidemiology
  - Alemtuzumab is Commonly Associated with Cytokine Release Syndrome
TGN1412: anti-CD28 superagonist
- Epidemiology
  - TGN1412 is Commonly Associated with Cytokine Release Syndrome
Anti-Thymocyte Globulin (ATG) (see Anti-Thymocyte Globulin)
Chimeric Antigen Receptor T-Cells (CAR-T) (see Chimeric Antigen Receptor T-Cells)
Basiliximab (Simulect) (see Basiliximab)
Bi-Specific Antibodies in Treatment of Leukemia
- Epidemiology
  - Case Reports
Haploidentical Mononuclear Cells in Treatment of Refractory Leukemia
- Epidemiology
  - Case Reports
Lenalidomide (Revlimid) (see Lenalidomide)
Muromonab-CD3 (Orthoclone OKT3) (see Muromonab-CD3): anti-CD3 monoclonal antibody
- Epidemiology
  - Muromonab-CD3 is Commonly Associated with Cytokine Release Syndrome
Oxaliplatin (Eloxatin, Oxaliplatin Medac) (see Oxaliplatin)
Rituximab (Rituxan) (see Anti-CD20 Therapy): chimeric monoclonal anti-CD20 antibody
- Epidemiology
  - Rituximab is Commonly Associated with Cytokine Release Syndrome
Tisagenlecleucel (Kymriah) (see Tisagenlecleucel)
- Epidemiology
  - May Occur
- Pharmacology
  - CAR-T (CD19-Directed T-Cell Medication) Therapy

Physiology

Systemic Release of Inflammatory Mediators Usually on First Exposure to a Therapeutic Monoclonal Antibody

TNF-α Release
Interferon-Gamma Release
Interleukin-6 (IL-6) Release
Lymphocyte Activation
- B-Cells
- T-Cells
- NK Cells: may play a role in anti-CD3 and alemtuzumab-related cases
Myeloid Cell Activation
- Dendritic Cells
- Macrophages
- Monocytes

Potential Mechanisms

Direct binding of Monoclonal Antibody to its Ligand on Target Cell Leading to Signaling Within the Cell
- Cytokine Release by the Target Cell
- Probably represents the mechanism by which Anti-CD28 superantigens cause cytokine release syndrome: these superantigens are believed to activate T-cells without the primary signal occurring through the T-cell receptor
Binding of Fc End of Monoclonal Antibody to Fc Receptors on Non-Target Cells Leading to Signaling Within the Non-Target Cell
- Cytokine Release by Non-Target Cell
Binding of Monoclonal Antibody to Fc Receptor Leading to Clustering and Signaling Within the Target Cell

Cytokine Release Syndrome Grading System (Modified from National Cancer Institute Common Terminology Criteria for Adverse Events, CTCAE v4.0 System) [MEDLINE]

Grade 1 (Symptoms are Not Life-Threatening and Require Symptomatic Treatment Only)
- Fatigue (see Fatigue)
- Fever (see Fever)
- Headache (see Headache)
- Nausea (see Nausea and Vomiting)
- Malaise
- Myalgias (see Myalgias)
Grade 2 (Symptoms Require and Respond to Moderate Intervention)
- Oxygen requirement <40% or hypotension responsive to fluids or low-dose of one vasopressor or grade 2 organ toxicity
Grade 3 (Symptoms Require and Respond to Aggressive Intervention)
- Oxygen requirement of at least 40% or hypotension requiring high dose or multiple vasopressors or grade 3 organ toxicity (coagulopathy, renal dysfunction, cardiac dysfunction) or grade 4 transaminitis
Grade 4 (Life-Threatening Symptoms)
- Requirement for ventilator support or grade 4 organ toxicity (excluding transaminitis)
Grade 5 (Death)
- Self-Explanatory

Clinical Manifestations

General Comments

Latency of Onset: symptoms typically occur within min-hrs after infusion starts
- Timing of symptom onset and severity depend on the inducing agent and the magnitude of immune cell activation
Duration: may last several hours
Co-Existent Macrophage Activation Syndrome (MAS): cytokine release syndrome may be associated with the findings of macrophage activation syndrome/hemophagocytic lymphohistiocytosis (HLH)
- Physiology of the syndromes may have overlap
Co-Existent Tumor Lysis Syndrome: cytokine release syndrome may be associated with concomitant tumor lysis syndrome, as the massive immune cell activation and expansion correlates with antitumor efficacy
Co-Existence of Neutropenia or Other Immune-Suppressing Condition: when present, exclusion of infection is crucial

Cardiovascular Manifestations

Hypotension (see Hypotension)
Myocardial Systolic Dysfunction (see Congestive Heart Failure)
- Resembles sepsis-induced cardiomyopathy or stress cardiomyopathy (Takotsubo cardiomyopathy): cardiac output may be increased early
Tachycardia (see Sinus Tachycardia)

Dermatologic Manifestations

Flushing (see Flushing)
Pruritus (see Pruritus)
Rash (see Urticaria): may be urticarial

Gastrointestinal Manifestations

Diarrhea (see Diarrhea)
Hepatitis (see xxxx)
- Hyperbilirubinemia
- Transaminitis
Nausea/Vomiting (see Nausea and Vomiting)

Hematologic Manifestations

Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)

Neurologic Manifestations

Asthenia/Generalized Weakness
Encephalopathy
- Delirium (see Delirium)
- Obtundation-Coma (see Obtundation-Coma)
Headache (see Headache)
Myalgias (see Myalgias)
Reversible Splenial Lesion Syndrome (RESLES) (see Reversible Splenial Lesion Syndrome)

Pulmonary Manifestations

Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)
Bronchospasm/Dyspnea (see Obstructive Lung Disease)
Pneumonitis (see Pneumonia)

Renal Manifestations

Acute Kidney Injury (AKI) (see Acute Kidney Injury)

Other Manifestations

Fatigue
Hypothermia/Fever (see Hypothermia or Fever)
- Fever may exceed 40 degrees C
Chills/Rigors

Treatment

Supportive Care

Hemodynamic Support

Intravenous Fluids: as required
Vasopressors: as required

Respiratory Support

Oxygen: as required
Mechanical Ventilation: as required

General Comments

It’s unclear to what extent the cytokines mediating the symptomology are required for the desired anti-tumor effect of the agent that was administered
- Therefore, the goal of therapy as noted below is not to extinguish all evidence of cytokine release syndrome but it is to prevent life-threatening toxicity while maximizing the potential for anti-tumor effects

Grade 1 Cytokine Release Syndrome

Symptomatic Treatment Only: usually preferred

Grade 2 Cytokine Release Syndrome

Immunosuppressive Treatment (see below)

May be considered in some cases

Grade 3-4 Cytokine Release Syndrome

Immunosuppressive Treatment (Recommended)

Tocilizumab (Actemra) (see Tocilizumab)
- Mechanism: prevents IL-6 binding to cell-associated and soluble IL-6 receptors -> inhibits both classical and trans-IL-6 signaling
- Clinical: effective first-line treatment for severe or life-threatening cytokine release syndrome
Corticosteroids (see Corticosteroids)
- Administration
  - Methylprednisolone (2 mg/kg/day): after response, wean over several days
  - Dexamethasone (0.5 mg/kg, max 10 mg per dose): may be used in cases with severe neurologic symptoms (due to more efficient penetration of the blood-brain barrier)
- Clinical
  - Effective first or second-line treatment (response to corticosteroids is generally believed to be slower than that to tocilizumab
  - May be used in combination with tocilizumab
Anti-Tumor Necrosis Factor-α (TNF-α) Therapy (see Anti-Tumor Necrosis Factor-α Therapy): may be used
- Etanercept (Enbrel) (see Etanercept)
- Infliximab (Remicade) (see Infliximab)
IL-1 Receptor Antagonists: may be used
- Anakinra (see Anakinra)

References

Fatal Cytokine Release Syndrome With Chimeric Anti-CD20 Monoclonal Antibody Rituximab in a 71-Year-Old Patient With Chronic Lymphocytic Leukemia. JCO June 1, 1999 vol. 17 no. 6 1962-1963
Cytokine-Release Syndrome in Patients With B-Cell Chronic Lymphocytic Leukemia and High Lymphocyte Counts After Treatment With an Anti-CD20 Monoclonal Antibody (Rituximab, IDEC-C2B8). Blood October 1, 1999 vol. 94 no. 7 2217-2224
Oxaliplatin may induce cytokine-release syndrome in colorectal cancer patients. Journal of Biological Regulators and Homeostatic Agents [2002, 16(2):105-9]
Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia. September 1, 2009 vol. 94 no. 9 1266-1273
Development of a human whole blood assay for prediction of cytokine release similar to anti-CD28 superagonists using multiplex cytokine and hierarchical cluster analysis. Int Immunopharmacol. 2011 Nov;11(11):1697-705 [MEDLINE]
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 [MEDLINE]