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Subsections
CAR T-Cell Therapy Associated Syndromes

Oncology

Chimeric Antigen Receptor T-cell Therapy Associated Syndromes

Background

  1. Definition
    • Chimeric Antigen Receptor (CAR) T-cell Therapy
      • Immunotherapy using T-cells genetically engineered to express a chimeric antigen receptor aimed at Tx of malignancies
      • Demonstrated clinical efficacy in targeting hematologic malignancies and solid tumors
    • Cytokine Release Syndrome (CRS)
      • A spectrum of inflammatory Sx due to cytokine elevations induced by T-cell activation/proliferation
      • Commonly referred to as an infusion reaction
      • Results from release of cytokines from cells targeted by antibody/immune effector cells recruited to the area
      • Most common toxicity associated with CART-19 and blinatumomab
    • CAR-T Related Encephalopathy Syndrome (CRES)
      • Second most occurring event
      • Toxic encephalopathy/neurotoxicity
        • Confusion, delirium, seizures, cerebral edema
      • Can occur concurrently with CRS
  2. Synopsis
    • CAR-T cells and bispecific T-cell-engaging antibodies have shown promising clinical responses
      • Hallmark results are nonphysiologic T- cell activation, correlating with increased efficacy
        • Also with severe toxicity in some cases
      • Most-common toxicities from CAR-T-cell therapy: CRS and CAR-T-cell-related encephalopathy syndrome (CRES)
        • Fulminant CRS may be life-threatening
          • CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH)
            • Also known as macrophage‑activation syndrome (MAS)
    • Management of CRS and CRES can be life saving

Pathophysiology

  1. Mechanism
    • CRS: Immune activation, cytokine release
      • CRS also seen with infusion of
        • Therapeutic monoclonal antibodies (mAbs)
        • Systemic interleukin-2 (IL-2)
        • Bispecific CD19-CD3 T-cell engaging antibody blinatumomab
      • Hallmark of CRS: elevated inflammatory cytokines
        • Activation of large numbers of lymphocytes (B-cells, T-cells, NK cells)/myeloid cells (macrophages, dendritic cells, monocytes)
          • Releases inflammatory cytokines
          • Evidence implicates IL-6 as central mediator of toxicity in CRS
            • IL-6: pleiotropic cytokine with anti-inflammatory and proinflammatory properties
          • CRS incidence and severity appears greater with larger tumor burdens
            • (probably due to higher levels of T-cell activation)
      • Case Studies
        • Increase in Tumor necrosis factor (TNF)-alpha first, followed by IFN-gamma, IL-1b, IL-2, IL-6, IL-8, and IL-10
          • Within 24 hrs, all subjects required transfer to ICU to manage respiratory distress and renal dysfunction
            • Ultimately required dialysis
        • Following Sx onset (day 1), all subjects were treated with corticosteroids
          • Within 3 days, cytokines returned to normal levels
          • Two subjects experienced prolonged organ dysfunction despite return of cytokine levels to baseline
    • CRES: biphasic manifestation of toxic encephalopathy
      • Mechanism yet to be determined; 2 postulates
        • Passive diffusion of cytokines into the brain (e.g., IL-6, IL-15)
        • Migration of T-cells into the CNS (detection of CAR-T cells in CSF)
  2. Etiology/Risk Factors
    • CRS has classically been associated with
      • Therapeutic mAb infusions
      • Most notably anti-CD3 (OKT3)
      • Anti-CD52 (alemtuzumab)
      • 19 anti-CD20 (rituximab)
      • CD28 super-agonist, TGN1412
  3. Epidemiology
    • Incidence/Prevalence
      • Final data on incidence of CRS/CRES in CAR-T patients ongoing
    • Mortality/Morbidity
      • CRS-related death after blinatumomab has been reported
      • Fulminant CRS can lead to HLH/MAS, which is life-threatening

Diagnostics

  1. History/Symptoms
    • CRS
      • Symptom onset occurs within minutes to hours after infusion begins
      • In most patients are mild and flu-like, with fevers and myalgias
      • Some patients experience a severe inflammatory syndrome, including
        • Vascular leak
        • Hypotension
        • Pulmonary edema
        • Coagulopathy
        • Results in multiorgan system failure
    • CRES
      • Confusion, disorientation, delirium
  2. Physical Exam/Signs
    • CRS
      • Constitutional
        • High fever, malaise, fatigue, myalgia, nausea, vomiting, diarrhea, anorexia
          • If fever, assess for infection
            • Blood/urine cultures
            • Chest radiography
            • Additional tests as indicated (e.g., CMV-PCR, RSV screening, CT Chest, etc.)
          • Perform tests before initiation of CAR‑T‑cell therapy if infection suspected
          • Delay CAR-T cell therapy until infection has been controlled/ruled out
      • Cardiovascular
        • Tachycardia/hypotension
        • Capillary leak
        • Cardiac dysfunction
      • Respiratory
        • Tachypnea, hypoxemia
      • Renal impairment
        • Azotemia
      • Hepatic failure
        • Transaminitis
        • Hyperbilirubinemia
      • Hematologic
        • Disseminated intravascular coagulation
        • Elevated D-dimer
        • Hypofibrinogenemia
        • Hemorrhage
      • Neurologic
        • Headache
        • Mental status changes, delirium
        • Aphasia
        • Hallucinations
        • Dysmetria
        • Seizures, altered gait
      • Skin rashes
    • CRES
      • Early signs: diminished attention, language disturbance, impaired handwriting
      • Agitation, aphasia
      • Somnolence
      • Tremors
      • Severe signs
        • Seizures
        • Motor weakness
        • Incontinence
        • Mental obtundation
        • Increased ICP
        • Papilledema
        • Cerebral edema
      • Biphasic
        • First phase: concurrent with high fever and other CRS symptoms within 5 days after initiation of immunotherapy
        • Second phase: after fever/CRS symptoms subside (after about 5 days after initiation of immunotherapy)
          • Delayed neurotoxicity (seizures, confusion) at 3rd or 4th week after initiation of immunotherapy (10%)
      • Usually lasts for 2-4 days, but can vary from a few hours to weeks
      • CRES occurring with CRS usually shorter in duration and of a lower grade (grade 1-2) than CRES occurring post‑CRS (usually grade ≥3 and protracted)
  3. Labs/Tests
    • CBC +Diff, CMP, electrolytes
    • Coagulation profiles
    • Serum CRP and ferritin levels
  4. Imaging
    • If required (i.e., due to toxicity)
      • Chest radiography
      • Echocardiography
      • CT/MRI brain/spine
  5. Other Tests/Criteria
    • If required (i.e., due to toxicity)
      • EKG, Electroencephalography if toxicity
      • Histology (e.g., hemophagocytosis in bone marrow or organs)
      • Lumbar puncture (opening pressure)
    • Cytokine Release Syndrome Grading
      • Grade 1
        • Fever, constitutional symptoms
      • Grade 2
        • Hypotension that responds to fluids/one low-dose pressor
        • Hypoxia that responds to < 40% O2
        • Grade 2 organ toxicity
      • Grade 3
        • Hypotension that requires multiple low-dose pressors/high-dose pressors
        • Hypoxia that requires ≥ 40% O2
        • Organ Toxicity grade 3, grade 4 transaminitis
      • Grade 4
        • Requires mechanical ventilation
        • Grade 4 organ toxicity, excluding transaminitis
    • CRES Grading
      • Grade 1: Mild Impairment
      • Grade 2: Moderate Impairment
      • Grade 3: Severe Impairment
        • CARTOX-10 score 0-2
        • Stage 1-2 papilledema 7 or CSF opening pressure < 20 mmHg
        • Partial seizure or non-convulsive seizures on EEG
          • Responds to benzodiazepines
      • Grade 4: Critical Condition or Obtunded/cannot perform tasks
        • Stage 3-5 papilledema 7 or CSF opening pressure ≥ 20 mmHg
        • Generalized seizures, status epilepticus (check EEG; may be non-convulsive), new motor weakness
    • Organ Toxicity Grading
      • Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 5
  6. Differential Diagnosis
    • Anaphylaxis
    • Epilepsy
    • Infectious process
    • DIC

Treatment

  1. Initial/Prep/Goals
    • ABCs, IV access, O2, monitor
      • Monitor:
        • Vital signs q4h, daily review of organ systems, labs
        • Strict daily fluid balance/body weights
        • Maintenance of IV hydration
      • Central venous access, with a double or triple lumen catheter, before CAR‑T‑cell infusion
    • Growth factor support with filgrastim if neutropenia
    • Corticosteroids: potential to block T-cell activation; may reduce efficacy of CAR-T-cell therapy
      • Considered only if toxicities of CAR‑T‑cell therapy refractory to anti‑IL‑6 therapy
      • Generally be avoided in order to avoid limiting CAR‑T‑cell therapy efficacy
    • Data suggests tocilizumab is effective at reversing CRS without inhibiting CART19 or blinatumomab efficacy
      • Tocilizumab or siltuximab (chimeric anti‑IL‑6 mAb) preferred for moderate-severe CRS
      • Tocilizumab does not seem to affect CAR‑T‑cell therapy efficacy
      • Tocilizumab binds competitively with IL-6R, decreasing IL-6 uptake into peripheral tissues, increasing serum IL-6
        • Can lead to neurotoxicity
    • Siltuximab might be more effective than tocilizumab for controlling CRS
      • Less likely to compete with IL-6R binding, binds directly with IL-6
    • Manage patients according to grade of CRS
  2. Medical/Pharmaceutical
    • CRS Management
      • Grade 1 CRS (Fever or Organ Toxicity)
        • Acetaminophen, ibuprofen, hypothermia blanket
        • Empiric antibiotics and filgrastim if infection and neutropenic
        • IV hydration, supportive/symptomatic care
        • If fever >3 days and refractory:
          • Consider tocilizumab (off-label: 8 mg/kg IV; max 800 mg/dose), OR
          • Siltuximab (off-label: 11 mg/kg IV)
      • Grade 2 CRS
        • Hypotension
          • IV fluids (Normal saline bolus 0.5-1.0 L)
            • Give second bolus if SBP remains < 90 mmHg
          • If hypotension refractory to fluids:
            • Tocilizumab (off-label: 8 mg/kg IV; max 800 mg/dose), OR
            • Siltuximab (off-label: 11 mg/kg IV)
              • Tocilizumab can be repeated after 6 hrs as needed
          • If persists despite fluids and anti-IL-6 therapy
            • Vasopressors
            • Consider ICU, echocardiogram, hemodynamic monitoring
          • High-risk or hypotension persists after 2 doses of anti-IL-6 therapy
            • Dexamethasone: 10 mg IV q6h
        • Hypoxia
          • O2
          • Tocilizumab (off-label: 8 mg/kg IV; max 800 mg/dose), OR
            • Siltuximab (off-label: 11 mg/kg IV)
          • +/- Corticosteroids
          • Supportive care
        • Organ Toxicity
          • Symptomatic management
          • Tocilizumab (off-label: 8 mg/kg IV; max 800 mg/dose), OR
            • Siltuximab (off-label: 11 mg/kg IV)
          • +/- Corticosteroids
      • Grade 3 CRS
        • Hypotension
          • IV fluids (Normal saline bolus 0.5-1.0 L)
            • Give second bolus if SBP remains < 90 mmHg
            • If hypotension refractory to fluids
              • Tocilizumab (off-label: 8 mg/kg IV; max 800 mg/dose), OR
              • Siltuximab (off-label: 11 mg/kg IV)
                • Tocilizumab can be repeated after 6 hrs as needed
            • If persists despite fluids and anti-IL-6 therapy
              • Vasopressors
          • Transfer to ICU, echocardiogram, hemodynamic monitoring
          • Dexamethasone: 10 mg IV q6h; if refractory give 20 mg IV q6h
          • Manage fever/constitutional symptoms as in grade 1
        • Hypoxia
          • O2, including high flow oxygen and non-invasive positive-pressure ventilation
          • Tocilizumab (off-label: 8 mg/kg IV; max 800 mg/dose), OR
            • Siltuximab (off-label: 11 mg/kg IV)
          • Corticosteroids
          • Supportive care
        • Organ Toxicity
          • Symptomatic treatment
          • Tocilizumab (off-label: 8 mg/kg IV; max 800 mg/dose), OR
            • Siltuximab (off-label: 11 mg/kg IV)
          • Corticosteroids
          • Supportive care
      • Grade 4 CRS
        • Hypotension
          • IV fluids, anti-IL-6 Tx, vasopressors, hemodynamic monitoring
          • Methylprednisolone 1 g/day IV
          • Manage fever and symptoms as grade 1
        • Hypoxia
          • Mechanical ventilation
          • Tocilizumab (off-label: 8 mg/kg IV; max 800 mg/dose), OR
            • Siltuximab (off-label: 11 mg/kg IV)
          • Corticosteroids
          • Supportive care
        • Organ Toxicity
          • Symptomatic treatment
          • Tocilizumab (off-label: 8 mg/kg IV; max 800 mg/dose), OR
            • Siltuximab (off-label: 11 mg/kg IV)
          • Corticosteroids
          • Supportive care
    • CRES Management
      • Grade 1 CRES
        • Supportive care, IV fluids, aspiration precautions
          • NPO, assess swallowing
            • Oral to IV medications/nutritions if swallowing impairment
          • Avoid CNS depressive medications
          • Lorazepam (0.25-0.5 mg IV q8h) or haloperidol (0.5 mg IV q6h)
            • Monitor if/for agitation
          • Consult neurology
          • Fundoscope for papilledema
          • MRI brain +/- contrast
            • MRI spine if focal peripheral deficits
            • CT brain if no MRI
          • Opening pressure (lumbar puncture)
          • EEG until toxicity symptoms resolve
            • If no seizures detected, continue levetiracetam (750 mg q12h)
        • If status epilepticus (non-convulsive)
          • ABCs, blood glucose
          • Lorazepam: 0.5 mg IV; additional 0.5 mg IV q5min PRN, NMT 2 mg to stabilize EEG
            • Maintenance: 0.5 mg IV q8h for 3 doses
          • Levetiracetam: 500 mg IV bolus, followed by maintenance doses
            • Maintenance: 1000 mg IV q12h
          • If refractory: ICU + phenobarbital (60 mg IV loading dose)
            • Maintenance: 30 mg IV q12h
      • Grade 2 CRES
        • Supportive care/neurological work-up as for grade 1 CRES
        • If concurrent CRS
          • Tocilizumab: 8 mg/kg IV; max 800 mg/dose, or
          • Siltuximab: 11 mg/kg IV
        • If refractory to anti-IL-6 therapy, or CRES without concurrent CRS
          • Dexamethasone: 10 mg IV q6h, or
          • Methylprednisolone: 1 mg/kg IV q12h
        • If CRES associated with grade ≥ 2 CRS
          • Consider ICU transfer
      • Grade 3 CRES
        • Supportive care/neurological work-up as for grade 1 CRES
        • Transfer to ICU
        • If associated with concurrent CRS and if not administered previously, see grade 2 above
        • Corticosteroids as for grade 2 CRES if symptoms worsen despite anti-IL-6 therapy, or for CRES without concurrent CRS
          • Continue corticosteroids until improvement to grade 1 CRES, then taper
        • Stage 1 or 2 papilloedema with CSF opening pressure < 20 mmHg; no cerebral edema
          • Acetazolamide: 1000 mg IV, followed by 250-1000 mg IV q12h
            • Adjust dose based on renal function and acid-base balance
              • Monitored 1-2 times daily
        • Consider repeat neuroimaging (CT or MRI) every 2-3 days if persistent grade ≥ 3 CRES
      • Grade 4 CRES
        • Supportive care/neurological work-up as for grade 1 CRES
        • ICU monitoring
          • Consider mechanical ventilation for airway protection
        • Anti-IL-6 therapy and repeat neuroimaging as for grade 3 CRES
        • High-dose corticosteroids continued until improvement to grade 1 CRES and then taper
          • Example: Methylprednisolone
            • 1 g/day IV for 3 days, followed by
            • Rapid taper at 250 mg q12h for 2 days, then
            • 125 mg q12h for 2 days, and
            • 60 mg q12h for 2 days
        • If status epilepticus (convulsive)
          • ABCs, blood glucose, transfer to ICU
          • Lorazepam: 2 mg IV; additional 2 mg IV, up to total 4 mg to control seizures
            • Maintenance: 0.5 mg IV q8h for 3 doses
          • Levetiracetam: 500 mg IV bolus, followed by maintenance doses
            • Maintenance: 1000 mg IV q12h
          • If refractory: add phenobarbital (15 mg/kg IV loading dose)
            • Maintenance: 1-3 mg/kg IV q12h
        • Stage ≥ 3 papilledema, with CSF opening pressure ≥ 20 mmHg or cerebral edema
          • High-dose corticosteroids as recommended for grade 4 CRES
          • Elevate patient's head to 30°
          • Hyperventilation to achieve PaCO2 of 28-30 mmHg, maintain for no longer than 24 hrs
          • Hyperosmolar therapy: Mannitol (20 g/dL solution) or Hypertonic saline (3% or 23.4%)
            • Hypertonic saline
              • Initial: 250 mL of 3% hypertonic saline
              • Maintenance: 50-75 mL/hr
              • Monitor electrolytes q4h
              • Withhold infusion if serum Na levels ≥ 155 mEq/L
            • Mannitol
              • Initial dose: 0.5–1 g/kg
              • Maintenance: 0.25-1 g/kg q6h
              • Monitor metabolic profile and serum osmolality q6h
              • Withhold mannitol if serum osmolality is ≥ 320 mOsm/kg, or osmolality gap is ≥ 40
          • If imminent herniation
            • Initial 30 mL of 23.4% hypertonic saline (repeat after 15 min as needed)
          • If Ommaya reservoir
            • Drain CSF until opening pressure < 20 mmHg
          • If burst-suppression pattern on EEG
            • Consider neurosurgery consultation and IV anaesthetics
          • Metabolic profiling q6h and daily CT head scan
          • Adjust medications to prevent rebound cerebral edema, renal failure, electrolyte abnormalities, hypovolemia, hypotension
    • HLH/MAS Management
      • Diagnostic criteria (Grading as per CTCAE, version 4) 5
        • Peak serum ferritin > 10,000 ng/mL during 1st 5 days of CAR-T-cell therapy, plus any 2 of the following
          • Grade ≥ 3 increase in serum bilirubin, AST, or ALT levels
          • Grade ≥ 3 oliguria or increase in serum creatinine levels
          • Grade ≥ 3 pulmonary edema
          • Presence of hemophagocytosis in bone marrow or organs (histology)
      • Treatment
        • Goal to suppress "overactive" CD8+ T-cells/macrophages
          • Future: specific IFN-gamma targeted therapy
        • Grade ≥ 3 toxicity: Anti-IL-6 therapy + corticosteroids as CRS treatment
        • If does not improve after 48 hrs (controversial; direct evidence in CAR‑T‑cell‑associated HLH is lacking)
          • Consider etoposide (75-100 mg/m2)
            • Can be repeated after 4-7 days, as indicated for adequate disease control
          • Consider intrathecal cytarabine (+/- hydrocortisone) if neurotoxicity

Disposition

  1. Admission Criteria
    • All
  2. Consult(s)
    • ICU, oncology, neurology, and others as indicated
  3. Discharge/Follow-up Instructions
    • Per primary care provider/oncologist recommendations
    • Regular follow-up with primary care most likely will be required

References

  1. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. Apr 20, 2016;3:16011
  2. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. Jul 10, 2014;124(2):188-195
  3. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. Mar-Apr 2014;20(2):119-122
  4. Breslin S. Cytokine-release syndrome: overview and nursing implications. Clin J Oncol Nurs. Feb 2007;11(1 Suppl):37-42
  5. U.S. Department of Health & Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (2010). Available at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
  6. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. Sep 19, 2017; doi: 10.1038/nrclinonc.2017.148
  7. Frisen L. Swelling of the optic nerve head: a staging scheme. J Neurol Neurosurg Psychiatry. Jan 1982;45(1):13-18

Contributor(s)

  1. Ho, Nghia, MD

Updated/Reviewed: January 2021