Chimeric Antigen Receptor T Cell (CAR T cell) Therapy Toxicities in the ED

Like Homer, I have thinning hair and really enjoy a cool CAR! Unlike Homer, I always wear my seatbelt and know a CAR can be hazardous! Oh… and yeah,… I also have learned that not all cars have 8 cylinders or turbochargers… some are engineered immune cells that help to treat cancer! Chimeric Antigen Receptor (CAR) T Cell therapy is a product of that really cool science that we learned early in medical school. Unlike the haphazard poisons (ie, chemotherapy) that are traditionally used to treat leukemia, CAR T Cell therapy is more targeted and uses the patient’s own immune system to fight the oncologic cells. While this is more evidence that science is awesome, it is not without potential complications or toxicities (after all, human physiology is super complicated). So, let us take a moment to learn about the potential Chimeric Antigen Receptor T Cell (CAR T cell) Therapy Toxicity that may present to our ED:

(What follows has some specific recommendations for our local/regional management considerations in Charlotte, NC. Please contact your oncology specialists to discuss the specific recommendations in your area when needed.)

Chimeric Antigen Receptor T Cell (CAR T cell) Therapy: Basics

[33230186: Seth, 2020; 32043764: Ali, 2020]
CAR T Cell therapy is a promising approach to treatment of cancers.
  • Currently, used for Acute Lymphoblastic Leukemia (ALL) and Diffuse Large B-Cell lymphoma.
  • Not primary therapy, but used for relapsing cases.
    • About 15-20% of childhood ALL cases will have relapses.
    • For ALL, post-relapse prognosis and survival is poor (~22% at 1 year and 7% at 5 years).
    • Relapse numbers are worse for Large B-Cell Lymphoma.
  • Complete remission rates have been reported in 60-90% of children with ALL who were treated with CAR T Cell therapy.

CAR T Cell therapy reprograms the patient’s own T Cell to fit the cancer cells.
  • A Chimera Antigen Receptor (CAR) T cell is a T cell harvested from the patient that has then had a transgene encoding a chimeric antigen receptor that recognizes a specific antigen known to be on the cancer cell.
  • The receptor has the ability to initiate T Cell activation and anti-tumor activity.
  • The receptor also helps enhance T Cell expansion.
  • Kymriah is the CAR T Cell Therapy that has CD-19 antigen, which helps treat refractory ALL in children and you adults (up to 25 years of age).

Chimeric Antigen Receptor T Cell (CAR T cell) Therapy Toxicity

[33230186: Seth, 2020; 31753925: Yakoub-Agha, 2020; 32043764: Ali, 2020]
No therapy is without risk and CAR T Cell treatment may lead to important adverse reactions.
  • Like many hematological active medications, CAR T Cell therapy may cause changes in cell lines:
    • Leucopenia, neutropenia, and lymphopenia is commonly enountered.
    • Thrombocytopenia and anemia are also possible.
  • Once bound, the CAR T Cell has marked proliferation and activation!
    • Leads to subsequent monocyte, endothelial cell, and stromal cell activation.
    • Creates high serum concentrations of pro-inflammatory cytokines.
      • Release of interferon-gamma, tumor necrosis factor- alpha, and interleukin-2…
      • Which, in turn, activate monocytes/macrophages and additional augmentation of IL-1, IL-6, IL-10… and many other cytokines I have long since forgotten.
  • Most concerning adverse reactions that are associated with CAR T Cell therapy are:
    • Cytokine Release Syndrome (CRS)
    • Immune Effector Cell-Associated Neurotoxicity Syndrome (iCANS)

Cytokine Release Syndrome (CRS)
  • CRS is a form of systemic inflammatory response, so it may look like SEPSIS.
    • It is the most frequent adverse drug reaction seen with CAR T Cell therapy.
    • Typically occurs in first 14 days … but consider CRS in patient within 45 days of infusion.
    • It is reversible in most cases and successfully managed with supportive care.
    • Exact mechanism is not fully understood.
  • Signs and Symptoms: similar to spectrum of SIRS and SHOCK.
    • Fever, rigors
    • Tachycardia
    • Tachypnea
    • Hypoxemia
    • Hypotension
    • Systemic Inflammatory Response Syndrome

Immune Effector Cell-Associated Neurotoxicity Syndrome (iCANS)
  • iCANS is spectrum of encephalopathy that is inclusive of a variety of neurologic manifestations that occur after CAR T Cell Therapy.
    • Second most common adverse event from CAR T Cell therapy.
    • Can develop with CRS, after CRS resolves, or without CRS.
    • Consider iCANS in patient within 45 days of infusion.
    • Exact mechanism is not understood… although increased blood-brain barrier permeability can lead to high levels of cytokines in the CSF.
    • May lead to cerebral edema and brain herniation.
  • Signs and Symptoms:
    • Deterioration in handwriting has been seen as an early indicator.
    • Impaired Speech
    • Headaches
    • Tremors
    • Hallucinations
    • Delirium, Confusion
    • Abnormal movements, Seizures
    • Focal Deficits
    • Papilledema
    • Coma

CAR T Cell Toxicities: Management

[33230186: Seth, 2020; 31753925: Yakoub-Agha, 2020; 32043764: Ali, 2020]
Cytokine Release Syndrome
  • CONTACT YOUR FRIENDLY PEDIATRIC ONCOLOGIST ASAP.
    • Patient may also have an informative card that can help direct management.
    • Don’t forget to use the very complete and helpful order sets that established in concert with pediatric oncology!
  • Supportive care is standard to all patients.
    • Patients will have weakened immune systems so at risk for infections.
    • Obtain cultures and treat with BROAD spectrum antibiotics empirically.
  • Anti-IL-6 therapy (ex, tocilizumab, a monoclonal antibody against IL-6 receptor)
    • Blocking IL-6 can block the cytokine cascade.
    • Does not harm the CAR T Cell action otherwise.
    • If you determine a bolus of fluids is required, then also give tocilizumab.
    • If patient needs oxygen, then also give tocilizumab.
  • Corticosteroids should be considered in life-threatening emergencies.
    • Should be discussed and coordinated with oncologist.

Immune Effector Cell-Associated Neurotoxicity Syndrome (iCANS)
  • CONTACT YOUR FRIENDLY PEDIATRIC ONCOLOGIST ASAP.
    • Patient may also have an informative card that can help direct management.
    • Don’t forget to use the very complete and helpful order sets that established in concert with pediatric oncology!
  • Supportive care is standard to all patients.
    • Early detection is critical… Obtain appropriate neuro imaging (CT or MRI)
    • Corticosteroids may be required for moderate and severe cases.
    • Intubation and management of cerebral edema may be required.

Moral of the Morsel

  • CARs are cool… and so is SCIENCE! Remember, that while your medical school education may have ended many years (decades) ago, the evolution of science did not stop. We must continue travel on our educational path.
  • CAR T Cell Therapy + Abnormal Vital Sign = Antibiotics +/- Tocilizumab. Invasive bacterial infection and Sepsis is concerning, but Cytokine Release Syndrome may also be playing a role. Treat both. Know when to use Tocilizumab.
  • CAR T Cell Therapy + Neurologic Complaint = iCANS. Get that neurologic image and worry about evolving Cerebral Edema!
  • Pediatric Oncologists are our friends! Contact the patients oncologists as soon as possible to ensure we are delivering the optimal care.

References

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Sean M. Fox
I enjoy taking care of patients and I finding it endlessly rewarding to help train others to do the same. I trained at the Combined Emergency Medicine and Pediatrics residency program at University of Maryland, where I had the tremendous fortune of learning from world renowned educators and clinicians. Now I have the unbelievable honor of working with an unbelievably gifted group of practitioners at Carolinas Medical Center. I strive every day to inspire my residents as much as they inspire me.
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