Chimeric antigen receptor (CAR) T-cell therapy (CAR-T) describes the use of genetically engineered T cells to attack cancer cells, and to improve the outcomes of patients with refractory/relapsed B-cell malignancies. Extended indications are being investigated (multiple myeloma, etc.)

Background of CAR-T

CAR-T products generally attack CD19 which is expressed by most B-cell malignancies. CAR-T can induce temporary or durable complete remission in the majority of patients.

CAR-T cells are "living drugs" individualised for each unique cancer patient. Prior to entering CAR-T cell therapy, patients are often bridged with cytotoxic drugs, B-cell antibodies (e.g. RTX), or radiotherapy. Prior to receiving CAR-T, patients receive lymphocyte-depleting chemotherapy to ensure tolerate and persistence of the CAR-T product.

After CAR-T, patients can develop significant acute toxicities, namely Cytokine Release Syndrome (CRS) and Immune effector Cell–Associated Neurotoxicity Syndrome (ICANS). These can range in severity from minor transient symptoms to severe life-threatening conditions.

CAR-T adverse toxicities correlate with high disease burden, higher peak of CAR-T cell expansion in the peripheral blood, and a high baseline inflammatory activity. More common in ALL than DLBCL

Cytokine Release Syndrome (CRS)

CRS is a systemic inflammatory syndrome caused by immunotherapy, characterized by fever and multiple organ dysfunction.

CRS is the most common acute toxicity following CAR-T cell therapy (incidence is 37-93%). Generally occurs within hours to 1 week post CAR-T cell infusion; late occurence up to 14 days has been described. About 1/2 of patients require some form of immunomodulatory therapy.

CRS is caused by excess immune reaction stimulated in the setting of infections, immunomodulating drugs, etc. Associated with increased IL-6 levels.

Diagnosis and Grading of CRS

  1. Fever (T >38℃) is required for the diagnosis of CRS.
  2. Nonspecific symptoms: malaise, myalgia, fatigue, GI symptoms, tachycardia, rash.
  3. Cardiac: arrhythmias, vasodilatory shock, systolic HF or new onset cardiomyopathy
  4. Respiratory: hypoxia
  5. AKI
  6. Labs:
    1. Hypophosphatemia, hypokalemia
    2. Concurrent tumour lysis syndrome
    3. Elevated CRP
  7. Can range from self-limiting symptoms improved with symptomatic care, all the way to severe SIRS and MODS with high rates of mortality.

CRS can co-exist with ICANS. After treatment with steroids and tocilizumab, fever may abate and is then not required for the diagnosis of CRS.

Management of CRS

  1. Consider empiric antimicrobial coverage, as differential frequently includes sepsis or septic shock.
  2. Avoid the use of G-CSF as this can exacerbate CRS.
  3. Consider the presence of ICANS as well, and treat as necessary. However, tocilizumab can worsen ICANS. Should lean more heavily on steroids if so.

Refractory CRS

Immune effector Cell–Associated Neurotoxicity Syndrome (ICANS)

ICANS is encephalopathy secondary to systemic inflammation. Often occurs in the context of CRS, but not always. Has parallels in pathophysiology to sepsis-induced encephalopathy, but full mechanisms of disease are not known at this time. Key features seem to be disruption of the BBB and cytokine induced cerebral edema.

ICANS is extremely common, occurring in perhaps ~75% of patients treated with axicabtagene ciloleucel or brexucabtagene autoleucel. Lower rates occur with other CAR-T constructs.

Risk factors for ICANS: Fludarabine use for pre-treatment lymphodepletion, anti-CD19 products, ALL> lymphoma >> multiple myeloma, higher burden of malignancy, pre-existing neurologic conditions, severe or early onset CRS, elevated inflammatory markers, DIC.

Timing of ICANS: generally begins within the first week after CAR-T therapy. Median onset of illness is 4-6 days, but can extend out to months after CAR-T therapy. Often ICANS starts 2-4 post CRS.

Duration of ICANS: about 2-3 weeks, but the encephalopathy can last months.

Diagnosis and Grading of ICANS

Clinical Manifestations

Radiology and Neurologic Investigations

  1. Neuroimaging is recommended for Grade 2 and above. MRI +/- contrast is the preferred modality. However, most patients with ICANS have normal neuroimaging. Potential findings on neuroimaging:
    1. Symmetric T2/FLAIR hyperintensities involving the thalami and dorsal pons and tectal plate.
    2. Patchy reversible T2 hyperintensities in the WM
    3. Diffuse cerebral edema.
    4. Leptomeningeal enhancement.
    5. PRES-like findings.
    6. Ischemic and hemorrhagic stroke.
    7. Nonaneurysmal convexity Subarachnoid Hemorrhage
  2. CSF analysis to exclude CNS infection - consider in higher grade ICANS.
    1. elevated OP suggests Grade 4 ICANS
    2. Cytologic ?malignancy or hemophagocytosis
    3. JC virus PCR r/o PML
  3. EEG to assess for seizures and the severity of encephalopathy.

Grading of ICANS

Calculate the ICE score (a measure of encephalopathy in ICANS): 500x500

Management of ICANS

  1. Supportive measures
    1. Aggressive fever control.
    2. Discontinue medications that are sedating or lower the seizure threshold.
    3. Consider high-dose thiamine supplementation.
  2. Management of Elevated ICP which can include ICP Monitoring

Steroids

Steroids are the mainstay of treatment of ICANS. Dexamethasone has greater CNS penetration thus is preferred over other steroids.

Steroid-Refractory ICANS

Steroids generally lead to rapid improvement. Consider anakinra or ruxolitinib.

Seizure Prophylaxis

Consider seizure prophylaxis (LEV) for axicabtagene ciloleucel with any grade of neurological toxicity, brexucabtagene autoleucel with Grade 2 or higher neurologic toxicity, patients at increased risk for seizures based on imaging or clinical history.