Immune Effector Cell Toxicity Monitoring and Management Guideline (Adults)

• Background
• Grading adverse events after IEC therapy
• Cytokine release syndrome (CRS)
• Tocilizumab therapy
• Immune effector cell-associated neurotoxicity syndrome (ICANS)
• Management of ICANS
• Management of status epilepticus after CAR-T therapy
• Management of raised intracranial pressure after CAR-T therapy
• CAR-T-related haemophagocytic lymphohistiocytosis and macrophage activation syndrome

Aims

To improve the diagnosis and management of complications of immune effector cell therapy

Back to top

Background

Chimeric antigen receptor T-cells (CAR-T) and related technologies are emerging as a highly promising new therapy for the treatment of malignancies, with products licensed in the UK for lymphoma and leukaemia and a range of therapies for other haematological malignancies and solid tumours under investigation in clinical trials. Importantly, these new immunotherapies are associated with unique toxicities rarely seen with other therapies. In particular, cytokine-release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) may be acute and severe; this guideline describes our mechanisms for monitoring patients for development of these complications and for the rapid initiation of appropriate treatment when they do occur.

Back to top

Grading adverse events

A number of scoring systems and management protocols have been proposed for these key CAR-T cell toxicities, informed by expanding experience of a growing range of CAR-T products. The protocol and recommendations here are based upon the latest ASBMT consensus criteria¹.

Back to top

Cytokine release syndrome (CRS) – diagnosis, investigation and management

This is a common adverse event after CAR-T therapy, which according to the ASBMT criteria is defined as:

“a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms can be progressive, must include fever at the onset, and may include hypotension, capillary leak (hypoxia) and end organ dysfunction.”

It typically occurs within the first 10 days (rarely after 14), and is typically manifest as high fever, hypotension, hypoxia and malaise, but can affect any organ system and culminate in multiorgan failure. There may be overlap of symptoms with haemophagocytic lymphohistiocytosis (HLH) or macrophage-activation syndrome (MAS). CRS can be fatal if not recognised and treated promptly.

Patients at high risk of severe CRS include those with:

• Bulky disease
• Comorbidities
• Early onset of CRS (i.e. within 3 days of infusion)

Table 1, taken from the ASBMT consensus criteria1 indicates the criteria for grading CRS adopted at our centre.

Table 1. ASBMT consensus criteria for grading CRS (as per Lee et al.1)

The CRS grade should be determined at least twice per day, and whenever a change in the patient’s status is observed. The CRS grade should be scored and recorded using the IEC CRS assessment chart. In addition, CRP and ferritin levels should be monitored daily in patients undergoing IEC therapy, as these are useful serum markers of CRS, though they should not be relied upon and clinical assessment is the mainstay of monitoring.

These guidelines recommend early review by the intensive care team, and in some cases early transfer, including some situations where patients receiving a different therapy may not require such intensive support; this reflects the potential for rapid deterioration.

Back to top

Management is generally determined by CRS grade:

Grade 1:
Grade 1 CRS is generally managed with supportive care: use of maintenance intravenous fluids is recommended to maintain hydration, with careful attention to fluid balance to avoid overload. Analgesia and antipyretics may be given. Consideration must be given to other potential causes of fever, in particular neutropenic infections and treatment should be started for neutropenic fever. Tocilizumab should be considered for persisting (e.g. >3 days) and refractory fever.

Grade 2:
Development of hypotension or hypoxia indicates ≥ grade 2 CRS. Hypotension should be treated promptly with intravenous fluid boluses (usually of 0.9% Sodium chloride unless otherwise contraindicated). Hypoxia should be managed with supplemental oxygen, titrating upwards in the usual manner (i.e. commencing with nasal cannulae and escalating as required). In addition tocilizumab should be considered and in particular for patients with:

• hypotension refractory to fluid boluses
• persistent fever ≥39°C despite antipyretics for 10 hours
• climbing oxygen requirements.

Patients with grade 2 CRS should be discussed with the intensive-care unit (ICU), though transfer to ICU may not necessarily be needed at this point.

Grade 3:
If hypotension persists or hypoxia requires oxygen at a level higher than nasal cannulae, this indicates grade 3 CRS; the patient should be discussed with the ICU team and low-dose vasopressors should be initiated and titrated upwards to achieve a satisfactory systolic blood pressure (e.g. >90 mmHg). Bedside echocardiography to determine ejection fraction is recommended for patients with persistent or repeated episodes of hypotension, because left ventricular dysfunction may occur in patients with CRS. Non-invasive monitoring of haemodynamic parameters, such as inferior vena cava filling pressures, passive leg raise, pulse pressure and stroke volume variation, can help guide the management of hypotension (i.e. IV fluids, vasopressors, inotropic drugs). Hypoxia associated with non-cardiogenic pulmonary oedema or pleural effusions should be managed with supplemental oxygen and diuresis or thoracentesis.

Tocilizumab is indicated (and can be repeated as needed) for patients with grade 3 CRS. The use of corticosteroids (10mg of dexamethasone every 6 hours, increased to 20mg IV every 6 hours if refractory) in addition to tocilizumab should be considered if hypotension persists after 1 to 2 doses of tocilizumab

Grade 4:
Patients with grade 4 CRS should be treated in the ICU to enable continuous monitoring, management of life-threatening arrhythmias, haemodynamic shock, and delivery of non-invasive positive pressure ventilation, mechanical ventilation and/or renal replacement therapy. Both tocilizumab and corticosteroids (methylprednisolone 1-2g/24h IV) should be used. Corticosteroid tapering should be individualised depending on the patient’s response and adverse effects, but in general terms should be as rapid as possible. Anti-tumour necrosis factor antibodies should be considered as clinically appropriate. Future CAR-T products may have a rituximab-responsive safety switch, so use of rituximab should be considered if appropriate.

Note on Tocilizumab:
The dose of tocilizumab is 8mg/kg infused over 1 hour. A single dose should not exceed 800mg. The dose may be repeated after 8 hours if no response is seen (and steroids should then also be added, as described above). Indications for tocilizumab are:

• Consider using early if persistent fever of ≥39°C despite antipyretics for 10 hours
• Persistent/ recurrent hypotension after initial fluid bolus, and initiation of oxygen supplementation
• Highly recommended – if left ventricular ejection fraction <40% by ECHO
• Creatinine >2.5-fold higher than the most recent level prior to CAR T cell infusion
• Norepinephrine requirement at a dose >2 pg/min for 48 hours since the first administration of norepinephrine, even if administration is not continuous
• Systolic blood pressure of 90 mm Hg that cannot be maintained with norepinephrine
• Oxygen requirement of fraction of inspired oxygen >50% or more for more than 2 hours continuously
• Dyspnoea that is severe enough to potentially require mechanical ventilation
• Activated PTT >2 x the ULN
• Clinically-significant bleeding
• Creatine kinase >5 x the ULN for longer than 2 days

Back to top

Immune effector cell-associated neurotoxicity syndrome (ICANS) – diagnosis, investigation and management

Another common toxicity observed after IEC therapy is neurotoxicity. Immune effector cell-associated neurotoxicity syndrome (ICANS) is often manifest as tremor, dysgraphia, defects in expressive speech (especially in naming objects), impaired attention, apraxia, and lethargy. Headache is a non-specific symptom. ICANS has features that overlap with other pathologies (e.g. hepatic encephalopathy, electrolyte abnormalities, immunosuppressive therapies etc.), however expressive aphasia progressing to global aphasia (an awake patient who is mute and does not respond verbally or physically to an examiner) appears to be a relatively specific symptom. Nonetheless, any neurological symptoms should be evaluated carefully, and ICANS considered as a potential explanation. The term CAR-related encephalopathy syndrome (CRES) has also been used to refer to the neurotoxicity associated with IEC therapy; whilst encephalopathy may certainly be a dominant features, the term ICANS is used in this guidance to reflect the fact that a broad range of neurotoxicities may occur.

The grading system adopted in our programme is that of the most recent ASBMT consensus criteria1, shown in table 2. Grading using these criteria includes measurement of an Immune Effector Cell-Associated Encephalopathy (ICE) Score, shown in table 3. As for CRS, ICANS grade should be determined using the above scoring system at least twice per day, and whenever a change in the patient’s status is observed.

Table 2, ASBMT consensus criteria for ICANS grading. (Taken from Lee et al.1)

Back to top

Management of ICANS

Management of ICANS should be in close consultation with a neurologist and is generally guided by grade as indicated in table 4.

General points:

• Neuroimaging and CSF opening pressure, if available, are much better surrogates of increased intracranial pressure and cerebral oedema that papilloedema, but may not be feasible when patients are restless or have coagulopathy.
• Repeated neuroimaging and review of these results by a neuroradiologist are recommended in patients with ≥G3 CRES and those with rapid increases in CRES grade.
• In unstable or agitated patients, CT may be feasible when MRI is not.
• The optimal duration of corticosteroid therapy remains unknown; limited evidence suggests short courses may be sufficiency but patients should be monitored closely for recurrence during tapering.
• As for CRS, these guidelines recommend early review by the intensive care team, and in some cases early transfer, including some situations where patients receiving a different therapy may not require such intensive support; this reflects the potential for rapid deterioration.

Back to top

Back to top

Back to top

CAR-T-related HLH and MAS – diagnosis and management

Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) encompass a group of life-threatening disorders characterised by immune hyperactivation. Patients with CRS after CAR-T have clinical and laboratory features in common with HLH/MAS, such as high fever, multiorgan dysfunction, CNS lesions, raised ferritin, LDH, and cytokine levels and low serum fibrinogen.

HLH/MAS should be considered after CAR-T therapy in patients with a peak ferritin of >10000ng/ml during CRS who subsequently develop any two of the following:

• Grade ≥3 increase (according to CTCAE criteria) in serum bilirubin, aspartate aminotransferase, or alanine aminotransferase levels
• Grade ≥3 oliguria or increase in serum creatinine levels*
• Grade ≥3 pulmonary oedema
• Presence of haemophagocytosis in bone marrow or organs based on histopathological assessment of cell morphology and/or CD68 immunohistochemistry

Fulminant HLH/MAS which is refractory to steroids and tocilizumab is seen in ~1% of patients treated with CAR-T therapy. If the patient shows no improvement clinically or biochemically within 48 hours of commencement of steroids and tocilizumab, additional therapy with etoposide 75-100mg/m2 should be strongly considered (may be used with hepatic and renal dysfunction). This may be repeated after 4-7 days as indicated. Intrathecal cytarabine, with or without hydrocortisone, should also be considered for patients with HLH-associated neurotoxicity.