The Cytokine Release Syndrome (CRS) is an acute immune reaction due to release or overproduction of inflammatory cytokines such as:

  • Tumour necrosis factor (TNF)
  • Interferon-γ
  • Interleukin 6 (IL-6)

The release of these and other cytokines are a result of a cascade of events which may be triggered by immune activation. CRS may result in cytokine storm and death, and has been observed with drug therapies designed to stimulate the immune system, particularly those that stimulate T cells e.g. CD-28 agonists.

Clinical Presentation

  • CRS can occur within 30-60 mins of infusion
  • Rarely, CRS may be delayed and present a few days after infusion
  • CRS can vary depending on what “drugs” are being used
    • Monoclonal antibodies
    • Chimeric antigen receptor (CAR) T cells
    • Bispecific antibodies

Initial signs may include:

  • Severe headache;
  • Rigors and fevers (possibly exceeding 40°C);
  • Myalgia, arthralgia;
  • Flushing;
  • Nausea, vomiting, diarrhea;
  • Tachycardia, hypotension;
  • Tachypnoea and a drop in oxygen saturation; and
  • Agitation, confusion, and seizures.

Progression:

  • Cardiac (Takosubo cardiomyopathy);
  • Disseminated Intravascular Coagulation (DIC);
  • Respiratory failure;
  • Renal failure;
  • Seizures, encephalitis; and
  • Skin desquamation.

Grading

The severity of CRS can be graded as shown in Table 1.

Table 1. Revised CRS grading scale (as per Lee et al).

  Toxicity Treatment
Grade 1 Symptoms are not life threatening and require symptomatic treatment only, e.g., fever, nausea, fatigue, headache, myalgias, malaise Vigilant supportive care:

– Assess for infection

– Treat fever and neutropaenia if present

– Monitor fluid balance

– Antipyretics

– Analgesics

Grade 2 Symptoms require and respond to moderate intervention Vigilant supportive care

+ Monitor cardiac and other organ function closely

or

If with co-morbidities or old age:

Vigilant supportive care

+ Tocilizumab 4-8mg/kg

+/- Hydrocortisone 100mg-200mg IV

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 Vigilant supportive care

+Tocilizumab 4-8mg/kg

+/- Hydrocortisone 100mg-200mg IV

Oxygen requirement ≥40% or
Hypotension requiring high dose or multiple vasopressors or
Grade 3 organ toxicity or grade 4 transaminitis
Grade 4 Life-threatening symptoms Vigilant supportive care

+ Tocilizumab 4-8mg/kg

+/- Hydrocortisone 100mg-200mg IV

Requirement for ventilator support or
Grade 4 organ toxicity (excluding transaminitis)

Management

If CRS is suspected, the immunotherapy infusion should be stopped and the medical oncology consultant contacted immediately. A thorough clinical assessment is required to exclude infection and other possible causes of the presenting symptoms. Treatment should be commenced early as delays prolong recovery. ICU admission and monitoring is required for patients with grade 3 or grade 4 CRS. Patients who are assessed as not requiring ICU treatment will stil require close monitoring as cardiac decompensation can occur without obvious signs.

Tocilizumab

Tocilizumab is a humanised monoclonal antibody that binds to IL-6 receptors. Although this medication is only registered for use in arthritis and giant cell arteritis, it has demonstrated rapid reversal of life-threatening symptoms in CRS.

Preparation:

Doses less than 300mg can be diluted in 50mL 0.9% sodium chloride bags as shown in Table 2.

Table 2. Tocilizumab preparation for doses <300mg.

Tocilizumab dose Volume of normal saline to be removed from the pre-filled 50mL 0.9% sodium chloride bag (bag contains 8mL overfill)* Volume of tocilizumab 20mg/mL to be added to normal saline bag
150mg 15.5mL 7.5mL
200mg 18mL 10mL
250mg 20.5mL 12.5mL

*The above figures are based on an estimated overfill amount of 8mL. The actual overfill amount in a diluent bag for IV administration may vary according to the manufacturer. This should be confirmed before preparation commences.

Doses greater than 300mg should be diluted in 100mL 0.9% sodium chloride as shown in Table 3.

Table 3. Tocilizumab preparation for doses >300mg.

Tocilizumab dose Volume of normal saline to be removed from the pre-filled 100mL 0.9% sodium chloride bag (bag contains 8mL overfill)* Volume of tocilizumab 20mg/mL to be added to normal saline bag
300mg 23mL 15mL
400mg 28mL 20mL
500mg 33mL 25mL
600mg 38mL 30mL
700mg 43mL 35mL
800mg 48mL 40mL

*The above figures are based on an estimated overfill amount of 8mL. The actual overfill amount in a diluent bag for IV administration may vary according to the manufacturer. This should be confirmed before preparation commences.

The diluted solution should be used immediately, but is stable for 24 hours at room temperature. It should be administered by intravenous infusion over 60 minutes. Other drugs should not be added to the solution or simultaneously infused through the same IV line.

References:

  1. Actemra® (tocilizumab) Australian approved product information. Sydney: Roche Products. Approved February 2018.
  2. Burridge N, Symons K (editors). Australian Injectable Drugs Handbook (7th edition). Collingwood: Society of Hospital Pharmacists of Australia; 2017.
  3. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124, 188-95.
  4. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner M, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006; 355: 1018-28.

Subscribe Knowledge Centre Updates

Enter your details to receive Knowledge Centre updates