Cytokine release syndrome

Every drug has a possible side effect. Dr Garrick Laudin expands on cytokine release syndrome, a side effect caused by certain immunotherapies.

You can listen to this article below, or by using your favourite podcast player at pod.link/oncologybuddies

What is cytokine release syndrome?

Cytokine release syndrome (CRS) is an inflammatory response that may affect all organ systems in the body. CRS occurs when certain novel (new) immunotherapies are used in cancer care. 

An immunotherapy is a specialised coach as it provides clear instructions for the immune system on how to fight cancer cells. These immunotherapies may include chimeric antigen receptor T-cells (immune cells manufactured to fight blood cancers), bi-specific T-cell engagers (molecules that engage cancer cells with immune cells) and stem cell transplantation. 

While immunotherapies are there to do good, they often produce side effects when the immune system is activated and overstimulated, producing an excessive amount of specialised messenger proteins (cytokines). 

These cytokines are crucial in maintaining normal health, however, their excess production, a cytokine storm, results in significant systemic toxicity.

What are the symptoms of CRS?

Just like a storm, the beneficial effects of immune therapy are quickly offset by the collateral damage inflicted by the cytokines on normal cells, tissues, and organ systems in the body. 

The symptoms are classified as:

Mild – Fever and fatigue.

Moderate – Fever, low blood oxygen levels, low blood pressure levels, fast heartbeat, skin rashes, headaches.

Severe – Life-threatening symptoms. 

How is CRS treated?

The treatment is dependent on early recognition of the symptoms and severity. In mild cases, symptoms are frequently managed in an out-patient setting, with fever-reducing medications (paracetamol), fluids, and antihistamines. 

Moderate CRS requires active management and possible hospital admission. Active measures used in moderate disease include supplemental oxygen administration or intravenous (medication into a vein) therapies aimed at maintaining adequate circulation (blood pressure). 

Severe cases are life-threatening and require intensive care unit (ICU) admission, with breathing support (mechanical ventilation), blood pressure support, and specific medications to reduce inflammation. 

Anti-cytokine drugs used to treat inflammation include tocilizumab and corticosteroids. Tocilizumab blocks the damaging effects of the cytokine molecules, in particular interleukin-6 (IL-6). Anakinra is another drug which targets a different cytokine molecule, interleukin-1 (IL-1). 

The use of these targeted anti-cytokine therapies is limited in certain settings when the drug is unavailable, or the cost is prohibitive. 

Corticosteroids are readily available and are added for severe or persistent CRS cases. The use of corticosteroids does come with side effects as they could potentially further weaken the immune system and produce weight gain, high blood glucose, and weakened bone. 

For CRS linked to certain cancer immunotherapy (bispecific antibodies), cancer therapy may be temporarily stopped together with instituting supportive care.  

What is the outcome and prognosis in CRS?

With timely recognition and treatment, most patients will recover from CRS without any long-term complications. Mild cases resolve within days, often with simple supportive measures. Severe cases tend to result in longer hospital admissions with intensive in-patient monitoring. Without prompt recognition and treatment, severe cases may quickly become life-threatening.  

The overall prognosis in CRS depends on the severity of symptoms, underling health conditions, physical fitness (performance status), cancer therapies, and the underlying cancer being treated.

Ongoing research in the field of CRS aims at improving symptoms, with the hope that new therapeutic molecules will aid in preventing the condition. 

It’s important that at the outset of your cancer journey your healthcare team discusses the benefits and potential risks of all therapies used in the treatment of your cancer.