Cytokine Release Syndrome

Cytokine release syndrome (CRS) is widespread immune activation and inflammation leading to multisystem organ damage that closely resembles sepsis and septic shock. This syndrome is triggered by a cytokine cascade ultimately resulting in fever, hypotension, and hypoxia.

How does CRS present?

CRS develops sequentially overtime. While that progression can be quick, multiorgan system failure does not present immediately. Rather, almost all CRS cases begin with persistent fever (T>38°C). If serious enough, then the fever can become refractory to antipyretic therapy and escalate to hypotension (systolic blood pressure < 90 mm Hg) and hypoxia (SpO2 < 90% on room air). Subsequently, end organ function can be compromised and will resemble sepsis such as transamnitis (which can be attributed to either hypotension and/or inflammation from the cytokine storm), renal dysfunction, rash, and in severe cases, can lead to hemophagocytic syndrome.

How is CRS investigated?

Clinical evidence and timing from immunotherapy is what typically points toward the diagnosis of CRS. CRS most commonly occurs within 7 days from CAR T-cell therapy and typically after the first or second dose of modified antibody therapies. Despite a reliance on clinical diagnosis, investigations should still be done to both confirm CRS and to rule out infectious possibilities such as blood tests: C-reactive protein (CRP), ferritin, blood cultures and sensitivities, urinalysis and culture, prothrombin time (PT)/international normalized ratio (INR), and in extreme cases, fibrinogen (to rule out disseminated intravascular coagulation). Radiographic imaging should be based on symptoms.

What kinds of treatments lead to CRS?

Not all immunotherapies can lead to CRS. For example, checkpoint inhibitor therapies are not commonly associated with this side effect. Instead, immunotherapies that are designed to rapidly recruit and activate T-cells (and Natural Killer cells) are more associated with CRS. Examples can include chimeric antigen receptor (CAR) T-cell therapy, bi-specific T-cell engagers (BiTEs) or duobodies. These treatments are designed to force immune cells to recognize malignancy, proliferate, and recruit other immune cells. The latter is thought to be the mechanism behind CRS where macrophages and monocytes become overstimulated leading to the cytokine cascade. 

How is CRS treated?

Because CRS represents a cytokine cascade, the key to treatment is to interrupt the domino effect before it gets too far. Interleukin-6 (IL6) is considered the main rate limiting step. Tocilizumab (8 mg/kg in adults; 12 mg/kg in pediatrics), a humanized monoclonal antibody, targeting IL6 has been the most effective treatment presently. Previous paradigms had been to reserve it until later in the disease course. The consensus now is to provide tocilizumab earlier on in CRS once it becomes clear that antipyretics are becoming ineffective or that other end organ damage is beginning to appear. In refractory cases or those that were not treated sufficiently early, siltuximab (a different IL6 antibody) has been attempted but often is not more successful than tocilizumab. Alternatively, others have tried to stop the T-cell activity using corticosteroids, anti-thymocyte globulin (ATG), cyclophosphamide, or alemtuzumab. Because the cytokine cascade has gone well past T-cell activation by this point, these treatments have had variable success rates. Plasma exchange has become an interesting option that has had effectiveness in limited case reports.

Does CRS treatment impact immunotherapy efficacy 

Anti-IL6 treatments do not seem to detract from the anti-neoplastic effect of either CAR T-cells or BiTEs. In fact, longer term follow-up suggests that earlier intervention with anti-IL6 therapies improves safety by reducing time in hospital and intensive care utilization while maintaining the same tumor response, remission and survival rates. Not surprisingly, earlier anti-IL6 intervention also reduces the need for anti-T-cell therapies. Corticosteroids appear to not have long term impact on CAR T-cells or BiTEs either.  

Last updated by Dr. Michael Chu February 2021