Cytokine Release Syndrome (CRS)

Definition and Occurrence

Cytokine release syndrome (CRS) is caused by a rapid and mild to massive release of cytokines from immune cells involved in immune reactions, particularly after immunotherapy. The frequency and severity of CRS after CAR-T cell therapy varies between products (any grade: 37–93%, G3/4: 1–23%) (Neelapu et al. 2017; Schuster et al. 2019; Abramson et al. 2020).

Diagnosis

Clinical Symptoms, Laboratory Diagnosis, Differential Diagnosis, and Predictive Factors

CRS usually manifests with fever preceding or accompanied by general symptoms, such as malaise, headache, arthralgia, anorexia, rigours, and fatigue, and can rapidly progress to hypoxia, tachypnoea, tachycardia, hypotension, arrhythmia, culminating in shock cardiorespiratory organ dysfunction, and failure.

Although the diagnosis of CRS cannot be established or ruled out by laboratory diagnostics, they can be used to monitor organ dysfunction. CRS symptoms and laboratory findings closely mimic infection; therefore, infectious workup and treatment are of primary importance. Other relevant differential diagnoses include tumour lysis and progression of the underlying malignancy.

Prediction of CRS in an individual patient is not yes possible. However, some factors, such as high tumour burden and CAR-T cell dose, seem to be associated with a higher risk of CRS.

Management

Patients receiving CAR-T cells should be monitored continuously or at regular intervals for cardiovascular function and temperature. The first sign of CRS is usually fever. Mild CRS (G1) can be managed conservatively. All higher grades require intensive monitoring and intervention. Early use now recommended (Table 26.1) (Yakoub-Agha et al. 2020).

Table 26.1 Scoring of CRS (adapted from Yakoub-Agha et al. 2020)
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Fig. 26.1
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Management of CRS—Modified according to EBMT recommendations

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Monitoring: Patients with CRS 1 can be monitored on the regular ward or Intermediate Care ward, starting from G2, and admission to an ICU should be considered.

Supportive therapy consists of fluids and antipyretics. The use of vasopressors automatically marks higher grade CRS.

Anti-Cytokines

Tocilizumab is EMA and FDA approved for the treatment of CRS. Prophylactic, preemptive or risk-adapted use may reduce the risk of severe CRS without attenuating antitumour efficacy.

(Locke et al. 2017; Caimi et al. 2020; Gardner et al. 2019; Kadauke et al. 2021). Clinical trial data on the use of siltuximab and anakinra are still lacking.

Steroids

In contrast to initial clinical studies, short courses of steroids do not seem to have detrimental effects on CAR-T cell expansion and survival or clinical outcome.

Antibiotics

Because CRS cannot be decisively differentiated from infection, most centres administer antibiotic treatment in cases of neutropenic fever. However, the use of growth factors during the first few weeks should be restricted. GM-CSF is to be avoided.

sHLH/MAS

Secondary or reactive haemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammation syndrome that occurs in the context of allo-HCT, haematological malignancies, infection, and rheumatic or autoimmune disease and is characterized by hyperactive macrophages and lymphocytes, haemophagocytosis, and multiorgan damage (Carter et al. 2019; Neelapu et al. 2018; Sandler et al. 2020). The proposed diagnostic criteria are summarized in Table 26.2. Management of sHLH generally follows similar algorithms as that for severe CRS. In refractory patients, treatment may follow the management framework proposed by Mehta et al. (2020), with a key role for anakinra.

Table 26.2 Diagnostic criteria for HLA (adapted from Neelapu et al. 2018)
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Key Points

  • Cytokine release syndrome is a frequent complication. However, severe CRS is rare if management is proactive.

  • sHLH/MAS is a rare but severe complication that requires prompt recognition and intervention.