Grading and Toxicity Management after Immune Effector Therapy

Cytokine Release Syndrome

Cytokine release syndrome (CRS) is the most commonly seen toxicity with immune effector therapies and is a term which describes a pattern of clinical signs and symptoms that develop as a result of robust immune activation resultant from a cell-mediated immune response after therapy. This clinical syndrome was recognized in pediatric acute lymphoblastic leukemia (ALL) patients treated with CD19-targeted CAR-T cells who developed fever, tachycardia, and hypotension consistent with a systemic inflammatory response and was subsequently seen following immune effector cell therapy in the adult population. The pathophysiology of CRS originates from the robust and widespread on-target activation and proliferation of engineered T cells and surrounding bystander inflammatory cells followed by the release of inflammatory cytokines and chemokines including interleukin-6 (IL-6), IL-2, IL-8, IL-10, interferon-γ (IFNγ), monocyte chemoattractant protein-1, and macrophage inflammatory protein-1b among others. Data suggests serum IL-6 is likely derived from macrophages, and peak CAR-T-cell and serum IL-6 levels correlate strongly with severity of CRS in clinical studies. The delayed onset of CRS supports the hypothesis that in the days after cell infusion CAR-T cells proliferate and recruit bystander immune effectors, including macrophages, ultimately resulting in the clinical features of CRS.

CRS of any grade has been reported in 37% to 93% of patients receiving CAR-T cells on clinical trials. Clinical manifestations must include fever that can be accompanied by other signs and symptoms ranging from mild flu-like symptoms to a severe inflammatory syndrome with hypotension and a capillary leak syndrome causing pulmonary edema, hypoxemia, and if left unchecked, eventually multisystem organ failure. Time of onset may vary depending on the product used but typically occurs within one week of CAR-T-cell infusion and peaks within 1 to 2 weeks after infusion. Timing of CRS onset and duration after bispecific antibody engager therapies are often much faster with the risk period beginning at the start of the product infusion, while those from TCR, CAR-NK, or other novel engineered cells remain to be determined.

Grading of Cytokine Release Syndrome

Prior to the development of the consensus grading established by the American Society for Transplantation and Cellular Therapy (ASTCT) in 2019, the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) versions 3 and 4 were used to grade CRS both on clinical trials and in the standard of care practice setting. However, both CTCAE v3 and v4 demonstrated significant shortcomings with regard to grading CRS resultant from cellular therapies and were perhaps more applicable to toxicities from monoclonal antibody therapies. For example, grading outlined in CTCAE v3 assumes CRS onset within 24 hours of T-cell infusion and fails to account for the delayed onset of symptoms seen in clinical practice. The CTCAE v4 scale is dependent upon infusion interruption, which is not applicable to CAR-T-cell treatments.

In response to inadequate CRS grading by the CTCAE, there were a number of attempts to standardize both the definition and grading of CRS across institutions. Lee et al. developed a structured grading system in which CRS severity was categorized by the degree of hypoxia, hypotension, and/or organ dysfunction and linked to a treatment algorithm. The group at the University of Pennsylvania, likewise, devised a grading system in which CRS severity was scaled according to the degree of hypoxia and/or hypotension and was associated with the intensity of therapy required for treatment of these toxicities. Additional grading systems were developed by Memorial Sloan Kettering Cancer Center as well as a multi-institutional group of investigators who adopted the Lee criteria but developed a unique scale for neurotoxicities called the CAR-T-Cell Therapy–Associated TOXicity (CARTOX) score. These CRS grading scales differed from one another in several ways. For example, the Penn scale categorized patients requiring any intravenous fluids or low-dose vasopressors as well as any supplemental oxygen as grade 3 CRS, while many of these same patients would be classified as grade 2 CRS under the Lee criteria. Due to classification differences such as this, the development of a standardized grading system was paramount to allow for comparison of patients treated across institutions.

Most recently, the ASTCT published international consensus grading guidelines in an effort to standardize the definition and grading scale of CRS ( Table 96.1 ). This group defines CRS 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 onset, and may include hypotension, capillary leak (hypoxia), and end organ dysfunction.” In this simplified consensus grading schema, fever is a prerequisite and CRS grade is determined by the degree of intervention necessary to address hypotension and/or hypoxia in patients. An added feature is that grading can be rapidly assessed by any practitioner at the bedside.