Real-World Incidence, Characteristics and Management of Cytokine Release Syndrome Induced By Chimeric Antigen Receptor T-Cell Therapy across Hematologic Malignancies

Background: Cytokine release syndrome (CRS) is a potentially life-threatening, supraphysiologic response following immunotherapy resulting in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. CRS occurs with varying frequency and severity, depending on the underlying disease and immunotherapy used, such as chimeric antigen receptor T-cell (CAR-T) therapy or off-the-shelf T-cell engaging bispecific antibodies. Limited research exists on the diagnosis and management of CRS in the real world. This study describes the real-world incidence, severity and clinical management of CRS induced by commercially available CAR-T therapies for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and multiple myeloma (MM).

Methods: Real-world data (RWD) were obtained from the Flatiron Health, US, nationwide electronic health record (EHR)-derived, de-identified database of cancer patients within a network comprised primarily of community cancer practices. The Flatiron Health network also includes practices designated as academic sites by the National Cancer Institute; however, relative proportions of community/academic practices may vary depending on the study cohort. Data as of August 31, 2022, on CAR-T therapy, clinical characteristics and disease outcomes specific to CAR-T therapy, as well as CRS and its clinical management, were abstracted from unstructured documents in EHRs (in addition to routinely available structured data), in a cohort of patients receiving commercial CAR-T therapy. Specifically, data for CRS including treatments and resolution were abstracted based on explicit mention of and attribution to CRS in charts.

Results: Table 1 summarizes data by indication. Incidence of CRS ranged from 56% (104/185) in DLBCL to 72% (66/92) in MCL. Excluding categories with small numbers of cases (<15), CRS incidence also varied by individual CAR-T therapy and underlying indication and ranged from 35% for idecabtagene vicleucel in MM to 73% for brexucabtagene autoleucel in MCL. Highest incidence of Grade ≥2 CRS was observed among MCL patients, whereas Grade ≥3 CRS was most commonly observed among FL patients. Time to onset of CRS ranged from 0 to 16 days, with median onset between 3-4 days among lymphoma patients and earlier median onset of 1 day for MM patients. Median time to CRS resolution ranged from 2 to 6 days across indications. While 81-95% of patients received CAR-T therapy at an academic center, 5-14% received CAR-T therapy at a community center. Tocilizumab and corticosteroids were the most commonly used treatments for CRS, including 37-48% use of tocilizumab for Grade 1 CRS (Table 2).

Discussion: This study uniquely summarizes RWD on CRS following the use of commercially available CAR-T therapies across multiple hematologic malignancies, based on information from clinical notes abstracted retrospectively from EHRs. Consistent with the timing of approval of commercially available CAR-T therapies, the sample size for MM was limited compared with other malignancies. Safety events are typically under-reported in RWD sources, specifically for CRS when relying on information documented in patients' EHRs, compared with other published literature. In accordance with other RWD on CRS, grading criteria for CRS as well as vasopressor and oxygen use were not consistently reported in patients' EHRs. CAR-T treatments were predominantly administered in academic centers. Limited use in community practices was also observed; however, further information to accurately characterize the size and capabilities of community centers was not available in this database. Data also showed considerable use of tocilizumab to treat low-grade CRS, suggesting the need for additional evidence on its role to treat CRS beyond its current regulatory approval. Increased evidence generation, specifically from usual clinical practice, can contribute to increased awareness and knowledge about CRS diagnosis and management, and in turn realize the maximum potential of T-cell therapeutics.