Management Practices of CAR T-cell-Related Inflammatory Toxicities: A Survey of Pediatric CAR T-cell Providers

Immune related adverse events (IRAE) are the most common nonhematologic adverse effects of chimeric antigen receptor (CAR) T-cell therapies. These events can be severe and refractory to upfront management. Tocilizumab is currently the only FDA-approved drug for the treatment of CAR T-cell induced inflammatory toxicities. However, an increasing number of anti-inflammatory therapies are now utilized for prevention and treatment of severe or refractory IRAE. Emerging evidence suggests the potential benefit of prophylactic or preemptive use of anti-inflammatory agents to mitigate severe toxicities. Guidance on the use of alternative anti-inflammatory therapies, preventative strategies, and management of refractory CAR T-cell toxicities is limited, with varying recommendations in society guidelines and the FDA labels for tisagenlecleucel and tocilizumab. Furthermore, there is a lack of pediatric-specific guidance. The primary objective of this study was to characterize CD19-CAR T-cell toxicity management practices for children and young adults with B-acute lymphoblastic leukemia by pediatric CAR T prescribers. A survey consisting of 28 questions focused on CAR T-cell toxicity management practices was distributed to pediatric CAR T-cell treatment centers with responses received between February and March 2024. Sixty unique responses with adequate data were received from 46 institutions. Forty-four respondents (73%) indicated using a preemptive treatment approach, defined as immunomodulatory therapy initiated for low grade toxicity to prevent the development of worsening toxicity, of which 33 (75%) used for high-risk patients and 9 (21%) used for all patients. Conversely, only 8 (14%) respondents indicated using a prophylactic approach defined as immunomodulatory therapy initiated prior to the onset of inflammatory toxicities. The most common feature leading to a patient being considered high-risk was high disease burden. Fifteen percent of respondents initiated tocilizumab for cytokine release syndrome (CRS) at grade 1, 48% at grade 2, and 18.3% at grade 3. Steroids were initiated at grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) in 43% of respondents and grade 3 in 28% of respondents. Most respondents had experience using alternative anti-inflammatory therapies, including anakinra (80%), siltuximab (50%), ruxolitinib (28%), emapalumab (22%), and dasatinib (15%). Anakinra was most often used for management of refractory CRS, refractory ICANS, or immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Most respondents indicated a need to prospectively study anakinra and emapalumab for treatment and/or prevention of CAR T inflammatory toxicities. Themes identified through analysis of semi-structured questions included the need for guidelines on use of alternative therapies, early preventative treatments, initial management of IRAE, and refractory IRAE management. This survey highlights significant practice variability in timing of initiation of CRS and ICANS treatment, frequent use of alternative anti-inflammatory therapies for CAR T toxicity management, and a consensus regarding the need for prospective study of therapies including anakinra and emapalumab. Survey results indicate a need for guidelines on management of CAR-induced inflammatory toxicities at their onset and in the refractory setting, and on the use of alternative therapies.