Advances in toxicity management
Despite advances in knowledge and management of CRS, it continues to be a significant cause of morbidity in patients treated with tisagenlecleucel. The challenge in toxicity management lies in controlling CRS symptoms without compromising clinical efficacy. Early recognition of CRS symptoms may allow for better control of symptoms through implementation of treatments before patients become critically ill. Our group at CHOP/UPenn demonstrated that IL6, CRP and ferritin all are strongly associated with development of severe CRS, but are not useful as predictive biomarkers early after infusion73. Other analytes collected in the first 72 hours, such as a model incorporating sgp130 + IFN‑g + IL1RA, strongly predicted later CRS. Use of prophylactic treatment strategies is also being explored. Gardner et al. reported on use of early administration of tocilizumab with and without dexamethasone after treatment with a 4-1BB second generation CAR T cell product with encouraging data of a modest decrease in severe CRS without an effect on engraftment and persistence of CAR T cells 74[clinicaltrials.org NCT02028455]. A similar clinical trial at CHOP [clinicaltrials.gov, NCT02906371] was conducted to evaluate the efficacy of early administration of tocilizumab after treatment with tisagenlecleucel in pediatric patients with high disease burden in an attempt to mitigate severe CRS. Patients with high disease burden (>40% BM blasts) on day-1 were allocated to receive a single dose of tocilizumab at the time of fever, after which they received standard CRS management. This trial testing pre-emptive tocilizumab met the endpoint for grade 4 CRS reduction (by 1/3) in these high-risk patients 74,75. Finally, our understanding of the mechanisms underlying neurotoxicity remains poor. There are no predictive models for the development or severity of neurotoxicity, although there is a strong correlation with severe CRS. Treatment with tocilizumab has not been effective, and clinicians often revert to corticosteroids for severe neurologic toxicities to avoid feared cerebral edema; although, this complication has not been reported after treatment with tisagenlecleucel 76.
The unification into a single grading system will allow for an objective assessment and reporting of clinical severity between different clinical trials and CAR T cell constructs going forward in order to further advance our current understanding and management of CRS17,24,25,77-82.