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.