Biomarkers associated with neurotoxicity in adult patients with relapsed or refractory B-ALL (R/R B-ALL) treated with CD19 CAR T cells.

Abstract

3019 Background: CD19-specific chimeric antigen receptor (CAR) modified T cells produce high and durable anti-tumor activity, but can be associated with treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity (NTX). NTX is poorly understood and it hasn't been clear where to focus further research. We report cerebrospinal fluid (CSF) data and neuroimaging characteristics of patients (pts) who developed severe NTX (sNTX) during our phase I clinical trial of CD19-specific 19-28z CAR T cells for adult pts with R/R B-ALL, which suggest new avenues for future research. Methods: 51 adult pts with R/R B-ALL were treated with 19-28z CAR T cells following conditioning chemotherapy at MSKCC. We analyzed the incidence and grade of NTX, CRS and correlative biomarkers in blood and CSF. Results: 21/51 treated pts developed sNTX (grade ≥3) complications such as encephalopathy, aphasia, depressed level of consciousness, myoclonus, and seizure. No pt developed grade 5 NTX and, in all but one case, neurologic symptoms fully resolved. We collected CSF by lumbar puncture and blood from 14 pts at the time of peak NTX. sNTX was correlated with pre-infusion disease burden (p = 0.013) and peak CAR T cell expansion in the blood (p = 0.0001), but we found no significant correlation between NTX grade and the CAR T cell concentration in the CSF during NTX. Instead CSF protein level was correlated with neurotoxicity grade (p = 0.0109). The cytokines IL6, IL8, IL10, IFNγ and GCSF were elevated in CSF over serum at the time of NTX and correlated with CSF protein levels (all p < 0.005). These were distinct from serum cytokines significantly associated with sNTX at d3 of T cell infusion: GMCSF, IFNγ, IL15, IL5, IL10, and IL2 (all p < 0.01). 4/21 patients developed a pattern of reversible MRI T2/FLAIR hyperintensity involving the bilateral thalami, dorsal pons, and medulla. Conclusions: NTX is predominantly reversible. MRI findings suggesting transient toxicity to deep grey structures and findings of a CSF-specific cytokine profile expand the hypotheses on the mechanism of NTX. Future studies will focus on determining the etiology of the CSF protein elevation and the distinct cytokine profile. Clinical trial information: NCT01044069.