Brain FDG-PET findings in chimeric antigen receptor T-cell therapy neurotoxicity for diffuse large B-cell lymphoma

Chimeric antigen receptor (CAR) T-cell therapy is potentially associated with treatment-related toxicities mainly consisting of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). We evaluated brain metabolic correlates of CRS with and without ICANS in diffuse large B-cell lymphoma patients treated with CAR-T.

Twenty-one refractory DLCBLs underwent whole-body and brain [18 F]-fluorodeoxyglucose (FDG) PET before and 30 days after treatment with CAR-T. Five patients did not develop inflammatory-related side effects, 11 patients developed CRS, while in 5 patients CRS evolved in ICANS. Baseline and post-CAR-T brain FDG-PET were compared with a local controls dataset to identify hypometabolic patterns both at single-patient and group levels (p < .05 after correction for family-wise error [FWE). Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were computed on baseline FDG-PET and compared between patients' subgroups (t-test).

ICANS showed an extended and bilateral hypometabolic pattern mainly involving the orbitofrontal cortex, frontal dorsolateral cortex, and anterior cingulate (p < .003 FWE-corrected). CRS without ICANS showed significant hypometabolism in less extended clusters mainly involving bilateral medial and lateral temporal lobes, posterior parietal lobes, anterior cingulate, and cerebellum (p < .002 FWE-corrected). When compared, ICANS showed a more prominent hypometabolism in the orbitofrontal and frontal dorsolateral cortex in both hemispheres than CRS (p < .002 FWE-corrected). Mean baseline MTV and TLG were significantly higher in ICANS than CRS (p < .02).

Patients with ICANS are characterized by a frontolateral hypometabolic signature coherently with the hypothesis of ICANS as a predominant frontal syndrome and with the more prominent susceptibility of frontal lobes to cytokine-induced inflammation.