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

Abstract

Background and PurposeChimeric 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.MethodsTwenty‐one refractory DLCBLs underwent whole‐body and brain [18F]‐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).ResultsICANS 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).ConclusionsPatients 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.

The Role of [18F]FDG PET/CT in Predicting Toxicity in Patients with NHL Treated with CAR-T: A Systematic Review

“…In line with the theory that ICANS is primarily a frontal syndrome, patients with this condition show a frontolateral hypometabolic signature. This trend is in line with the frontal lobes' increased vulnerability to cytokine-induced inflammation [16].…”

“…Morbelli et al [16] CRS, ICANS Five of the eleven patients who had CRS went on to develop ICANS. Whereas ICANS was associated with a more widespread hypometabolic pattern in the frontal cortex, CRS without ICANS revealed hypometabolism in bilateral medial and lateral temporal lobes, posterior parietal lobes, and other regions.…”

FDG-PET in Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy Toxicity: A Systematic Review

“…After removing 35 duplicates, 92 titles and abstracts were screened, with the majority of the articles not aligning with the study's objectives, primarily focusing on CAR T-cell therapeutic efficacy. Ultimately, only 17 articles met the criteria for inclusion and were further evaluated after retrieving the full-text versions [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. An additional study [42] was found during the cross-reference check, bringing the total number of qualified studies to 18 for further analysis (Figure 2A).…”

“…A total of 11 studies were identified exploring the predictive capabilities of PET in CAR T-cell toxicity. Utilizing the QUIPS tool, two studies were found to exhibit a moderate risk of bias in the study attrition domain [25,31], and two were discovered to have a moderate risk of bias in the study confounding domain [28,31]. Four other studies [26,36,39,41] had a high risk of bias in the study confounding domains (Figure 2B).…”

Blood–brain barrier breakdown, central nervous system cell damage, and infiltrated T cells as major adverse effects in CAR-T-related deaths: a literature review

“…However, conducting additional autopsies and microscopic investigations would provide further insights into this subject. The investigation of CAR-T DNA presence in directly affected tissues presents an intriguing avenue for research that should be rigorously explored, validated, and potentially standardized in future ( 54–57 ). In the field of forensics, a more comprehensive understanding of CAR-T therapy-related deaths would help in determining the causes of death and resolving issues related to any legal disputes.…”