CAR t-cell therapy in BOlogNa–NEUrotoxicity TReatment and Assessment in Lymphoma (CARBON–NEUTRAL): proposed protocol and results from an Italian study

Pensato, Umberto; Amore, Giulia; Muccioli, Lorenzo; Sammali, Susanna; Rondelli, Francesca; Rinaldi, Rita; D’Angelo, Roberto; Nicodemo, Marianna; Mondini, Susanna; Sambati, Luisa; Asioli, Gian Maria; Rossi, Simone; Santoro, Raffaela; Cretella, Lucia; Ferrari, Susy; Spinardi, Luca; Faccioli, Luca; Fanti, Stefano; Paccagnella, Andrea; Pierucci, Elisabetta; Casadei, Beatrice; Pellegrini, Cinzia; Zinzani, Pier Luigi; Bonafè, Massimiliano; Cortelli, Pietro; Bonifazi, Francesca; Guarino, Maria

doi:10.1007/s00415-023-11595-4

Cited by 10 publications

(18 citation statements)

References 43 publications

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“…Patients with CRS either associated or not with ICANS showed regions of hypometabolism with respect to controls; however, voxel‐based analyses demonstrated a more extended and prominent involvement of the frontolateral cortex in patients who evolved to ICANS. This pattern was highlighted in all patients with ICANS also at a single patient's level and is in keeping with the pathophysiological hypothesis of ICANS as a predominant frontal syndrome 29,37 …”

Section: Discussionsupporting

confidence: 86%

“…This pattern was highlighted in all patients with ICANS also at a single patient's level and is in keeping with the pathophysiological hypothesis of ICANS as a predominant frontal syndrome. 29,37 In previously published case series, clinical features of ICANS have more often been discussed with respect to patients' MRI findings. 9,15,38 Actually, many patients with ICANS have a negative MRI, and typical MRI features of ICANS have not yet been defined.…”

Section: Discussionmentioning

confidence: 99%

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

Morbelli

Gambella

Raiola

et al. 2023

Journal of Neuroimaging

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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.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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

Morbelli

Gambella

Raiola

et al. 2023

Journal of Neuroimaging

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“…This hypothesis has been recently supported by the study of Pensato and colleagues, who reported a frontal lobe dysfunction in 65% of patients developing ICANS after CAR T cell therapy, characterized by a variable association of behavioral disinhibition, verbal and motor perseveration or apathy, and motor signs. Frontal lobe involvement was further proven by brain FDG-PET, showing bilateral frontal-predominant hypometabolism, and by EEG, revealing frontal predominant EEG abnormalities [ 11 ]. Interestingly, the electroclinical features of the frontal lobe dysfunction in ICANS share several aspects with other encephalopathies associated to cytokine storm, i.e., SARS-CoV-2 and sepsis-related encephalopathies [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Pensato and colleagues demonstrated that the presence of electroencephalogram (EEG) abnormalities—even if mild—at baseline (i.e., one day before the infusion) correlated with the development of ICANS [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Pre-existing frontal lobe dysfunction signs as predictors of subsequent neurotoxicity in CAR T cell therapy: insights from a case series

et al. 2023

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Background Chimeric Antigen Receptor (CAR) T cell therapies are innovative treatments against hematological malignancies, with increasing therapeutic indications. Despite their great efficacy, these therapies are hampered by high rates of neurotoxicity (immune effector cell–associated neurotoxicity (ICANS)). In the past few years, several risk factors have been associated with ICANS and grouped together in the attempt to build validated models able to predict neurologic complications. However, little is known about pre-existing neurologic conditions possibly related to the development of neurotoxicity. Methods and results In our case series, including sixteen consecutive patients treated with CAR T cells, we observed that (i) neurotoxicity only occurred in the two patients who presented subtle clinical signs of frontal lobe impairment at baseline and (ii) neurologic manifestations of ICANS consisted of language disturbances and cortical frontal myoclonus, which were both manifestations of a frontal predominant dysfunction. Discussion Based on our experience, we suggest that a pre-existing frontal lobe impairment, even if at a subclinical level, may eventually drive to ICANS, which in turn shows symptoms compatible with a frontal encephalopathy. It is remarkable that this focal neurotoxicity involved the same CNS regions that were responsible of subtle neurological signs at baseline. Future studies on larger numbers of patients are needed to confirm the possible role of baseline frontal lobe dysfunction as a predictor of ICANS, in order to enhance efforts to safely deliver CAR T cell therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s10072-023-06841-6.

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“…headache and vomiting), and it is not preceded by the typical subacute encephalopathy with predominant frontal dysfunction described in ICANS patient. 14 Therefore, the appearance of signs suggestive of intracranial hypertension should be specifically pointed out. Given the dramatic rapidity of evolution, the diagnosis of FCE needs to be initially based on clinical suspicion only, without relying on neuroimaging, which is often unremarkable at the onset, in order to avoid any delay in the neurointensive approach.…”

mentioning

confidence: 99%

Intracranial pressure management in fulminant cerebral oedema after CAR T‐cell therapy: Not all is lost!

Asioli,

Castioni,

Zinzani

et al. 2023

Br J Haematol

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CAR t-cell therapy in BOlogNa–NEUrotoxicity TReatment and Assessment in Lymphoma (CARBON–NEUTRAL): proposed protocol and results from an Italian study

Cited by 10 publications

References 43 publications

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

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

Pre-existing frontal lobe dysfunction signs as predictors of subsequent neurotoxicity in CAR T cell therapy: insights from a case series

Intracranial pressure management in fulminant cerebral oedema after CAR T‐cell therapy: Not all is lost!

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