Magnetic Resonance Imaging in Immune Effector Cell-Associated Neurotoxicity Syndrome

The treatment of large-cell B-cell lymphomas refractory to more than 2 lines of therapy has recently been revolutionized by the use of immunotherapies consisting of autologous genetically modified cells or CAR-T CELLS (chimeric antigen receptor-T cells), which very significantly increase progression-free survival and overall survival. Nevertheless, this therapy is frequently associated with cytokine release syndrome and in approximately 20% to 60% of patients with neurological complications that can sometimes be dramatic and are associated with a significant mortality rate.

The mechanisms behind this neurotoxicity are unclear but may include :

• A "systemic" toxicity associated with the cytokine release syndrome. This toxicity would thus be favoured by the associated inflammatory response syndrome manifested in particular by hyperthermia, changes in blood pressure, and an increase in CRP, ferritin and the number of white blood cells.
• A breakdown of the blood-brain barrier, as evidenced by increased protein levels, cellularity and cytokine levels in the cerebrospinal fluid. Among other things, this rupture could be promoted by the synthesis of proinflammatory cytokines (IL6, TNF-alpha, IFN-gamma) that would promote endothelial activation.
• Direct toxicity to neurons and/or microglial cells.

Despite the frequent occurrence of neurological toxicity characterized in particular by headache, tremor, and encephalopathy that is most often transient, brain imaging by CT or, preferably, MRI are most often normal. The rare abnormalities that have been identified suggest the presence of cytotoxic edema associated with the existence of transient modifications of the blood-brain barrier.

To date, the management of neurotoxicity associated with CAR-T CELLS remains empirical. It combines early management of cytokine release syndrome (by administration of anti-IL6) and treatment with corticosteroids, the objective of which would be to control neurotoxicity more specifically. A better understanding of the pathophysiological mechanisms associated with this neurotoxicity appears essential today in order to be able to propose adapted prevention and treatment methods.

Objectives:

Main:

• To Compare tissue permeability by quantitative MRI measurement of Ktrans to the theoretical peak of neurotoxicity between patients with CAR-T Cell-induced neurotoxicity and those without neurotoxicity.

Secondary:

• To Study, by MRI, the evolution of tissue microcirculatory parameters (from D-3 to D7) between groups of patients with or without the occurrence of neurotoxicity associated with CAR-T CELL treatment.
• To Correlate the values of the MRI parameters with the usual clinical and biological parameters known to be associated with the occurrence of neurotoxicity (at D0 and theoretical peak).
• To Correlate the values of the MRI parameters with the values (at D0 and at NADIR) of a panel of cytokines of interest (V-PLEX Neuroinflammation Panel Human 1 Kit, Meso Scale Discovery®).

Inclusion criteria

• Subject aged from 18 years old
• Subject able to understand the nature, purpose and methodology of the study
• Subject with diffuse large B-cell lymphoma to be treated with axicabtagene ciloleucel, tisagenlecleucel or brexucabtagene autoleucel for their lymphoma.

Exclusion criteria

• Refusal to sign the informed consent
• Subject presenting a cerebral localization of his lymphoma
• Contraindication to the realization of an MRI (metallic foreign body, pace-maker, cochlear implants)
• Claustrophobic subject
• Subject with a neurodegenerative disease (Parkinson's, Alzheimer's...)
• Subject with psychiatric disorders such as psychosis, except for anxiety-depressive episodes
• Subject with a systemic pathology with neurological manifestation
• Subject with a previous or evolving neurological pathology
• Subject with or with a history of severe head trauma (group 2 or 3 according to the Masters classification)
• Contraindication to the use of gadoline contrast products (severe renal insufficiency, liver transplantation, known or suspected hypersensitivity to the product)
• Pregnant or breastfeeding women
• Patient under tutelage
• Patient under curatorship
• Patient deprived of liberty
• Not a beneficiary of a social security system