Magnetic Resonance Imaging in Immune Effector Cell-Associated Neurotoxicity Syndrome

Lymphoma, B-Cell Clinical Trial

— MR-ICANS  

Official title:

Contribution of Magnetic Resonance Imaging in Immune Effector Cell-Associated Neurotoxicity Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05510596
• Other study ID #: RECHMPL20_0424
• Status: Completed
• Phase: N/A
• Start date: September 22, 2022
• Est. completion date: September 14, 2023

Study information

• Verified date: April 2024
• Source: University Hospital, Montpellier
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Main objectives are 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 and 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.

For this purpose, 25 subjects will be included (the investigators hypothesize 40% with treatment-induced neurological impairment).

Description:

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®).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: September 14, 2023
• Est. primary completion date: September 13, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma, B-Cell
• Neurotoxicity
• Neurotoxicity Syndromes
• Syndrome

Intervention

Other:
• Magnetic Resonance Imaging with contrast injection
Magnetic Resonance Imaging with contrast injection
• Blood withdrawal
Blood withdrawal : serum, plasma, cytokine assay
• Neuropsychological tests
Neuropsychological tests

Locations

Country	Name	City	State
France	Neurology department, Montpellier University Hospital	Montpellier	Occitanie

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Montpellier

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Study of tissue permeability evolution	Quantitative measurement of KTRANS (rate of contrast agent transfer from plasma to the extravascular extracellular space, reflecting capillary permeability).; (Time in second)	10 days
Secondary	Qualitative analysis of tissue signals	FLAIR hypersignals analysis by MRI (signal of a tissue superior to the signal of the surrounding tissues) (visual assessment)	10 days
Secondary	Qualitative analysis	Microbleeding analysis (3DEPI T2*)	10 days
Secondary	Qualitative analysis	Analysis of contrast on injected 3DT1 MRI	10 days
Secondary	Semi-quantitative analysis of parameters associated with permeability	Wash-in, Wash-out (Time in second)	10 days
Secondary	Semi-quantitative analysis of parameters associated with permeability	Time to peak (TPP) (Time in second)	10 days
Secondary	Semi-quantitative analysis of parameters associated with permeability	AUC (area under the curve shows blood volume) (SI x Time)	10 days
Secondary	Quantitative analysis of parameters associated with permeability	Kep: rate of return transfer of the contrast agent from the extravascular extracellular space to the plasma (Volume/Time/Volume)	10 days
Secondary	Quantitative analysis of parameters associated with permeability	Ve: volume fraction of the extravascular space (Percentage %)	10 days
Secondary	Quantitative analysis of parameters associated with permeability	Vp: volume fraction of the plasma space. (Percentage %)	10 days
Secondary	Quantitative analysis	Cerebral blood flow analysis (3DPCASL) (L/min)	10 days
Secondary	Quantitative analysis	Cerebral volumetric analysis (3DT1) (cm3)	10 days
Secondary	Quantitative analysis	Diffusion coefficient (ADC) (mm²/s)	10 days
Secondary	Quantitative analysis	Perfusion factors (perfusion fraction f) (Percentage %)	10 days
Secondary	Quantitative analysis	Perfusion factors (pseudo-diffusion D* at the microvascular compartment) (x10^-3 mm²/s)	10 days
Secondary	Qualitative analysis : comparison with clinical data	Presence, absence of neurotoxicity and inflammation	10 days
Secondary	Comparison with biological data from standard care and "Neuroinflammation Panel Human 1 Kit"	Comparison of MRI data with biological markers (such as CRP, ferritin, white blood cell count, LDH, procalcitonin, fibrinogen) and cytokine profile of neuroinflammation by multiplex immunoassay kit. An ultrasensitive multiplex using electrochemiluminescence.	10 days