Clinical and radiologic correlates of neurotoxicity after axicabtagene ciloleucel in large B-cell lymphoma

Abstract

Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients.

Therapeutic Potential of TNFα and IL1β Blockade for CRS/ICANS in CAR-T Therapy via Ameliorating Endothelial Activation

“…IL1 has been reported to precede IL6 production by several hours to induce the secretion of IL6 as well as sIL6R ( 33 ). Therefore, it has been speculated that CRS might be primarily initiated by IL1 release from circulating monocytes, and IL1 blockade by anakinra was shown to be highly effective due to its systemically pharmacological intervention, including the responsiveness of neurotoxicity in mouse model ( 14 , 15 , 34 ). This further confirmed the vital role of IL1 in the development of CRS and ICANS during CAR-T therapy.…”

The Association Between Glucocorticoid Administration and the Risk of Impaired Efficacy of Axicabtagene Ciloleucel Treatment: A Systematic Review

“…To date, the management for ICANS is nonspecific, and primarily represented by glucocorticoids, supportive care, and antiepileptics. Different studies had conflicting results on the association between ICANS and efficacy of Axi-cel therapy, therefore, although most ICANS events were reversible, the indirect effects of ICANS on Axi-cel therapy could not be ignored, and proper prophylaxis treatment may be necessary for patients at high risk of ICANS (26,33). Several studies attributed the decreased severe CRS and ICANS rate to earlier and more systematic intervention of tocilizumab and corticosteroids, which provided evidence to support the use of glucocorticoids, however, none of these studies specifically analyzed the effects of glucocorticoids timing on CAR-T cell efficacy (22,24,27).…”

Bilateral anterior cerebral artery occlusion following CD19- and BCMA-targeted chimeric antigen receptor T-cell therapy for a myeloma patient

“…Although there were two patients who had neurological complications, none of them had cerebral infarction [ 5 ]. Strati et al [ 9 ] recently reported that 68 of 100 patients with relapsed or refractory large B-cell lymphoma (LBCL) treated using axicabtagene ciloleucel developed immune effector cell-associated neurotoxicity syndrome (ICANS) and 41 (41%) had grade ≥ 3. Of 38 patients with ICANS who underwent MRI, three had MRI findings with features of stroke.…”