Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is an emerging highly effective treatment for refractory haematological malignancies. Unfortunately, its therapeutic benefit may be hampered by treatment-related toxicities, including neurotoxicity. Early aggressive treatment is paramount to prevent neurological sequelae, yet it potentially interferes with the anti-cancer action of CAR T-cells. We describe four CAR T-cells infused patients who presented with reiterative writing behaviours, namely paligraphia, as an early manifestation of neurotoxicity, and eventually developed frontal predominant encephalopathy (one mild, three severe). Paligraphia may represent an early, specific, and easily detectable clinical finding of CAR T-cell therapy-related neurotoxicity, potentially informing its management.

Keywords: Anakinra; B-cell lymphoma; CAR-T therapy; Cytokine release syndrome (CRS); Cytokine storm-associated encephalopathy (CySE); Immune effectors cell-associated neurotoxicity syndrome (ICANS).

Fig. 1

Disease course in case 1. Neurological manifestations, ICANS severity, CRS severity, serum IL-6 and ferritin levels, timing of treatments and diagnostic investigations during disease course. ICANS and CRS severity were graded according to the consensus by Lee et al. [2] ICE score modified during disease course as follows: day0 = 10; day1 = 3 day2 = 7; day3 = 4; day5 till death = 0. ICANS immune effector cell-associated neurotoxicity syndrome. CRS cytokine release syndrome. ICE score immune effector cell-associated encephalopathy score

Fig. 2

Writing findings in ICANS patients. Within the black box, the faithful drafting of the Italian sentence written by the patients is reported, followed by the same Italian sentence reported with no letter repetitions and then its English translation. Rewriting of letters produced by patient 1 at ICANS onset (A) and by patient 3 at ICANS onset (B) and after complete clinical resolution (C). ICANS immune effector cell-associated neurotoxicity syndrome

Fig. 3

Brain MRI findings in case 1. Axial 1.5 Tesla brain MRI. Unremarkable baseline brain MRI (A, D, G). Left parietal periventricular T2-weighted hyperintensity (white arrows) with radiological features initially consistent with vasogenic oedema [↑DWI (E); ↑/ = ADC (H)], and then with cytotoxic oedema [↑DWI (F); ↓ADC (I)]. FLAIR fluid-attenuated inversion recovery; DWI diffusion-weighted image; ADC apparent diffusion coefficient

Fig. 4

Brain FDG-PET findings in case 2. Matched axial brain FDG-PET (A,B,C) and CT scan (D,E,F) showing diffuse bilateral hypometabolism with frontal predominance. Additionally, a focal area of severe hypometabolism (A, B), resulting from a spontaneous parenchymal haematoma associated with subarachnoid haemorrhage (D, E), is observable in the left parietal lobe. FDG-PET [¹⁸F]FDG positron emission tomography. CT computed tomography