Acute leucoencephalomyelopathy and quadriparesis after CAR T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapy maybe associated with neurologic toxicity, also referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), that typically manifests as encephalopathy. Here, we report two patients, with no known prior neurological disease, treated on ZUMA-1 trial, who developed acute leucoencephalomyelopathy with quadriparesis after treatment with axicabtagene ciloleucel (axi-cel). Patient 1 is a 41-year-old female with refractory diffuse large B-cell lymphoma after four lines of systemic therapy including high-dose chemotherapy plus autologous stem cell transplantation. She had bulky nodal and splenic disease (Online Supplementary Figure S1A) prior to treatment with axi-cel. Her baseline C-reactive protein (CRP) and ferritin were elevated at 136 mg/L and 9,821 ng/mL, respectively (Figures 1A and B). She experienced intermittent grade 1 cytokine release syndrome (CRS) with fever and tachycardia from days 1-6. On day 2, she developed grade 3 ICANS with confusion concurrently with fever, which resolved promptly with tocilizumab and dexamethasone administration along with a dose increase of levetiracetam that was started on day 0 for seizure prophylaxis. On day 4, grade 3 ICANS recurred with aphasia which was non-responsive to a second dose of tocilizumab. On day 5, she developed grade 4 ICANS with clonic seizures evolving to status epilepticus requiring ventilator support, additional anti-epileptic medications, and high-dose methylprednisolone. On days 6 and 7, she had two generalized tonic-convulsive seizures with further electrographic seizures (Online Supplementary Figures S5-6). The seizures were eventually controlled with lorazepam, phenytoin, levetiracetam, and phenobarbital. On day 8, as patient mental status improved, she was noted to be weak in the lower extremities with rapid progression to quadriparesis, mute plantar reflexes, and lack of bladder control. Cerebrospinal fluid (CSF) analysis showed an increased protein level but no evidence of infection. Magnetic resonance imaging (MRI) of the brain and spine on day 9 showed findings concerning for acute leucoencephalomyelopathy with symmetrical T2 hyperintensity within the centrum semiovale with sparing of the U-fibers, the superior cerebellar peduncle and striking diffuse cerebral edema (Figure 2A). There was involvement of the diffuse periventricular white matter, external capsule, and posterior limb of the internal capsule, and posterior limb of the internal capsule. MRI of the spine demonstrated centromedullary holocord involvement (Figure 2A). By day 11, upper extremity strength started to improve and she self-extubated. Her cognitive function quickly improved but she experienced retrograde amnesia spanning a time period of about 2 weeks prior to this event. By