Severe dysautonomia as a manifestation of neurotoxicity after <scp>CAR‐T</scp> cell therapy for diffuse large <scp>B‐cell</scp> lymphoma
Authors: Firas El Chaer, Ariel Siegel, Noa G. Holtzman, Ali Bukhari, Forat Lutfi, Nirav G. Shah, Jean A. Yared, Aaron P. Rapoport, Michael T. McCurdy, Saurabh Dahiya
Journal: American Journal of Hematology (2020)

To the Editor: Anti-CD19 chimeric antigen receptor T-cell (CART) therapy is associated with off- and on-target adverse effects including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).1 Note, ICANS is likely due to endothelial injury and blood-brain barrier (BBB) disruption, with either diffusion of cytokines into the brain or activated T-cells into the central nervous system (CNS).2, 3 The pathophysiology of ICANS is thought to be related to endothelial injury leading to BBB disruption, due to either passive diffusion of cytokines into the brain or the presence of activated T-cells in the CNS.2, 3 Herein, we report a patient with lymphoma treated with anti-CD19 CART therapy who developed severe dysautonomia due to ICANS. Parasympathetic overactivity led to asystolic cardiac arrest followed by a sympathetic storm. Along with complete remission (CR), CART therapy resulted in irreversible neurological sequelae. Pre-CART Therapy Course: A 57-year-old man with hypertension and hyperlipidemia presented with leukopenia and lymphadenopathy. Excisional biopsy diagnosed follicular lymphoma grade I/II. Seven months later, he developed back pain and imaging showed spinal lesions with cord edema. The surgical specimen from the laminectomy showed disease transformation to diffuse large B-cell lymphoma. Fluorescence-in-situ-hybridization (FISH) studies identified BCL-2 and c-Myc rearrangements in 34% and 24% of the analyzed cells, respectively, and were negative for BCL-6 rearrangement. The patient was treated with six cycles of R-CHOP chemotherapy. Post-treatment positron emission tomography/computed tomography (PET/CT) imaging showed progressive disease in the spine. He underwent salvage chemotherapy to which his disease was refractory. Post CAR-T Therapy Course: The patient next received fludarabine and cyclophosphamide followed by the FDA-approved anti-CD19 CART therapy with axicabtagene ciloleucel (Axi-Cel). His pre-infusion labs were notable for a ferritin of 3533 ng/mL (normal range 17.9-464 ng/mL), lactate dehydrogenase (LDH) 1161 U/L (normal range 313-618 U/L), and platelet count 10 K/mcL (normal range 150-450 K/mcL). Two days later, he developed grade II CRS with fevers and tachycardia and was treated with two doses of tocilizumab (8 mg/kg/dose). Subsequently, he developed worsening altered mental status (AMS) with somnolence and confusion consistent with grade IV ICANS. He was given one dose of intravenous (IV) siltuximab (11 mg/kg) followed by 1 g IV methylprednisolone daily for 3 days. He was intubated on day 7 for airway protection due to somnolence from grade IV ICANS. Magnetic resonance imaging (MRI) of the brain only revealed a new 12 mm focus of petechial hemorrhage within the cerebellum without evidence of edema (Figure 1,B). The electroencephalogram showed nonspecific findings. Severe Dysautonomia Post-CART Therapy: On day 8, the patient developed parasympathetic system instability with severe bradycardia and hypotension. Initially, this appeared to be associated with agitation and coughing, however repeat episodes of bradycardia occurred without vagal stimuli. These episodes led to asystolic cardiac arrest requiring intubation with neuromuscular blockade, transcutaneous pacing and eventually transvenous pacing (TVP). Atropine and epinephrine were administered, resulting in sinus tachycardia. Of note, prior to day 8, the patient exhibited no signs of heart rate and blood pressure instability. Transthoracic echocardiogram revealed an ejection fraction of 30%-35% (down from 60% at baseline) with a normal functioning right ventricle and no evidence of a pericardial effusion. The patient was TVP dependent for 2 days, but sympathetic storm manifested by hypertensive emergency set in on day 10. Hypertensive emergency was managed with IV antihypertensives and sedation with ketamine and dexmedetomidine (Figure 1C,D). Six days later, the patient was extubated and his TVP was removed, however, he remained lethargic and disoriented despite lack of focal neurological deficits. Three weeks later, due to the persistence of his neurologic symptoms without CRS, a repeat MRI of the brain showed mild diffuse FLAIR hyperintensity in the periventricular white matter and brainstem, consistent with leukoencephalopathy. A second course of high-dose 1 g daily IV methylprednisolone for 3 days was administered. Cerebrospinal fluid (CSF) analysis was negative for lymphoma, it identified three white blood cells (86% lymphocytes and 14% monocytes), decreased glucose 34 mg/dL (normal range 40-7 mg/dL), increased protein 167 mg/dL (normal range 12-60 mg/dL), and absent red blood cells. Cerebrospinal fluid was negative for infectious work-up except human herpes virus 6 (HHV6) type B with a viral load of 2910 copies/mL (normal range zero), with the same value for HHV6 qPCR in the blood. The patient was started on daily 5 mg/kg IV ganciclovir treatment. Two weeks later, repeat HHV6 qPCR was undetectable in the CSF with blood levels <1000 copies/mL, but his neurological symptoms persisted. Thirty days after CART infusion, imaging showed CR. Three months post-CART therapy, the patient remained in CR with persistent AMS. Four months after CART therapy, the patient had a lymphoma relapse after which he was enrolled in hospice and passed. Note, CART therapy has emerged as an effective adoptive cellular immunotherapy for R/R hematologic malignancies with unprecedented response rates. However, this potentially curative therapy is associated with unique toxicities, often manifested as CRS and ICANS. Cardiac toxicities have ranged from tachycardia, dysrhythmias, heart block, and decreased ejection fraction. However, in this case, severe ICANS led to severe autonomic neuropathy. First, the patient experienced severe bradycardia and eventually asystole, likely as a result of high parasympathetic stimulation from a disrupted BBB.4 Later, the patient had hypertensive emergency as a result of an overactive sympathetic system from the disrupted BBB. Autonomic neuropathy as a manifestation of ICANS from CAR-T therapy has not been reported in the literature. Furthermore, ICANS is most commonly reversible unless seizures have occurred or fulminant cerebral edema.1 Our patient suffered from irreversible neurotoxicity with short-term memory loss, disorientation, and confusion without any precedent seizure or cerebral edema. Lower platelet counts upon CART infusion,5, 6 high disease burden, and high-grade CRS are associated with severe ICANS, as observed in our patient.3 Vascular dysfunction, manifested by endothelial activation and systemic capillary leak with BBB disruption, could be the underlying mechanisms for development of neurotoxicity.2, 3 In conclusion, although CART therapy is effective for hematologic malignancies, it can be associated with long-term debilitating sequalae, at times irreversible undermining the curative intent of this cellular immunotherapy. The authors have no relevant conflict of interest to report. S.D. identified the described case. F.E.C. wrote the manuscript with assistance from A.S., N.A.M., N.S., A.P.R., M.T.M. & S.D. All authors provided critical feedback and helped shape the manuscript.