Transverse Myelitis With Paraplegia: An Atypical Manifestation of Neurotoxicity Following CAR T-Cell Therapy

Presentation 

A 28-year-old female with no significant medical history was diagnosed with B-lymphoblastic leukemia with a KMT2A mutation. She was initially treated with CALGB 10403 (prednisone, vincristine, daunorubicin, peg-asparaginase) with intrathecal chemotherapy (cytarabine and methotrexate). Cerebrospinal fluid (CSF) studies were negative for aberrant blast population. Her disease was refractory to treatment based on the Day 28 bone marrow biopsy, and she was reinduced with Hyper-CVAD B (cytarabine and methotrexate) with intrathecal chemotherapy (cytarabine and methotrexate). Her CSF studies remained negative for leukemic involvement. Repeat bone marrow biopsy after one cycle of Hyper-CVAD B showed persistent disease with approximately 20% blasts and abnormal mixed-lineage leukemia rearrangement. She was referred for CAR T-cell therapy evaluation and, after determining eligibility, proceeded with T-cell collection for brexucabtagene autoleucel. In preparation for CAR T-cell therapy, she underwent MRI of the brain, which showed no evidence of leptomeningeal involvement. She was cleared to proceed with lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by brexucabtagene autoleucel.

On Day 3 post product infusion, the patient’s vital signs were the following:

These values were consistent with cytokine release syndrome (CRS) grade 1. Her m-EASIX score was calculated to be 23.6 on Day 3, indicating high risk for severe CRS/immune effector cell-associated neurotoxicity syndrome (ICANS). She was neutropenic, and thus was started on piperacillin and tazobactam for injection for board-spectrum antimicrobial coverage and given acetaminophen 650 mg orally for fever. The infectious workup (chest x-ray, blood, and urine cultures) was negative.

On the evening of Day 4, her vital signs were the following:

She was given 2 liters of normal saline bolus, acetaminophen 650 mg orally for fever, and one dose of tocilizumab for grade 2 CRS. Overnight into Day 5, the patient continued to be febrile and hypotensive. Her lactate level was 4.5, and interleukin-6 (IL-6) was 164. She received an additional 1.5 liters of normal saline, dose 2 of tocilizumab, 10 mg of IV dexamethasone, and 650 mg of oral acetaminophen for fever. She continued to have grade 2 CRS throughout the day of Day 5, and she was continued on dexamethasone 10 mg IV every 6 hours.

On Day 6, she continued to have grade 2 CRS and received dose 3 of tocilizumab. She developed ICANS grade 2 with an immune effector cell-associated encephalopathy (ICE) score of 8. She was unable to count backward from 100 by 10s or to write the sentence in the evaluation. Her IL-6 level was greater than 1,500. She was on levetiracetam 500 mg twice daily for seizure prophylaxis. CT of the head and electroencephalogram EEG were unremarkable. On Day 7, her mental status continued to decline, indicated by an ICE score of 5. Neurology was consulted, and dexamethasone was increased to 20 mg IV every 6 hours.

Workup, Diagnosis, and Treatment 

On Day 8, her CRS was resolved. However, her ICE score was 0; she had weakness in her bilateral lower extremities, was unable to bear weight on her legs, and had loss of both bowel and bladder continence. An MRI of the brain showed signal abnormality involving the midbrain, superior cerebellar peduncles, medulla, and upper cervical core consistent with ICANS. An MRI of the lumbar and thoracic spine showed diffuse patchy signal abnormality involving the cord and conus medullaris, with mild cord expansion consistent with ICANS and nonspecific transverse myelitis. A lumbar puncture with intrathecal cytarabine and hydrocortisone was performed. Flow cytometry of the CSF fluid was negative for blast population, and she had a predominance of T cells with a skewed CD-4 to CD-8 ratio, indicating the presence of CAR T cells in the CSF. Dexamethasone was discontinued, and she was started on methylprednisolone 1 gm daily for 3 days, anakinra 200 mg every 8 hours, and intravenous immunoglobulin (IVIG) 1 gm/Kg.

On Day 11, her ICE score improved to 9; however, she had no improvement in her paraplegia. She received dose 2 of IVIG and lumbar puncture with IT cytarabine and hydrocortisone. The CSF studies again were negative for aberrant blasts. Her IL-6 levels had decreased to 24. Over the next week, her steroids were tapered off, and she participated in physical therapy.

The patient was discharged on Day 22 without improvement in her paraplegia. As of this writing, the patient is more than 5 months post CAR T-cell therapy and remains paraplegic. She has continued with extensive outpatient physical therapy and has regained some sensation in her legs. A commercially available CAR T-cell persistency assay failed to detect CAR vector copies 4 months post CAR T-cell therapy. Studies have indicated that CAR T-cell persistence is associated with lower relapse rates and longer progression-free survival.1 As such, further treatment options, such as allogeneic hematopoietic stem cell transplant, should be considered.  

Discussion 

Neurotoxicity following CAR T-cell therapy is common, affecting approximately 60% of patients, and the symptoms are usually reversible.2 Clinical manifestations of neurotoxicity can vary from headaches, tremors, and lethargy to encephalopathy, seizures, and cerebral edema. However, atypical manifestations of ICANS such as acute leukoencephalopathy and transverse myelitis have been reported.3,4 Risk factors for the development of neurotoxicity include younger age, high tumor burden, and a history of early and/or high‐grade CRS.5 Additionally, product‐related characteristics may contribute to risk, such as CAR construct design and choice of lymphodepletion regimen.6 Management of ICANS primarily involves supportive care, frequent neurological evaluations, and consultation with neurology. Once symptoms present, neurologic imaging, such as CT, MRI, and EEG, are essential for identifying the cause and confirming the diagnosis of ICANS. For patients who develop moderate to severe ICANS, supportive care and the use of corticosteroids are the mainstays of treatment.5

Neurotoxicity presenting as transverse myelitis is rare; however, its effects can be detrimental and can affect the patient’s overall quality of life. In a case studies published by Sheikh et al.3 and Santomasso et al.,7 patients were treated with high-dose corticosteroids, IVIG, and plasma exchange and experienced improvement in symptoms. In the case presented by Sheikh et al.,3 it took more than 4 months from the time of presentation for the symptoms to improve. Similarly, Nair et al.4 reported on two patients with leukoencephalopathy and quadriplegia who responded to high-dose corticosteroids.

Advanced practice providers play an integral role in the treatment and management of toxicities in patients undergoing CAR T-cell therapies. Early recognition, diagnosis, management, and expert consultation is integral to ensuring positive outcomes for these medically complex patients. Further, the need to increase awareness of rare presentations of ICANS is essential to advancing the expertise in managing these challenging cases and to improving outcomes.

References 

1. Wittibschlager V, Bacher U, Seipel K, et al. CAR T-cell persistence correlates with improved outcome in patients with B-cell lymphoma. Int J Mol Sci. 2023;24:5688. 

1. Siegler EL, Kenderian SS. Neurotoxicity and cytokine release syndrome after chimeric antigen receptor T cell therapy: insights into mechanisms and novel therapies. Front Immunol. 2020;11:1973. 

1. Sheikh S, Mokhtari S, Silverman JA, et al. Transverse myelitis after anti-CD19 directed CAR T cell therapy for relapsed large B cell lymphoma. EJHaem. 2021;3:223-227.

1. Nair R, Drillet G, Lhomme F, et al. Acute leucoencephalomyelopathy and quadriparesis after CAR T-cell therapy. Haematologica. 2021;106:1504-1506.

1. Jain T, Bar M, Kansagra AJ, et al. Use of chimeric antigen receptor T cell therapy in clinical practice for relapsed/refractory aggressive B cell non-Hodgkin lymphoma: an expert panel opinion from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019;25:2305-2321.

1. Santomasso BD, Park JH, Salloum D, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8:958-971.

1. Santomasso BD, Gust J, Perna F. How I treat unique and difficult-to-manage cases of CAR T-cell therapy–associated neurotoxicity. Blood. 2023;141:2443-2451.