Title: Neurological complication, possibly related to anti-BCMA CAR-T cell therapy
Submitted by Felipe Peña Muñoz. Clinical Hematology Department, Institut Catala d’Oncologia–Hospitalet, Barcelona, Spain
Physician's expert perspective: Dr. Roser Velasco. Neurology Department, Neuro-oncology Unit, Institut Catala d’Oncologia–Hospitalet, Barcelona, Spain
A 56-year-old female patient with no drug allergies, active smoker, affected of diabetes and latent tuberculosis infection was diagnosed on December 2023 of multiple myeloma IgG kappa ISS 1, ISSR 1. Started 1L treatment DVRd x 6 on 09/01/24 and achieved a strict complete remission. As consolidation treatment she received anti-BCMA CAR T cell therapy infused on 04/07/24.
As a treatment-related complication, she presented with persistent G1 cytokine release syndrome from day +2 to +4 and received tocilizumab in a single dose to control symptoms. She was discharged on day +14 without further complications.
On day +21, she presented with sudden onset of lower back pain and was admitted for assessment and treatment. There were no other referred symptoms at that time. MRI showed no fractures or spinal lesions. The next day she fell on her knees while walking around her room and mentioned weakness in her left limb. After a rapid progression, she was unable to raise both knees and required assistance to walk for the next 48 h. On neurological examination, we also noted proximal paraparesis of the lower limbs with arreflexia and left peripheral facial paralysis associated with proximal paraparesis of both limbs. Brain MRI showed gadolinium enhancement of the right facial nerve. Spinal MRI was unremarkable.
On day +27 a lumbar puncture was performed and empirical IV immunoglobulins and therapeutic acyclovir were started. All cultures and viral PCRs were negative. The CSF showed mild hyperproteinuria (0.58 g/L), 13x 10^6/L leucocytes and normal glucose. CSF flow cytometry showed 11 cells/uL, 75% T lymphocytes. No CAR T cells or myeloma cells were detected in the CSF. High-dose IV dexamethasone (10 mg/6h) was then added to the treatment with rapid tapering, which was stopped after 10 days.
With this information, what would be your diagnostic options?
A. Acute spinal cord compression
B. Neurological Infection
C. Immune-mediated polyradiculoneuropathy
D. Acute medullar ischemia
On day +34 after the CART infusion, the patient showed progressive neurological improvement, was able to get out of bed without assistance and walked without new falls. On day +84 the symptoms were completely resolved. Finally, the patient was diagnosed with Guillain-Barre syndrome motor axonal variant, probably related to CAR-T cell therapy.
At the 3-month follow-up, the patient had regained normal function and independence. The myeloma remains in complete remission.
Expert opinion by Roser Velasco:
Guillain-Barré syndrome (GBS) is a rare neurological disorder characterised by acute immune-mediated peripheral neuropathy. It presents with variable severity and includes subtypes such as acute inflammatory demyelinating polyneuropathy and axonal variants. GBS typically presents with back pain and progressive symmetric muscle weakness starting in the legs and progressing upwards, accompanied by areflexia, sensory changes, autonomic dysfunction and, in severe cases, respiratory failure. Bilateral facial nerve palsy is a common feature, occurring in approximately 50-70% of cases, depending on the subtype.
Reports of GBS following anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy or CD19 CAR-T therapy are limited, but suggest an onset typically a few weeks after infusion. Notable cases include a fatal Miller-Fisher variant with polyradiculoneuritis, encephalopathy and speech disturbance, and a pharyngo-brachial-cervical variant with a favourable outcome. Isolated cranial nerve palsy following anti-BCMA CAR-T cell infusion is a rare (3-9%) early complication, predominantly affecting the facial nerve bilaterally in about one third of patients. Its potential association with underlying GBS warrants consideration in such cases.
Diagnosis of classical GBS relies on clinical presentation, supported by CSF analysis and electrodiagnostic studies. CSF findings of "albuminocytologic dissociation" (elevated protein with normal or mildly increased cell counts) are diagnostic but may be absent in the first three days, appearing in 84% of cases after seven days. Electrodiagnostic studies can differentiate GBS subtypes (demyelinating or axonal), though they may be normal in early stages, necessitating repeat testing after 1–2 weeks in some cases.
Management of CAR-T-associated GBS requires tailored considerations. First, spinal MRI with gadolinium is essential before lumbar puncture to exclude alternative diagnoses such as spinal cord compression, leptomeningeal disease, or infection-related myelopathy. Second, testing for CAR-T cells in blood and CSF may provide insights into this neurotoxicity. Third, high-dose corticosteroids should be considered alongside standard GBS treatments like IV intravenous immunoglobulin or plasma exchange, consistent with management of other immune-mediated GBS forms associated with immunotherapy.
The pathophysiology of CAR-T-associated GBS remains unclear. Direct nerve involvement is unlikely, as no evidence exists of CD19 or BCMA expression or cross-reactivity with peripheral nerve components. Increased CAR-T cell expansion and higher exposure levels are risk factors for facial palsy. Patients in CARTITUDE-4 with cranial nerve palsy demonstrated higher IL-10, IL-2Rα, and CAR-T cell expansion levels than unaffected patients. Unfortunately, no cytokine data was available for the current patient. Immune reactivation phenomena after CAR-T therapy resembling an immune reconstitution syndrome could have played a role in this patient.
Diagnosis of classical GBS is based on clinical presentation, supported by CSF analysis and electrodiagnostic studies. CSF findings of "albuminocytologic dissociation" (elevated protein with normal or slightly elevated cell counts) are diagnostic, but may be absent in the first three days and are present in 84% of cases after seven days. Electrodiagnostic studies can differentiate GBS subtypes (demyelinating or axonal), although they may be normal in the early stages, requiring repeat testing after 1-2 weeks in some cases.
Management of CAR-T-associated GBS requires tailored considerations. First, spinal MRI with gadolinium is essential before lumbar puncture to exclude alternative diagnoses such as spinal cord compression, leptomeningeal disease or infection-related myelopathy. Second, testing for CAR-T cells in blood and CSF may provide insight into this neurotoxicity. Third, high-dose corticosteroids should be considered alongside standard GBS treatments such as intravenous immunoglobulin or plasma exchange, consistent with the management of other immune-mediated forms of GBS associated with immunotherapy.
The pathophysiology of CAR-T-associated GBS remains unclear. Direct nerve involvement is unlikely as there is no evidence of CD19 or BCMA expression or cross-reactivity with peripheral nerve components. Increased CAR T cell expansion and higher exposure levels are risk factors for facial paralysis. Patients in CARTITUDE-4 with cranial nerve palsy had higher levels of IL-10, IL-2Rα and CAR T cell expansion than unaffected patients. Unfortunately, cytokine data were not available for the current patient. Immune reactivation phenomena after CAR-T therapy, similar to immune reconstitution syndrome, may have played a role in this patient.
This case illustrates a favourable outcome in a patient with CAR-T-associated GBS, highlighting the diagnostic challenge of alternative considerations and the need for a high and prompt clinical suspicion. It highlights the importance of documenting and analysing rare but serious neurological adverse events associated with CAR-T therapy. A better understanding of non-ICANS atypical toxicities such as GBS is critical as CAR-T expands into haematological malignancies and potentially autoimmune diseases.
Correct Answer: C
References:
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