Management of prolonged delirium in the hospital after CAR T-cell therapy (CAR-T): Targeting prolonged neuroinflammation

Virtual

Presenting Author(s)

TZ

Tyler Zahrli, MD, MA

Consultation-Liaison Psychiatry Fellow
Stanford University
Menlo Park, California

Co-Author(s)

Daniel Fishman, MD (he/him/his)

Clinical Assistant Professor
Stanford University
Mountain View, California
Sheila Lahijani, MD, FACLP

Associate Clinical Professor
Stanford University School of Medicine
Palo Alto, California

Abstract:

Background: Chimeric antigen receptor T-cell therapy (CAR-T) is a novel, potentially curative, treatment for patients with certain relapsed hematological cancers. CAR-T is associated with high prevalence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). While there are management protocols for CRS and ICANS, there is limited published data on managing neuropsychiatric complications, including neurotoxicity-mediated delirium. Typically, delirium occurs in the context of ICANS, with symptoms improving after the neurotoxicity resolves; however, prolonged cognitive changes can occur.

Methods: I will discuss a complex case seen by inpatient psycho-oncology of persistent cognitive changes and sustained delirium post CAR-T in an elderly patient with a sustained pro-inflammatory response. The authors completed a literature review to provide treatment recommendations to pharmacologically target suspected psychiatric sequela and a sustained pro-inflammatory response.

Results: Patient is an 83-year-old male with Stage IV DLBCL who received CAR-T via axicabtagene ciloleucel. His psychiatric history included only mild impairment on cognitive testing. Patient was considered high risk for CRS and ICANS due to elevated baseline CRP and ferritin. Two days after CAR-T infusion, the patient developed CRS and ICANS, with management per institutional guidelines. There were no acute imaging findings or seizures. The patient demonstrated evidence of delirium for several weeks post-infusion and had paradoxical effects to psychoactive medications. About six weeks post-infusion, the patient continued to have delirium and developed new onset escalation of inflammatory markers, leukocytosis, and elevated ferritin and CRP. No coinciding source of infection or evidence of persistent CAR-T activity was identified. This patient had persistent symptoms of delirium and a newly assessed neurocognitive disorder while remaining in a pro-inflammatory state; therefore, treatment recommendations focused on improving cognition and targeting suspected neuroinflammation.

Discussion: Psycho-oncology had concerns of sustained neuroinflammation at least temporally related to CAR-T. Since CAR-T is theorized to increase glutamate, psycho-oncology recommended treatment modalities to decrease such effects. The patient had paradoxical effects from dopamine modulators; therefore, we recommended starting the patient on guanfacine to decrease noradrenergic tone, mitigating both anxious distress and neuroinflammation. The patient was started on donepezil to correct the theoretical deficiency of acetylcholine, stimulating nicotinic receptors essential to working memory, and reducing activation of microglial cells and astrocytes. Thirdly, we recommended memantine to decrease cortical glutamatergic activity in the setting of neuroinflammation. Our patient demonstrated overall positive findings on mental status exam.

Conclusions: There are no published guidelines on managing patients with prolonged delirium post CAR-T. Our patient was treated based on a theoretical approach previously described to manage cognitive changes and neuroinflammation in other patient populations. Our two goals were to attenuate neurocognitive impairment post-CAR-T infusion and mitigate contribution from sustained proinflammatory response. More evidence is needed to guide practitioners managing these complex neuropsychiatric presentations.

References:

Arnsten A, Ishizawa Y, and Xie Z. Scientific rationale for the use of alpha2A-adrenoceptor agonists in treatment neuroinflammatory cognitive disorders. Molecular Psychiatry. 2023.

Castaneda-Puglianini O, Chavez JC. Assessing and Management of Neurotoxicity After CAR-T Therapy in Diffuse Large B-Cell Lymphoma. J Blood Med. 2021 Aug 24;12:775-783.

Presentation Eligibility: Not previously published or presented.

Diversity, Equity, and Inclusion: This case and literature review outlines treatment recommendations for patients who have prolonged cognitive changes and a sustained pro-inflammatory response after receiving chimeric antigen receptor T-cell therapy (CAR-T), which is a topic not currently described in the psycho-oncology literature.