As more pediatric patients are being treated with chimeric antigen receptor (CAR) T-cell therapy, researchers at the Children’s Hospital of Philadelphia (CHOP) have described new, very rare toxicities of paraparesis and quadriparesis. In a paper published in Blood, the researchers described five such clinical cases. They also showed that these toxicities do not appear to be due to inflammation.
Some patients infused with CAR T cells develop immune effector cell-associated neurotoxicity syndrome (ICANS). Although the pathophysiology of ICANS is not well understood, it is thought to be inflammation based and related to excessive cytokine production when the body is exposed to activated CAR T cells. Most cases of ICANS are mild, but it can be a potentially severe and even fatal adverse event (AE). ICANS is characterized by acute neurologic symptoms that occur after a CAR T-cell infusion and can manifest as a range of clinical symptoms from mild to severe encephalopathy, seizures, focal neurologic deficits, and fatal cerebral edema.
“The hypothesized mechanism of ICANS is that it is an inflammatory, cytokine-related condition that is associated with endothelial dysfunction. ICANS is associated with severe cytokine release syndrome (CRS) and typically occurs following CRS,” said study author Caroline Diorio, MD, a pediatric clinician scientist at the Cancer Center at CHOP.
“However, the term ICANS encompasses a wide array of neurologic symptoms from mild confusion to seizures, cerebral edema, and coma. These cases reinforce the idea that this array of symptoms may represent a subset of ICANS with differing pathophysiologies,” Dr. Diorio added.
In the current study, Dr. Diorio and her colleagues described the clinical course of five children with B-cell acute lymphoblastic leukemia (B-ALL) who developed acute onset of quadriparesis or paraparesis associated with abnormal brain and/or spine neuroimaging after infusion of CD19 or CD22-directed CAR T-cell therapy, out of approximately 500 treated at CHOP to date. Patients were 34 months, 7 years, 7 years, 13 years, and 14 years of age, and all had relapsed or refractory disease. Three patients were treated with CD19-directed CAR T-cell therapy and two with CD22-directed CAR T-cell therapy. These CAR T-cell–associated AEs were not previously reported in children. In one child, an alternative cause of possible cytomegalovirus myelitis was identified; however, no cause was identified in the others. Multiple treatment strategies were trialed without evidence of significant improvement. Four of the patients died from progressive leukemia.
“We think it is very important to better understand the mechanism of ICANS so we can prevent and treat it, and to think about specific ICANS phenomena when we try to understand pathophysiology,” Dr. Diorio said. “CAR T-cell therapy has been lifesaving for many patients, and we want to make the administration of CAR-T as safe as possible.”
Postmortem examinations were performed on two patients — an autopsy of the spinal cord of one 7-year-old patient and a complete autopsy of the second 7-year-old patient. Both cases showed leukoencephalopathy or leukomyelopathy and an absence of lymphocytic infiltrates. Cerebrospinal fluid (CSF) analyses via flow cytometry from two other patients were performed and compared to control CSF samples from patients who also received CAR T-cell therapy but did not have ICANS symptoms.
From either the autopsy analyses or the CSF flow cytometry analyses, the study authors were unable to identify an association between an inflammatory lymphocyte population and paresis development.
The authors also analyzed cryopreserved CSF from four of the patients and compared these to 150 control CSF samples from patients who also received CAR T-cell therapy but did not have paresis symptoms. Patients with paresis had lower levels of pro-inflammatory cytokines, including interferon gamma, CCL17, CCL23, and CXCL10, compared to the control patients. The two most highly differentially expressed cytokines were interferon gamma and CCL17 and were notably lower among the four patients with paresis compared to 78 patients who developed other symptoms of ICANS but not paresis (p=0.067 and p=0.017, respectively, for the two cytokines).
“We were very surprised that we were unable to find evidence of inflammation contributing to the paresis pathophysiology in our patients. This finding helps us think about patients with ICANS differently. Different phenomenology of ICANS may have unique pathophysiology,” Dr. Diorio said.
“Other cases of paraparesis and quadriparesis have been reported in adult patients; however, in these cases the findings were associated with inflammation. Because this is such a rare phenomenon, it is hard to generalize and say that this is an age-related issue,” she added.
As a follow-up to the current study, Dr. Diorio and her colleagues are now assessing the rates of ICANS among all of their patients at CHOP treated with CAR T-cell therapy to see if they can better identify clinical, laboratory, and biologic risk factors associated with the development of ICANS.
In parallel, they are studying patient, tumor, and CAR T-cell target-related factors that may contribute to various ICANS phenomena as well as the CSF metabolic profiles of patients who received CAR T-cell therapy to understand if there may be a metabolic contributor to different ICANS phenotypes.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Diorio C, Hernandez-Miyares L, Espinoza BA, et al. Quadriparesis and paraparesis following chimeric antigen receptor T-cell (CART) therapy in children and adolescents [published online ahead of print, 2024 June 21]. Blood. doi: 10.1182/blood.2024023933.
