CAR T-cell therapy-related neurotoxicity linked to low blood phosphate levels
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Researchers have discovered a link between neurotoxicity related to chimeric antigen receptor T-cell therapy and development of subsequent hypophosphatemia.
Results of their prospective analysis, published in Cancer Immunology Research, suggest incidence and severity of CAR T-cell therapy complication known as immune effector cell-associated neurotoxicity syndrome (ICANS) are associated with decreasing blood phosphate levels.
Background
The impetus for the study arose from the clinical observation of one patient who received CAR T-cell therapy at University of California, Los Angeles and developed severe ICANS related to the treatment, according to Theodore S. Nowicki, MD, assistant professor-in-residence in the departments of pediatrics (hematology/oncology) and microbiology immunology and molecular genetics at UCLA’s David Geffen School of Medicine.
"We noticed that one patient had profound low blood phosphate levels that were quite refractory to repletion,” he told Healio. “As this person’s neurological symptoms improved, her phosphate levels also stabilized.”
Having observed this phenomenon, Nowicki looked at charts of previous CAR-T recipients who developed ICANS and noticed the same pattern of decreasing phosphate levels.
Knowing that CAR T cells cause an increase in metabolic consumption of phosphate in the body, he and his group decided to investigate a potential correlation between hypophosphatemia and emergence of ICANS after the administration of CAR T cells.
Methodology
Nowicki and colleagues first examined whether CAR T-cell activity resulted in increased extracellular phosphate consumption by co-culturing lymphoma cells that expressed CD19 along with CD19-targeted CAR T cells.
The investigators then conducted a retrospective cohort study of 77 patients to identify any association between hypophosphatemia and the emergence of ICANS after CAR T-cell therapy. The analysis included patients with B-cell malignancies who received CD19-targeted CAR-T at UCLA between March 2018 and July 2020.
Key findings
The investigators noted an association between lipoma cell death and reduced phosphate concatenations in cultured media also containing CD19-directed CAR T cells. Additionally, CAR T cells co-cultured with CD19-positive lymphoma cells consumed significantly more phosphate than when cultured alone.
Twenty-three patients (30%) in the clinical cohort developed ICANS after CAR T-cell therapy, with 17 patients (87%) experiencing severe ICANS of grade 2 or higher.
The researchers found a significant association between low blood phosphate levels and the development of ICANS (P = .0003). Ninety-one percent of patients with ICANS after CAR-T infusion had concurrent hypophosphatemia; conversely, only 46% of patients who did not experience ICANS had concurrent hypophosphatemia.
Median time to the lowest blood phosphate levels occurred 5 days after CAR T-cell infusion, which coincided with the median time to onset of ICANS in the study cohort.
Investigators observed no significant differences in ICANS severity regardless of blood phosphate levels. However, the researchers noted that patients with hypophosphatemia experienced significantly longer ICANS (mean duration, 6.5 days vs. 1 day; P = .008) than those who had phosphate levels within the range of normal.
Clinical implications
Researchers did not design the study to determine whether hypophosphatemia caused ICANS, which is the subject of future larger prospective study Nowicki and colleagues are exploring.
“Our results indicate there is at least a correlative temporal association between hypophosphatemia and the incidence of neurotoxicity,” he told Healio. “We can't say this is a causative phenomenon, but this is something worthy of further study and that we will be focusing on.”
A useful implication of the results is that clinicians now have another surrogate biomarker to monitor patients after administration of CAR T cells, Nowicki said.
“This may serve as a warning sign of potential neurotoxicity when phosphate levels drop,” he noted. “If future studies can establish a causative relationship, it will have a significant impact on how this condition is managed or even prevented.”
For more information :
Theodore S. Nowicki, MD, can be reached at Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 12-159 Factor Building, 10833 Le Conte Ave., Los Angeles, CA 90095; email: tnowicki@mednet.ucla.edu.
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