Phosphorous Monitoring May Be Optimal for Detecting Serious ICANS in Patients Receiving CAR T-Cell Therapy

Theodore Scott Nowicki, MD, PhD

Monitoring a patient’s phosphorus levels may be an effective way to anticipate the development of severe immune effector cell–associated neurotoxicity syndrome (ICANS) following CAR T-cell therapy, according to findings published in the American Association for Cancer Research Journal. The results suggest that patients who experience decreases in extracellular phosphorous are at an increased risk of developing hypophosphatemia and ICANS.

In individual patients, investigators observed that decreased in serum phosphorus within the threshold for clinical hypophosphatemia also overlapped with the onset of ICANS. Based on this observation, a linear mixed-effects model was developed, with serum phosphorus representing the outcome variable, and time from CAR T-cell infusion and ICANS grade/CARTOX-10 score representing the fixed effects of the model.

In this model, ICANS grade was negatively associated with serum phosphorous, and each unit decreased in ICANS grade was linked to a 0.29 mg/dL decrease in phosphorous (P < .001). CARTOX-10 score was positively associated with serum phosphorus, and each point of reduction corresponded to a 0.11 mg/dL decreased on phosphorous (P = .003).

The relationship between phosphorous and both ICANS and CARTOX-10 diminished the longer the patient was post-infusion, indicating that the active agents were the drivers, or this serum phosphorus changes and consequent neurotoxicity.

“Despite their clinical effectiveness, the serious [adverse] effects of CAR T-cell therapies often require escalation to an intensive care setting,” wrote Theodore Scott Nowicki, MD, PhD, assistant professor-in-residence in the Departments of Pediatrics (Hematology/Oncology) and Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, UCLA, and coinvestigators in the paper. “ICANS affects approximately 50% of all CAR T-cell recipients [and] the need for biomarkers of ICANS represents an important area of potential improvement in these therapeutic protocols.”

ICANS, commonly occurs concomitantly with cytokine release syndrome and is characterized by confusion, delirium, aphasia, impaired motor skills, and somnolence. In severe cases, seizures and comas may occur as well. Targeted therapies, such as anti-IL6 tocilizumab (Actemra), may be used to managed cytokine release syndrome (CRS), the bulk of ICANS management is supportive care with nonspecific immunosuppression—which may reduce the efficacy of CAR T-cell therapy. Because of this, authors identified an unmet need for predictive markers for ICANS.

Hypophosphatemia is a clinical anomaly which has been observed in patients who received CAR T-cell therapies or adoptive cell therapies. Hypophosphatemia is characterized by weakness, confusion, altered mental status, seizure, and coma. It is also associated with an acute increase in metabolic demand, which as with sepsis and refeeding syndrome. Hypophosphatemia occurs when cells suddenly need to consume high amounts of phosphate to synthesize certain substrates, this sudden redistribution of extracellular phosphorus results in these striking neurologic symptoms for patients.

Because the physical manifestations of hypophosphatemia manifest like ICANS, investigators hypothesized that an increase of metabolic activity and consequent extracellular phosphate consumption might be at play with both adverse events. They therefore sought to determine whether CAR T-cell engagement with targeted antigens results in an increased in metabolic activity and extracellular phosphate consumption.

Investigators retrospectively examined data from 77 patients who received CD19-targeted CAR T-cell therapy at UCLA. In this cohort, 23 patients (30%) developed ICANS following treatment. The median onset time was 5-days post infusion. Among these patients, 17 (86.7%) developed severe ICANS, defined as grade 2 or worse severity. ICANS development or severity was not linked to any patient characteristics, disease characteristics, or infusion product. Moreover, 69% of all patients developed ICANs.

Hypophosphatemia, defined as serum phosphate concentrations lower than 2mg/dL, was significantly associated with ICANS (P = .0003). The median time to nadir for phosphorous was 5 days, which coincided with the median onset time of ICANS development. In addition, the median nadir serum phosphorus of the ICANS group was significantly lower than among those who did not develop ICANs (1.391 mg/dL vs 2.130 mg/dL; P = .002).

“In a clinical setting, decreases in patient serum phosphorus levels correlated with the incidence and severity of ICANS,” study authors concluded. “These results have implications for monitoring for the development of ICANS in the growing number of patients receiving adoptive cell therapies for cancer.”

Reference

Tang JP, Peters CW, Quiros C, et al. Hypophosphatemia due to increased effector cell metabolic activity is associated with neurotoxicity symptoms in CD19-targeted CAR T-cell therapy. Cancer Immunol Res. Published online October 19, 2022. doi:10.1158/2326-6066.CIR-22-0418