Hypophosphatemia as a Marker for Immune Effector Cell-Associated Neurotoxicity Syndrome in Chimeric Antigen Receptor T Cell Recipients

Background:
Hypophosphatemia is a common electrolyte abnormality in patients receiving chimeric antigen receptor T-cell (CAR-T) therapy. Its relationship with immune effector cell-associated neurotoxicity syndrome (ICANS) remains incompletely understood. This study investigates the incidence, timing, and clinical correlations of hypophosphatemia and its relationship with ICANS.
Methods:
We conducted a retrospective chart review of patients who received CAR-T therapy at an academic center. Hypophosphatemia was defined as <2.5 mg/dL post-CAR-T infusion. The timing of ICANS onset and phosphorus (Pi) nadir were collected. Associations were assessed using chi-square or Fisher’s exact tests. Ordinal logistic regression, linear regression, Cox regression and time-dependent Cox model evaluated the relationship between ICANS and Pi trends.
Results:
Of 186 CAR-T recipients, 75 had non-Hodgkin’s lymphoma (NHL), 103 had multiple myeloma (MM), and 8 had acute lymphoblastic leukemia. Hypophosphatemia occurred in 71.5% (95% CI: 64.4%–77.8%), with an incidence of 82.6% in patients receiving idecabtagene-vicleucel (Abecma) and 75.4% in patients receiving axicabtagene-ciloleucel (Yescarta) (
P
 = 0.002). Among those with hypophosphatemia, mean nadir phosphate was 1.78 mg/dL (95% CI: 1.7–1.84), occurring at a median of 5.94 days post-infusion (95% CI: 5.12–6.7; SD 4.78). Hypophosphatemia was associated with increased ICANS risk (hazard ratio 2.87, 95% CI 1.63–5.1,
P 
= 0.001) and typically preceded ICANS by a median of 2 days (95% CI: 0.83–3.2,
P
< 0.001 Wilcoxon). In NHL patients, lower nadir phosphate predicted higher ICANS grade (
β
 = –1.76,
P
< 0.001). We concluded that Hypophosphatemia is common post-CAR-T and typically occurs within the first week. Its temporal association with ICANS suggests a potential biological link. Hypophosphatemia may serve as an early predictor of ICANS, warranting further study of phosphate correction as a preventive strategy and potentially a predictor marker.