Hypophosphatemia after CAR-T cell therapy: a prospective study of inflammation, tubular injury and phosphate handling.

Abstract

Background Hypophosphatemia is a frequent electrolyte abnormality after chimeric antigen receptor T-cell (CAR-T) therapy, but the clinical and biological factors associated with phosphate decline remain poorly defined. We prospectively evaluated the incidence, determinants, and potential biological associations of hypophosphatemia after CAR-T therapy. Methods We conducted a prospective study including 63 adults with B-cell lymphoma treated with CAR-T therapy between June 2020 and December 2023. Serum phosphate was measured daily during hospitalization. First-morning urine and blood samples were obtained at infusion (D0) and on days +7 (D7) and +14 (D14). Fractional excretion of phosphate (FEPO₄), urine protein-to-creatinine ratio (uPCR), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) were assessed. Patients were stratified according to the presence of moderate hypophosphatemia. Results Hypophosphatemia occurred in 49/63 patients (78%), including 26 (41%) with moderate hypophosphatemia. Median time to phosphate nadir was 6 days. Patients with moderate hypophosphatemia had higher baseline lactate dehydrogenase levels and Endothelial Activation and Stress Index scores, lower phosphate and creatinine levels at infusion, and a higher frequency of prior ifosfamide exposure. Higher uPCR at D7, higher peak interleukin-6 levels and higher FEPO₄ at D7 were associated with lower phosphate nadir values (ρ = -0.55, P < .001; ρ = -0.55, P < .001; and ρ = -0.31, P = .018, respectively). FGF23 levels were not associated with hypophosphatemia in the primary analysis, while PTH showed a modest inverse association with phosphate nadir in exploratory analysis. Moderate hypophosphatemia was associated with inferior overall survival in univariable analysis. Conclusions Hypophosphatemia is common after CAR-T therapy and was associated with systemic inflammation, urinary markers compatible with partial proximal tubular dysfunction and altered renal phosphate handling. Secondary hyperparathyroidism may have contributed in a subset of patients, whereas FGF23 did not appear to be a dominant explanatory pathway in this cohort.