Chimeric Antigen ReceptorT Cell Therapy-Induced Hypophosphatemia (HypoPhos) Due to Renal Phosphate Wasting

Introduction: Chimeric antigen receptor T cell (CAR-T) therapy for refractory malignancies has been a major advance in the field of oncology. Several electrolyte abnormalities related to CAR-T therapy have been reported including hyponatremia, hypokalemia, and hypoPhos. The role of phosphaturia in the pathogenesis of CAR-T related hypoPhos has not been well defined. Case Description: A 36-year-old male with relapsed B-acute lymphoblastic leukemia underwent CAR-T therapy. The patient developed grade 1 cytokine release syndrome (CRS) which was treated with single dose tocilizumab. He developed severe hypoPhos (<1.0 mg/dl) one week later. His fractional excretion of phosphate (FePO4) was initially 36.64% (nl < 20%) and peaked at 116.46%. Fibroblast growth factor 23 (FGF23) was measured daily with initial value <14 pg/ml and peak 31 pg/ml at day 4 day. Markers for CRS are depicted below with serologies in table 1. Oral sodium or potassium phosphate replacement started at day 2, twice or thrice daily (at the discretion of the treating team). While the patient did develop hyponatremia, he did not develop glucosuria, AKI or metabolic acidosis. Discussion: The mechanism of CAR-T induced hypoPhos has not been well defined. It has been speculated that it might be related to increased metabolic consumption of extracellular phosphorus by CAR-T cells, but the potential role of increased renal wasting has not been examined. While animal models of AKI or CKD have shown a relationship between IL-6 induction of FGF23 and subsequent hypoPhos, this has not been shown in CAR-T cell models. We demonstrated that increased renal excretion does play a significant role. Though FGF23 levels increased, they remained within the normal range. Nevertheless, the FEPO4 greater than 100% indicates addition of phosphate to the urine beyond the amount filtered, i.e. tubular secretion, which might be mediated by FGF23. The absence of glucosuria and acidosis suggests that this was not due to diffuse proximal tubular dysfunction. Further study is necessary to define the mechanism(s) underlying renal phosphate wasting with CAR-T therapy.