Hypophosphatemia Correction Reduces ICANS Incidence and Duration in CAR T-cell Therapy: A Pooled Clinical Trial Analysis

Abstract

A common complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR T-cell therapy across multiple clinical trials between 2015 and 2020. In addition to clinical toxicities experienced by the patients, we also interrogated the impact of serum electrolyte data and repletion of corresponding electrolyte deficiencies with ICANS incidence, severity, and duration. Hypophosphatemia was a common occurrence in CAR T-cell recipients and the only electrolyte derangement associated with a significantly higher cumulative incidence of ICANS. Moreover, phosphorus repletion in patients with hypophosphatemia was associated with significantly decreased ICANS incidence and duration. Hypophosphatemia was uniquely associated with encephalopathy neurological adverse events, which also showed the strongest positive correlation with both ICANS and cytokine release syndrome severity. These findings suggest that serum phosphorus could be a reliable biomarker for ICANS, and expeditious, goal-directed phosphorus repletion in response to serum hypophosphatemia could be a safe, inexpensive, and widely available intervention for such patients.

Significance: Herein we show that phosphorus repletion in patients with hypophosphatemia receiving anti-CD19 chimeric antigen receptor T-cell therapeutics was associated with significantly decreased immune effector cell-associated neurotoxicity syndrome (ICANS) incidence and symptom duration. Given the significant morbidity associated with ICANS and lack of targeted interventions, hypophosphatemia may serve as both a useful biomarker and an inexpensive intervention for ICANS.

Figure 1

Incidence of ICANS in patients stratified by the presence or absence of electrolyte derangements. Kaplan–Meier analyses comparing time to ICANS for patients stratified by the presence or absence of electrolyte derangements including (A) hypophosphatemia, (B) hypokalemia, (C) hypomagnesemia, and (D) hypocalcemia. Shaded area represents the upper and lower bounds of the 95% confidence interval (CI).

Figure 2

ICANS incidence and symptom duration in patients with various electrolyte derangements stratified by receipt of any repletion of the deficient electrolyte. ICANS incidence (top row, error bars represent 95% confidence interval (CI) in patients with (A) serum hypophosphatemia, (B) serum hypokalemia, (C) serum hypomagnesemia, and (D) serum hypocalcemia, stratified by receipt of any electrolyte products containing the deficient electrolyte, from time of CAR T-cell infusion (day 0) until either ICANS symptom onset or day +14. ICANS symptom duration (represented as mean ± SEM) in patients with (E) hypophosphatemia or (F) hypocalcemia stratified by receipt of any electrolyte products containing the deficient electrolyte, from time of CAR T-cell infusion (day 0) until either ICANS symptom onset or day +14. G, ICANS symptom duration in patients with serum hypocalcemia stratified by no repletion (n = 28), any calcium repletion (n = 21), calcium and phosphorus repletion (n = 19), and calcium repletion containing no phosphorus (n = 2). H, ICANS symptom duration in patients with hypokalemia (H) or hypomagnesemia (I) stratified by receipt of any electrolyte products containing the deficient electrolyte, from time of CAR T-cell infusion (day 0) until either ICANS symptom onset or day +14. *, P < 0.05; **, P < 0.01; Fisher exact test for ICANS incidence, unpaired t test for ICANS symptom duration.

Figure 3

Correlation between ICANS, CRS, and various electrolyte derangements with categories of neurological adverse events reported in CAR T-cell recipients. Data are represented as a bar graph showing Spearman rank correlation. Solid bars represent P < 0.05, and translucent bars represent P > 0.05.