Phosphorus Disruption Is Associated with the Incidence and Severity of Neurotoxicity Symptoms in CD19-Targeted CAR-T Cell Therapy: A Pooled Clinical Trial Analysis

Abstract

Background Hypophosphatemia due to increased cell metabolic activity as seen in refeeding syndrome and sepsis, has a similar neurologic presentation to immune effector cell-associated neurotoxicity syndrome (ICANS), an associated risk of CAR-T cell therapy. CAR-T patients who develop ICANS are observed to have a higher incidence and more severe degrees of hypophosphatemia (Tang et al, 2022). We further explored the association of hypophosphatemia and other electrolyte disturbances with ICANS incidence across pooled CAR-T clinical trial patients to assess how serum electrolytes correlated with risk of ICANS. Methods We analyzed 593 patients with relapsed/refractory B-cell acute lymphoblastic leukemia or non Hodgkin's lymphoma, with ICANS (n=325), and without ICANS (n=268) treated with CD19-targeted CAR-T cell therapy across pooled clinical trial data from the Medidata Enterprise Data Store. Patients were grouped by ICANS status. A Fisher exact test was performed for categorical variables. A Mann-Whitney was performed for numerical variables. Variables of interest were baseline patients characteristics (age, gender, indication) and ICANS status. Common lab values investigated were nadir values and time to nadir for phosphate (Phos), magnesium (Mg), calcium (Ca), and potassium (K), peak value for C-reactive protein (CRP), and creatinine (Cr) at the time of infusion. To assign a hypo- phosphatemia, -kalemia, -magnesemia and -calcemia status to each patient, we used thresholds of <2 mg/dL, 3.5 mmol/L, 1.5 mg/dL and 2.0 mmol/L respectively. We performed a univariable logistic regression with ICANS status as the outcome variable and the following: Baseline value at infusion for Mg, K, Phos, Ca, CrNadir values between day 0 and 14 for Mg, K, Phos, Ca, CrSlope (between baseline and nadir) for Mg, K, Phos, Ca, CrPeak CRP, Cr and Urate between day 0 and 14 The odds ratios were calculated. Kaplan Meier curves were plotted. The log rank test was performed for time to event of ICANS, grouped by hypo- phosphatemia, -kalemia, -magnesemia and -calcemia status. We performed an analysis on the effect of the preemptive use of electrolyte replacement. We defined preemptive use as any electrolyte replacement given to patients either before the occurrence of ICANS or if patients did not get ICANS. For those with hypophosphatemia, we examined the preemptive use of electrolyte replacements for any electrolyte excluding Phos and any electrolyte with Phos. For those 2 groups we compared the rates of ICANS. Results CRS, and hypo- phosphatemia, -kalemia, -magnesemia and -calcemia status were statistically significantly different between ICANS and no ICANS groups. When looking at the nadir values, these 4 electrolyte disturbances were also statistically significant, with lower values associated with ICANS. For the time to nadir, only K was significant and higher for the ICANS group. Peak CRP was also higher for patients with ICANS, but did not meet the 0.05 threshold to be statistically significant. For the univariate logistic regression, variables positively associated with ICANS and significant were peak values for creatinine and CRP, OR of 3.8 (1.6-9.2) and 2.1 (0.9 - 5.0) respectively. Variables negatively associated with ICANS and significant were nadir values for Phos (OR 0.3 (0.1 - 0.8)), K (OR 0.2 (0.1-0.7)), Ca (OR 0.2 (0.1-0.6)), Mg (OR 0.17(0.1-0.5)) and urate (0.3(0.1-1)), and slope for Mg (OR 0.0 (0.0-0.2)). When plotting the Kaplan Meier curves, ICANS seems to develop sooner for patients with either hypo- phosphatemia, -kalemia, -magnesemia or -calcemia and the log rank test showed to be statistically significant (Figure 1). Among the patients with hypophosphatemia, the use of Phos as part of electrolyte replacement reduces the ICANS rate: 52% (0.39-0.65) versus 71% (0.58-0.84) for the electrolyte replacement without Phos. Conclusion Our data demonstrate that ICANS incidence is associated with disruptions in serum phosphorus levels, and that supplementation of phosphorus is able to mitigate the incidence of ICANS as well. Monitoring phosphorus may serve as a useful biomarker for ICANS, while goal directed phosphorus supplementation may serve as an inexpensive and readily available means to treat or prevent ICANS. Prospective studies with goal-directed phosphorus repletion are necessary to further study the therapeutic impact of electrolyte supplementation on ICANS incidence and severity.