Modified EASIX predicts severe cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells

Abstract

Patients who develop chimeric antigen receptor (CAR) T-cell-related severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase [LDH; U/L] × creatinine [mg/dL]/platelets [PLTs; 109 cells/L]) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX [m-EASIX], which replaces creatinine with CRP [mg/dL]), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve [AUC] at lymphodepletion, 80.4%; at day -1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell-related toxicities.

Graphical abstract

Figure 1.

Association of EASIX/s-EASIX/m-EASIX with severe CRS and severe ICANS. This figure shows a Forest plot for odds ratios (ORs) and 95% confidence intervals (CIs) for prediction of severe CRS (top) and ICANS (bottom) by EASIX/s-EASIX/m-EASIX calculated at preinfusion (lymphodepletion and day −1) and postinfusion (days +1 and +3) time points.

Figure 2.

Prediction of severe CRS and ICANS by EASIX/s-EASIX/m-EASIX. ROC curves are shown at all pre- and postinfusion time points for severe CRS (A-D) and ICANS (E-F). AUCs are calculated for all curves and compared in pairs with ROC tests at all time points.

Figure 3.

Distribution of m-EASIX levels across CRS and ICANS subgroups. The boxplots summarize median and IQR of m-EASIX levels at day of lymphodepletion (A), day −1 (B), day +1 (C), and day +3 (D) for patients presenting with no symptoms (red) or mild (blue) or severe (green) CRS and at day +1 (E) and day + 3 (F) for patients with no symptoms (red) or mild (blue) or severe (green) ICANS. CRS and ICANS were defined mild if grade 1 or 2 and severe if grade 3 to 5.