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

Abstract

Patients who develop CAR T-cells-related severe cytokine release syndrome (CRS) and immune-effector-cells-associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial-Activation and Stress-Index) score [lactate dehydrogenase (LDH, U/L) x creatinine (mg/dL) / platelets (10^9 cells/L)] is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low platelets 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 two 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-cells 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 three formulas showed similar predictive power for severe CRS and ICANS. However, low platelets 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 (AUC: at lymphodepletion 80.4%, day -1 73.0%, 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-cells-related toxicities.

Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma

“…External validation of these models in independent cohorts is warranted to assess their implementation in routine clinical practice. 32,33 Regarding efficacy, median PFS and OS in the ITT analysis were comparable to the pivotal trials, despite a longer turnaround time in our study. 3,5 Our results were also similar to other real-world data, albeit some differences in patients characteristics and logistical country-specific aspects.…”

Prophylactic Tocilizumab Prior to Anti-CD19 CAR-T Cell Therapy for Non-Hodgkin Lymphoma

“…While tumor burden is associated with risk of severe CRS in NHL, several groups are investigating the use of baseline, pre – lymphodepletion laboratory parameters as risk predictors of CRS and ICANS. More recently, investigators have evaluated the use of the Endothelial Activation and Stress Index (EASIX) [lactate dehydrogenase (U/L(x creatinine (mg/dL)/platelet count (10 9 cells/L)] ( 40 ), with either use of CRP concentration instead of creatinine (modified EASIX, mEASIX) ( 41 ) or in combination with ferritin and CRP concentrations (EASIX-FC) ( 42 ). These modifications of the EASIX score can predict the risk of CRS and) ICANS and mEASIX can also predict disease response ( 41 ).…”

“…More recently, investigators have evaluated the use of the Endothelial Activation and Stress Index (EASIX) [lactate dehydrogenase (U/L(x creatinine (mg/dL)/platelet count (10 9 cells/L)] ( 40 ), with either use of CRP concentration instead of creatinine (modified EASIX, mEASIX) ( 41 ) or in combination with ferritin and CRP concentrations (EASIX-FC) ( 42 ). These modifications of the EASIX score can predict the risk of CRS and) ICANS and mEASIX can also predict disease response ( 41 ). Pre-lymphodepletion risk stratification may permit patient selection for the prescription of pre-infusion prophylactic strategies, including tocilizumab, for patients identified to have high risk of CRS.…”

CAR T Cell Therapy in Hematological Malignancies: Implications of the Tumor Microenvironment and Biomarkers on Efficacy and Toxicity

“…One option is to combine biomarkers into a scoring system. Pennisi et al proposed a modified EASIX (endothelial activation and stress index) score that calculated peri-CAR T cell infusion, this could discriminate patients who developed severe (grade ≥ 3) CRS and ICANS [112]. The EASIX score (lactate dehydrogenase (LDH; U/L) X creatinine (mg/dL)/platelets (PLTs; 109 cells/L)) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation [113].…”