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

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          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.

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          Blood Advances
          American Society of Hematology
          September 14 2021
          September 14 2021
          September 7 2021
          August 25 2021
          : 5
          : 17
          : 3397-3406
          [1 ]Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
          [2 ]Hematology Service, Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;
          [3 ]Department of Hematology, University Hospital Marqués de Valdecilla – IDIVAL, Santander, Spain;
          [4 ]Department of Epidemiology and Biostatistics,
          [5 ]Lymphoma Service, Department of Medicine, and
          [6 ]Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
          [7 ]Department of Medicine, Weill Cornell Medical College, New York, NY, and
          [8 ]Cellular Therapeutics Center,
          [9 ]Department of Anesthesiology and Critical Care Medicine, and
          [10 ]Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY
          © 2021


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