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

2021; Elsevier BV; Volume: 5; Issue: 17 Linguagem: Inglês

10.1182/bloodadvances.2020003885

2473-9537

Martina Pennisi, Miriam Sánchez‐Escamilla, Jessica Flynn, Roni Shouval, Ana Alarcón Tomás, Mari Lynn Silverberg, Connie Lee Batlevi, Renier J. Brentjens, Parastoo B. Dahi, Sean M. Devlin, Claudia Diamonte, Sergio Giralt, Elizabeth Halton, Tania Jain, Molly Maloy, Elena Mead, Maria Lia Palomba, Josel D. Ruiz, Bianca Santomasso, Craig S. Sauter, Michael Scordo, Gunjan L. Shah, Jae H. Park, Lucrecia Yáñez, Miguel-Ángel Perales,

CAR-T cell therapy research

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.