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

Martina Pennisi, Miriam Sanchez-Escamilla, Jessica R. Flynn, Roni Shouval, Ana Alarcon Tomas, Mari Lynn Silverberg, Connie Batlevi, Renier J. Brentjens, Parastoo B. Dahi, Sean M. Devlin, Claudia Diamonte, Sergio Giralt, Elizabeth F. Halton, Tania Jain, Molly Maloy, Elena Mead, Maria Lia Palomba, Josel Ruiz, Bianca Santomasso, Craig S. SauterMichael Scordo, Gunjan L. Shah, Jae H. Park, Lucrecia Yanez San Segundo, Miguel Angel Perales

Research output: Contribution to journalArticlepeer-review

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] 3 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 21, 73.0%; and at day 11, 75.4%). At day 13, 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.

Original languageEnglish (US)
Pages (from-to)3397-3406
Number of pages10
JournalBlood Advances
Volume5
Issue number17
DOIs
StatePublished - Sep 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • Hematology

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