Predictors of Cytokine Release Syndrome and Neurotoxicity in Patients with Large B-Cell Lymphoma and Their Impact on Survival
Authors: Shouval Roni , Strouse Christopher , Kim Soyoung , Oloyede Temitope , Ahmed Sairah , Awan Farrukh T. , Bachanova Veronika , Badar Talha , Barba Pere , Beitinjaneh Amer M. , Cashen Amanda F , Dholaria Bhagirathbhai , Elsawy Mahmoud , Ganguly Siddhartha , Ramakrishnan Geethakumari Praveen , Greenbaum Uri , Hashmi Hamza , Hill Laquisa C. , Jain Michael D. , Jain Tania , Kebriaei Partow , Kittai Adam S , Locke Frederick L. , Lulla Premal D. , Mead Elena , McGuirk Joseph P , Mussetti Alberto , Nishihori Taiga , Olson Amanda L. , Pennisi Martina , Perales Miguel-Angel , Riedell Peter A. , Saber Wael , Mirza Sayeef , Magalhaes-Silverman Margarida , Shpall Elizabeth J. , Sorror Mohamed , Wudhikarn Kitsada , Turtle Cameron J. , Pasquini Marcelo , Moskop Amy 
Published: December 2023

Background: Autologous CAR-T therapy targeting CD19 is an effective treatment for relapsed or refractory large B-cell lymphoma (LBCL). However, morbidity and mortality related to CAR-T toxicity remain significant concerns. This study aims to evaluate the patterns, risk factors, and implications of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19-CAR-T therapy in LBCL.
Methods: This retrospective analysis includes 1916 LBCL patients treated with CD19-CAR-T cell therapy (axicabtagene-ciloleucel [axi-cel] 75% and tisagenlecleucel 25%) between 2018 and 2020 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patient demographics, baseline characteristics, treatment-related variables, and clinical outcomes were collected. The incidence, severity and timing of onset of CRS and ICANS (according to median time to onset) were analyzed, factors associated with these outcomes and their impact on overall survival as time dependent covariates were done using Cox Regression multivariate analyses.
Results: The median age of the patients was 64 years, with a majority having a Karnofsky performance status (KPS) below 90% (61%) and not receiving bridging therapy (67%). CRS was observed in 75.1% of patients, with 9% experiencing severe CRS (grades ≥ 3). Similarly, 43% of patients experienced ICANS, with 20% having severe ICANS (grade ≥ 3). The median time to toxicity was shorter for CRS (4 days) compared to ICANS (7 days). Nearly all the patients who developed ICANS also experienced CRS (98%; ), and the correlation between these two events and respective severities are shown in the Figure 1a. In the multivariate analyses, factors associated with development of CRS were gender (women, Odds ratio [OR] 1.39, 95% confidence interval [CI] 1.10- 1.76, p=0.006), high LDH at time of infusion (OR 1.56; 95% CI 1.22 - 2.00, p=0.002) and product (axi-cel OR 4.60, 95% CI 3.56 -5.81, p&lt;0.001). Factors associated with the development of ICANS included age (&gt; 65 years, OR 1.83; 1.50-2.24, p&lt;0.001), KPS (&lt;80%, OR 2.48; 1.88-3.27, p&lt;0.001), disease status at infusion (treatment resistant disease, OR 1.98; 1.09-3.58, p=0.024; and untreated relapse OR 2.62, 1.35-5.10, p=0.004) and product (axi-cel, OR 5.85; 4.47-7.64, p&lt;0.0001). Factors associated with severe and early onset CRS and ICANS are listed in the table below.
The median follow-up of 14.2 months, the estimated 12-month overall survival, progression-free survival (PFS), and treatment-related mortality were 61.6% (95% CI: 59.4-63.9), 42.2% (39.9-44.5), and 4.3% (3.4-5.3), respectively. Overall CRS, early onset CRS and overall ICANS were not associated with higher mortality, however grade &gt;3 CRS (HR 1.79; 1.41-2.28, p&lt;0.001), grade &gt;3 ICANS (hazard ratio [HR] 1.34; 95% CI 1.13-1.59, p=0.002) and early onset ICANS (&lt;7 days, HR 1.23; 1.05-1.44, p=0.01) were associated with higher mortality. The impact of severe CRS on survival are shown in the landmark analysis at 30 days from infusion in the figure 1B.
Conclusion: In the largest analysis of CD19-CAR-T cell therapy toxicities to date, we observed a high burden of CRS and ICANS among LBCL patients. The CAR T cell product type was consistently associated with higher incidence, shorter onset and higher severity of both toxicities. High LDH, older age and low performance score also influence the severity and onset of these outcomes. Additionally, patients who developed higher grades of CRS/ICANS and earlier onset ICANS had a higher mortality, stressing the need to develop novel strategies to mitigate the incidence and optimize management of these patients to improve their outcomes.