Factors Predictive Of Car T Cell Associated Hemophagocytic Lymphohistiocytosis (Hlh)

Introduction: HLH is a T cell mediated inflammatory syndrome associated with immune activation and NK cell dysfunction. In the context of CAR T cells, HLH occurs in a subset of those with cytokine release syndrome (CRS), yet predisposing factors are not yet well established. Utilizing our ongoing phase I study of CD22/4-1BB CAR T cells in children and young adults with CD22+ B cell malignancies (NCT02315612), we evaluated patient and product characteristics to elucidate factors associated with HLH. Methods: We retrospectively reviewed multiple variables to identify correlates of HLH in those infused. Definitions for CRS and HLH are in Table 1. Multiple univariate analyses were performed to identify risk factors for HLH; variables with significance were incorporated into a multiple logistic regression model to predict those at risk of HLH-like CRS. Results: 52 of 60 (86.7%) treated subjects developed CRS; 21 (40.4%) of whom subsequently developed HLH. The following factors were associated with HLH: lower baseline blood and marrow NK% and higher CD3% cells; CD4/CD8 T cell selection (TCS) of the apheresis product (which increased CD3 and reduced NK cell populations); and higher IL18. Following infusion, distinct cytokine profiles and prolonged predominance of CD8 T cells distinguished those with HLH from those without it. Multiple logistic regression identified a) use of TCS, b) higher grade CRS and c) high baseline bone marrow T/NK ratio as most predictive of HLH; leading to a model with 75% sensitivity and 80% specificity. Conclusion: Our results provide novel insights into factors associated with CAR T cell related HLH and implicate preexisting T and NK cell populations, baseline cytokines, apheresis selection methodologies and CAR T cell expansion parameters in the pathophysiology. With a goal of earlier intervention to prevent HLH, the predictive model will be prospectively evaluated. Biologic correlative studies and assessment of generalizability in alternate CAR T cell constructs are planned. Citation Format: Daniel A. Lichtenstein, Seth M. Steinberg, Steven L. Highfill, Bonnie Yates, Ping Jin, Jianjian Jin, Sandhya Panch, Haneen Shalabi, David F. Stroncek, Terry J. Fry, Nirali N. Shah. Factors predictive of CAR T cell associated hemophagocytic lymphohistiocytosis (HLH) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4231.