{
  "abstract": "Background Recent data have suggested that germline genetic aberrations can affect outcomes in patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CART). However, a comprehensive analysis of germline determinants of response and toxicity after CART has not yet been described.Methods Genome-wide genotyping was performed in 170 patients with LBCL treated with standard of care axicabtagene ciloleucel. Polygenic risk score instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice-2. Exploratory gene-based and genome-wide association study analyses were performed. Genetic ancestry of the patients with LBCL was estimated using ADMIXTURE. Analysis was conducted to identify genetic risk of toxicity and efficacy endpoints.Results Increasing PRS for monocyte count was associated with increased risk of cytokine release syndrome of any grade (OR 2.49, 95% CI 1.18 to 5.25, p=0.016). Similarly, genetically predicted interleukin (IL)-1Rα and (IL)-27 levels were decreased (p=0.002) and increased (p=0.012) in patients with G3-4 day 30 cytopenia, respectively. The latter was also associated with variation in the hemophagocytic lymphohistiocytosis-related gene RAB27A (p=0.041). Genome-wide significant (p<5×10−8) variants were identified in association with progression-free and overall survival, including SPOCK1, SLC28A2-AS1 and DUOX1. No significant differences in outcomes were observed based on ancestry, except for a decrease in risk for D30 G3-4 cytopenia for patients of European ancestry (p=0.026).Conclusion Germline genetic aberrations relevant to myeloid cell biology can predict toxicity and efficacy of CART in patients with LBCL. Elucidating such intrinsic determinants may help improve patient selection and develop strategies to enhance the therapeutic index of CART.",
  "authors": [
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Paolo Strati"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Amanda Brandt"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Anath C Lionel"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Jared Henderson"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Jason R Westin"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Sherry Adkins"
    },
    {
      "affiliations": [
        "Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Elizabeth J Shpall"
    },
    {
      "affiliations": [
        "Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Partow Kebriaei"
    },
    {
      "affiliations": [
        "Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Jeremy Ramdial"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
        "Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Neeraj Saini"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
        "Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Sairah Ahmed"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Christopher Flowers"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Sattva S Neelapu"
    },
    {
      "affiliations": [
        "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Michelle A T Hildebrandt"
    }
  ],
  "title": "Germline determinants of toxicity and efficacy in patients with large B-cell lymphoma treated with CAR T-cell therapy",
  "uid": "5b67aea8-94bc-597b-9ac5-c28eade9b2b6"
}