Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy

J Clin Oncol. 2022 Feb 1;40(4):369-381. doi: 10.1200/JCO.21.02143. Epub 2021 Dec 3.


Purpose: Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T.

Materials and methods: Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre-CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status.

Results: We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type (P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration.

Conclusion: TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antigens, CD19 / immunology*
  • Biological Products / therapeutic use
  • Biomarkers, Tumor / genetics*
  • DNA Copy Number Variations
  • Female
  • Gene Dosage
  • Gene Expression Profiling
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunotherapy, Adoptive* / adverse effects
  • Immunotherapy, Adoptive* / mortality
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / immunology
  • Lymphoma, B-Cell / mortality
  • Lymphoma, B-Cell / therapy*
  • Male
  • Middle Aged
  • Mutation
  • Predictive Value of Tests
  • Receptors, Antigen, T-Cell / therapeutic use
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / immunology*
  • Retrospective Studies
  • Risk Assessment
  • Risk Factors
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation*
  • Time Factors
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / genetics*


  • Antigens, CD19
  • Biological Products
  • Biomarkers, Tumor
  • CD19 molecule, human
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • tisagenlecleucel
  • axicabtagene ciloleucel