Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy

N Engl J Med. 2024 Jun 13;390(22):2047-2060. doi: 10.1056/NEJMoa2401361.


Background: The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.

Methods: We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.

Results: A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.

Conclusions: Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

Publication types

  • Case Reports

MeSH terms

  • Antineoplastic Agents, Immunological* / adverse effects
  • Antineoplastic Agents, Immunological* / therapeutic use
  • Biological Products / adverse effects
  • Biological Products / therapeutic use
  • Clonal Hematopoiesis
  • Female
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / immunology
  • Humans
  • Immunotherapy, Adoptive* / adverse effects
  • Lymphoma, Large B-Cell, Diffuse* / genetics
  • Lymphoma, Large B-Cell, Diffuse* / immunology
  • Lymphoma, Large B-Cell, Diffuse* / therapy
  • Lymphoma, T-Cell* / etiology
  • Lymphoma, T-Cell* / genetics
  • Lymphoma, T-Cell* / immunology
  • Lymphoma, T-Cell* / therapy
  • Middle Aged
  • Neoplasms, Second Primary* / etiology
  • Neoplasms, Second Primary* / genetics
  • Receptors, Chimeric Antigen* / immunology
  • Receptors, Chimeric Antigen* / therapeutic use
  • Virus Integration


  • axicabtagene ciloleucel
  • Biological Products
  • Receptors, Chimeric Antigen
  • Antineoplastic Agents, Immunological