On 12 June 2024, Dr. Mark P. Hamilton and colleagues from the Stanford University in Stanford, CA, US described in The New England Journal of Medicine the risk of second cancers in 724 recipients of chimeric antigen receptor (CAR) T-cell therapy who were treated in their institution. The authors report a relatively low incidence of second cancers, but describe a 59-year-old woman in whom a lethal Epstein–Barr virus (EBV)–positive T-cell lymphoma developed 54 days after she received a CD19-targeting CAR T-cell infusion for EBV-positive diffuse large B-cell lymphoma (DLBCL).
DLBCL and T-cell lymphoma shared identical DNMT3A and TET2 mutations, a finding that suggests independent derivation from preexisting clonal haematopoiesis. The authors found no evidence of CAR vector integration in the T-cell lymphoma and conclude that it was not directly related to CAR T-cell therapy.
In a separate article, published also on 12 June 2024 in The New England Journal of Medicine, Dr. Metin Ozdemirli of the MedStar Georgetown University Hospital in Washington, DC, US, and colleagues described a 71-year-old woman in whom an uncommon T-cell lymphoma subtype developed 5 months after she had received a B-cell maturation antigen (BCMA)-targeting CAR T-cell infusion for multiple myeloma.
T-cell lymphoma harboured a CAR vector integration in the second intron of SSU72, a gene with roles in T-cell homeostasis. However, the authors found no evidence that the insertion affected SSU72 mRNA expression and identified other genetic aberrations that plausibly drove the neoplasm. Ascertainment of whether a precursor clone was present before transduction was not possible. Overall, the evidence of viral vector integration and the development of T-cell lymphoma 5 months after CAR T-cell infusion are suggestive of a causal link to CAR T-cell therapy.
In an accompanied editorial article, Drs. Emily Mitchell and George S. Vassiliou of the University of Cambridge in Cambridge, UK wrote that side effects can arise as a direct result of receipt of CAR T-cells or from the cytotoxic and immunosuppressive regimens used to administer CAR T-cells safely. Acute adverse effects include cytokine release syndrome, neurotoxicity syndrome, cytopenia, and infection. The main potential long-term risk is the occurrence of second cancers.
Available data suggest that the risk of a second cancer is not higher than expected among patients with substantial previous exposure to chemotherapy. However, the 20 to 25 reported cases of T-cell cancer are attracting particular interest owing to the possibility of a direct causal link to CAR therapy that would mirror cancer arising from genetically modified haematopoietic stem cells that were used to treat inherited immunodeficiencies.
Beyond the risks associated with the cytotoxic and immunosuppressive regimens that accompany CAR therapies, the treatment could theoretically lead to T-cell cancer in at least three other ways: as a consequence of CAR vector integration into a cancer gene, as a result of genetic or epigenetic changes occurring during ex vivo T-cell expansion, and from excessive antigen-driven proliferation of T-cells. Current understanding of the relevance of these processes remains poor and is compounded by the possibility that harvested T-cells may already harbour cancer-associated somatic variants that make their malignant progression more likely.
Thousands of CAR therapy recipients must have harboured preexisting clones, providing considerable reassurance that clonal haematopoiesis is not associated with a substantially increased risk of T-cell cancer or other second haematologic malignancy. Nevertheless, despite the lack of a clear aetiologic path, the case reported by Ozdemirli et al. shows that CAR T-cells themselves can occasionally progress to T-cell lymphoma, the risk of which may be higher when premalignant T-cell clones are present before harvest. Similarly, the findings by Hamilton et al. suggest the possibility that EBV-positive lymphoid malignancy may be more likely to arise from premalignant or clonal haematopoiesis clones after CAR T-cell therapy.
Given the paucity of long-term outcome data and the continuing evolution of CAR T-cells and other cellular therapies for both malignant and non-malignant conditions, the risk of CAR-induced second cancers must continue to be closely scrutinised. In addition to current best practice, screening for preexisting clonal haematopoiesis mutations, including those affecting genes linked to mature T-cell cancer, should be considered.
Nonrelapse mortality after CAR T-cell therapy
In a systematic review and meta-analysis, published on 8 July 2024 in the Nature Medicine, Dr. Kai Rejeski of the Department of Medicine III—Hematology/Oncology, LMU University Hospital, LMU Munich in Munich, Germany and colleagues searched MEDLINE, Embase and Cochrane for reports of nonrelapse mortality after CAR T-cell therapy in patients with lymphoma and multiple myeloma up to March 2024. They identified 7604 patients across 18 clinical trials and 28 real-world studies.
Nonrelapse mortality point estimates were highest in patients with mantle-cell lymphoma (10.6%), followed by multiple myeloma (8.0%), large B-cell lymphoma (6.1%) and indolent lymphoma (5.7%). Entity-specific meta-regression models for large B-cell lymphoma and multiple myeloma revealed that axicabtagene ciloleucel and ciltacabtagene autoleucel were independently associated with increased nonrelapse mortality point estimates.
Of 574 reported nonrelapse deaths, over half were attributed to infections (50.9%), followed by other malignancies (7.8%) and cardiovascular/respiratory events (7.3%). Conversely, the CAR T-cell-specific side effects, immune effector cell-associated neurotoxicity syndrome/neurotoxicity, cytokine release syndrome and haemophagocytic lymphohistiocytosis, represented only a minority of nonrelapse deaths, cumulatively 11.5%.
These findings underline the critical importance of infectious complications after CAR T-cell therapy and support the comprehensive reporting of nonrelapse mortality, including specific causes and long-term outcomes.
References
- Hamilton MP, Sugio T, Noordenbos T, et al. Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. N Engl J Med 2024;390:2047-2060.
- Ozdemirli M, Loughney TM, Deniz E, et al. Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy. N Engl J Med 2024;390:2074-2082.
- Mitchell E, Vassiliou GS. T-Cell Cancer after CAR T-Cell Therapy. N Engl J Med 2024;390:2120-2121.
- Cordas dos Santos DM, Tix T, Shouval R, et al. A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy. Nature Medicine; Published online 8 July 2024. DOI: https://doi.org/10.1038/s41591-024-03084-6