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Secondary malignancies, including T-cell lymphomas, have emerged as a significant concern following chimeric antigen receptor (CAR) T-cell therapy. While CAR T-cell therapy has demonstrated remarkable success in treating hematologic malignancies, concerns have arisen regarding its potential to induce secondary malignancies, particularly T-cell lymphomas. This article aims to provide an in-depth exploration of secondary T-cell lymphomas following CAR T-cell therapy, with a focus on incidence rates and potential underlying causes.

Incidence Rates of Secondary T-cell Lymphomas

The incidence of secondary T-cell lymphomas following CAR T-cell therapy remains a subject of research. Several case reports and retrospective studies have shed light on this rare but clinically significant phenomenon. A retrospective analysis of patients treated with CD19-targeted CAR T-cell therapy reported secondary T-cell lymphomas in approximately 1-2% of cases.¹ Furthermore, studies focusing on other CAR-T cell types, such as ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), have reported instances of secondary T-cell lymphomas, albeit at varying frequencies.²

Potential Causes of Secondary T-cell Lymphomas

The etiology of secondary T-cell lymphomas following CAR T-cell therapy remains complex and not fully elucidated. Several hypotheses have been proposed to explain the potential mechanisms underlying the development of these secondary malignancies:

• Genetic alterations. CAR T-cell therapy may induce genetic alterations in T cells, leading to their malignant transformation.³
• Immunosuppression. CAR T-cell therapy can induce profound immunosuppression, compromising the immune system's ability to surveil and eliminate nascent malignant cells, thereby creating a permissive environment for the development and progression of secondary T-cell lymphomas.⁴
• Viral integration. The use of viral vectors in CAR T-cell transduction carries the risk of random genomic integration, which may disrupt tumor suppressor genes or activate oncogenes, predisposing to T-cell lymphomas.⁵
• Inflammatory responses. The intense inflammatory responses elicited by CAR T-cell therapy may contribute to tissue damage and chronic inflammation, both of which have been implicated in carcinogenesis.⁶

Conclusion

Secondary T-cell lymphomas following CAR T-cell therapy represent a rare but clinically significant complication. Ongoing surveillance and research are essential to better understand the underlying mechanisms and risk factors associated with these secondary malignancies. Clinicians should remain vigilant in monitoring patients following CAR T-cell therapy for signs of secondary malignancies, and future studies should focus on optimizing CAR-T cell design and minimizing potential risks to ensure the long-term safety and efficacy of this transformative therapy.

References

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Dr. Ombada indicated no relevant conflicts of interest.

Acknowledgment: This article was edited by Drs. Miriam Osei and Julian Sprague. Faculty review was performed by Drs. Teresa Gentile and Adam Binder.