T-cell lymphoma following chimeric antigen receptor-T therapy: a cause for concern?

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory B-cell malignancies and multiple myeloma, with tens of thousands of patients treated worldwide. As survival improves, long-term safety has come into focus, and rare reports of T-cell lymphomas occurring after CAR T-cell infusion have prompted regulatory scrutiny and heightened clinical attention.

Drawing on pivotal trials, real-world registries, meta-analyses, pharmacovigilance data, and detailed molecular case reports, we review the incidence, biological plausibility, and clinical relevance of lymphomas arising after CAR T-cell therapy. Registry data and large institutional series consistently show that secondary T-cell malignancies are exceedingly rare, with reported incidences of approximately 0.03-0.3% depending on the cohort, and far less common than therapy-related myeloid neoplasms, solid tumors, and non-melanoma skin cancers in heavily pretreated populations. Most molecularly characterized post-CAR T-cell lymphomas lack evidence of CAR vector-driven transformation and appear to reflect pre-existing or therapyselected clonal T-cell populations in the context of clonal hematopoiesis, immune dysregulation, and, in some cases, viral reactivation. Nevertheless, rare CAR-positive cases with informative integration-site data confirm that vector-related transformation is biologically possible, although exceptional and probably dependent on cooperating host or clonal events.

We also discuss pathogenetic mechanisms, diagnostic pitfalls, and practical recommendations for surveillance and patient counseling.

In conclusion, secondary T-cell lymphomas represent a concerning but extremely uncommon complication of CAR T-cell therapy. Vigilance through standardized long-term follow-up and rigorous molecular investigation of suspected cases is warranted, but current evidence does not undermine the overwhelmingly favorable benefit-risk profile of CAR T-cell therapy.