Asian Hematology Research Journal

Background: Chimeric antigen receptor (CAR) T-cell therapy has become an important treatment option for relapsed or refractory haematological malignancies. Its expanding use has increased attention to late adverse events, including secondary primary malignancies (SPMs).

Aim: This narrative review summarises the reported clinical spectrum of SPMs after CAR-T therapy, considers potential mechanisms and risk factors, and outlines approaches to long-term monitoring.

Methods: The review draws on the case reports, clinical studies, pharmacovigilance analyses, meta-analytic findings, and mechanistic studies discussed in the manuscript.

Results: Reported SPMs include haematological malignancies, solid tumours, and non-melanoma skin cancers. A meta-analysis of 5,517 patients estimated an overall SPM frequency of 5.8%; haematological malignancies accounted for 37%, solid tumours for 27%, non-melanoma skin cancers for 16%, and T-cell malignancies for 1.5% of reported events. Other analyses identified secondary malignancies in 18 of 783 patients (2.3%) across 38 gene-modified T-cell therapy trials. Proposed mechanisms include vector integration and insertional mutagenesis, clonal selection, prior treatment-related genotoxicity, and impaired immune surveillance. The contribution of each mechanism remains uncertain, partly because molecular testing and follow-up have varied across studies.

Conclusion: SPMs are uncommon but clinically important late events after CAR-T therapy. Current evidence supports continued surveillance and further investigation of long-term safety, while recognising that prior treatment exposures and underlying clonal abnormalities may also contribute to risk.