Secondary malignancy of T-cell origin after CAR T-cell therapy: EMA’s conclusions from the evaluation of 38 suspected cases

Abstract This article provides a regulatory perspective on secondary malignancy of T-cell origin as a rare adverse reaction to the currently marketed CD19- or BCMA-directed chimeric antigen receptor (CAR) T-cell therapies. To assess the risk, causality between reported suspected adverse reactions and CAR T-cell therapy was assessed applying the principles of the World Health Organization-Uppsala Monitoring Centre causality categories, alongside a review of scientific publications and data from registries/ databases. By 11 April 2024, 38 cases of T-cell malignancy after CAR T-cell therapy were reported in patients aged 29–80 years. In 19 patients, tumour samples were tested for the presence of CAR transgene, which was detected in seven cases. Most of the T-cell malignancies were diagnosed within 12 months of treatment (22/33; 67%). The reporting rate is approximately one case per 1000 patients treated. An overall causal relationship was established with at least a reasonable possibility. Regulatory measures included updates to the product information, risk management plan, and educational materials. An additional pharmacovigilance activity was requested from the marketing authorisation holders (MAHs) to strengthen the process of genetic testing of residual tumour samples. To further characterise this risk and understand underlying mechanisms, continued efforts from healthcare professionals, MAHs and regulators are essential. Well-documented case reports, including information on genetic testing of tumour samples, are considered crucial elements.