CAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts.

Suspected adverse reactions following chimeric antigen receptor T-cell (CAR T) treatment include more and more cases of secondary T-cell malignancies. The causality assessment of such suspected reactions challenges established evaluation practices due to (i) patient and product-specific risk factors and (ii) incomplete data available with post-marketing reports submitted to competent authorities. This is of particular relevance for gene therapy products that integrate into the host genome. We present a summary of case reports related to different CAR T products and the rationale for case causality assessment. In this context, possible pathophysiologic mechanisms and differences between CAR T products to be taken into account are discussed. The unparalleled complexity of the case follow-up and the multistep process of cancer development necessitates a case-by-case consideration. This highlights challenges in the pharmacovigilance of advanced therapy medicinal products and underlines the importance of testing for vector presence, integration location and gene expression profile for an informed case assessment of suspected secondary malignancies with the aim to obtain a better understanding of contributing factors.