Regulatory challenges of personalized medicine in the real world: are the right patients being treated with CD19-targeting CAR T-cells?

Despite the clinical success of CD19-directed CAR T-cell therapies, less than 50% of patients achieve long-term remission. Emerging evidence indicates that loss or reduced expression of CD19-due to mutations, deletions, alternative splicing-is a significant, underrecognized mechanism of treatment failure. Notably, CD19-negative subpopulations can be detected even prior to therapy, and patients with low CD19 expression consistently show poorer outcomes. Although current clinical guidelines do not mandate routine CD19 testing before treatment, this situation reflects both scientific and technical challenges. Importantly, patients with partial/ low CD19 expression may still benefit from therapy, complicating the definition of "target positivity." From a regulatory perspective, targeted therapies should ideally be used only when target expression is confirmed. This principle is difficult to implement, considering the scarcity of data and the difficulties of current diagnostic tools, risking both undertreatment and overtreatment. EU regulators have addressed the issue by introducing harmonized warnings in product information, but more is needed. We highlight this regulatory-clinical gap and advocate for improved diagnostic standards, better data integration, and dialogue among clinicians, developers, and regulators.