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.
The authors highlight this regulatory-clinical gap and advocate for improved diagnostic standards, better data integration, and dialogue among clinicians, developers, and regulators.
New and more precise methods for detecting CD19 expression should be thoroughly explored to better identify the patients who will benefit most from these targeted therapies.
Collecting and analyzing expression data alongside clinical outcomes—such as treatment response—will be essential both in clinical practice and prospective clinical trials. To further strengthen the evidence base, systematic additional data collection should be encouraged. The latest ESMO Lymphoma Guideline recommends assessment of CD19 expression at least in the relapse setting (Eyre et al, 2025). Incorporating this parameter into postapproval registry data collection could facilitate the establishment of a structured evidence base to inform future scientific, clinical, and regulatory decision-making