Spectrum, pathobiology, mechanistic insights and diagnostic challenges of post-CAR T cell therapy lymphoproliferative disorders.

This review article focuses on lymphoproliferative and lymphomatous complications emerging after CAR T‑cell therapy, a toxicity area that is increasingly recognized but still poorly defined.

Key points:

• Clinical spectrum:

• Describes a range of post–CAR T lymphoproliferative disorders, from polyclonal/reactive proliferations to overt lymphomas.
• Includes both CAR-transgene–positive and transgene‑negative lymphomas, which can have overlapping clinical presentations and timing relative to CAR T infusion.

• Diagnostic challenges:

• Causality is difficult to establish because these events arise in a complex milieu that often includes prior therapies, immune suppression, infections, inflammatory states, and clonal haematopoiesis.
• The review emphasizes the need for detailed immunophenotypic, molecular, and integration-site analyses to distinguish CAR-driven events from background or therapy‑related malignancies.

• Proposed mechanisms and risk factors:

• Pre‑existing clonal haematopoiesis or occult malignant clones that may expand under immune and inflammatory pressure.
• Dysregulated signalling pathways and chronic inflammatory stimuli following CAR T therapy.
• Rarely, vector integration events involving the CAR construct that may contribute to transformation.

• Pathological and molecular features:

• Summarizes recurrent pathological patterns and molecular alterations observed in published cases, highlighting heterogeneity but suggesting emerging themes that may define subgroups.

• Implications for practice and research:

• Argues for a more formal framework and nomenclature for post–CAR T lymphoproliferative disorders to enable earlier recognition, structured diagnostic work‑up, and more consistent reporting.
• Stresses the importance of pharmacovigilance, case aggregation, and mechanistic studies to refine risk stratification, guide management, and inform CAR design and monitoring strategies.

Overall, the article synthesizes limited but growing evidence to clarify what is currently known about post–CAR T lymphoproliferative disorders and outlines priorities for classification, clinical evaluation, and future research.