Discussing the Risk of Secondary Cancers From CAR T Therapy in Patients With B-Cell Lymphoma

Dr Jacobson addresses the December 2023 news about T-cell leukemias and lymphomas in CAR T patients, emphasizing the need for proper risk-benefit perspective. The primary lymphoma represents an immediate, life-threatening condition with certain poor outcomes if untreated, while the T-cell malignancy risk is extraordinarily low (approximately 1 in 10,000 to 1 in 30,000 patients). Most reported cases haven't demonstrated clear insertional mutagenesis causation.

Many T-cell lymphomas in CAR-positive patients carry CHIP mutations (TET2, DNMT3A) that likely represent “first hits” present before CAR T manufacturing. The subsequent proliferative stress from CAR T activation may contribute to additional mutations and potential malignant transformation. This suggests a complex multistep process rather than direct CAR T causation, though the small number of cases makes definitive conclusions difficult.

Dr Friedman discusses myelodysplastic syndrome risk, which he considers potentially more concerning than T-cell malignancies but still emphasizes the small absolute risk. Both physicians agree that secondary malignancy risk must be contextualized against patients' cumulative prior therapy exposure, including fludarabine and cyclophosphamide from CAR T lymphodepletion. Lynch inquires about CHIP mutation screening, but Dr Jacobson notes insufficient data to establish predictive thresholds given the rarity of these complications and the commonality of CHIP mutations in the general population.