Global Health Regulators Investigate Secondary T-Cell Malignancies as Rare Complication of CAR T-Cell Therapy

AMSTERDAM —December 22, 2025— The European Medicines Agency (EMA) has released its final conclusions following an extensive evaluation of 38 suspected cases of secondary T-cell malignancies in patients treated with CAR T-cell therapy. While the groundbreaking treatment has revolutionized the care of hematologic cancers such as acute lymphoblastic leukemia and non-Hodgkin lymphoma, the emergence of T-cell-derived cancers post-treatment is prompting a global re-examination of long-term patient surveillance protocols.

EMA Analysis and Causal Links

The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) reviewed data from approximately 42,500 patients. Key findings from the 38 reported cases include:

• Transgene Detection: In 19 patients where tumor samples were available for testing, the CAR transgene—the specific genetic sequence used to reprogram the cells—was detected in seven cases. This suggests a direct causal relationship between the genetic modification and the secondary malignancy in those instances.

• Rapid Onset: Most of these secondary malignancies were diagnosed within 12 months of treatment (67%), although cases have been reported up to several years later.

• Class Effect: The EMA has concluded that this risk is a “class effect,” applying to all currently marketed BCMA- and CD19-directed CAR T-cell therapies.

Mechanisms and Genomic Insights

The transformation of quiescent T-cells into malignant counterparts may be linked to “insertional mutagenesis,” where the viral vector used to deliver the CAR gene inadvertently activates oncogenic pathways. However, researchers also point to “survivor bias” and the cumulative impact of heavy prior treatments like chemotherapy and radiation, which can predispose the immune system to secondary mutations regardless of the CAR T-cell intervention.

New Mandates for Lifelong Monitoring

In response to these findings, the EMA and the FDA have updated product information and risk management plans to include boxed warnings. Healthcare providers are now advised to:

1. Lifelong Surveillance: Maintain lifelong monitoring for new malignancies in all patients receiving CAR T-cell products.

2. Genetic Testing: Facilitate the genetic testing of any residual tumor samples to identify the presence of the CAR construct if a secondary cancer develops.

3. Biomarker Research: Utilize genomic studies to identify patients at a higher baseline risk for T-cell transformation.

Despite these concerns, the EMA emphasizes that the benefit-risk balance remains positive. For many patients with refractory blood cancers, CAR T-cell therapy offers a high probability of durable remission that far outweighs the rare risk of a secondary malignancy.