US regulators have ordered black-box warnings for all CAR T cell therapies on a risk of secondary cancers, but maintain that the benefit of these treatments outweighs their risks in patients with blood cancers.

The US Food and Drug Administration (FDA) concluded that an increased risk of T cell malignancy, and serious outcomes such as hospitalisation and death, is applicable to all BCMA- and CD19-directed genetically modified autologous T cell immunotherapies.

As such, it has requested the inclusion of a black-box warning to the product labels of all CAR T therapies on the market, and that patients and clinical trial participants treated with them receive life-long monitoring for new malignancies (link here).

News of the safety warning came as the European Medicines Agency announced it would review data on secondary malignancies related to T-cells, including T-cell lymphoma and leukaemia, for the six CAR T-cell medicines approved for use in Europe*.

The review, which will look at evidence including data from 23 patients with T-cell lymphoma or leukaemia, will inform the decision on whether any further regulatory action is required.

The move also follows a safety warning from the FDA last year, triggered by reports of at least 25 cases of T-cell cancers occurring among around 30,000 patients who had received T-cell therapies, both in clinical trials and in clinical practice (see our story here).

However, causation or the mechanisms behind the development of secondary cancers are yet to be established, and US oncologist Dr Caron Jacobson, Medical Director of the Immune Effector Cell Therapy Program at the Dana-Farber Cancer Institute, told JAMA Medical News that the blanket box warning for all CAR T therapies might be “premature”.

“The small and uncertain risk of developing one of these secondary T-cell cancers and is likely to be lower than the risk of developing other secondary cancers from their prior therapies,” she told the publication.

“The FDA did not do a good enough job making it clear that the majority of these cases have not yet been linked directly to the CAR T-cell therapy, and patients with B-cell cancers are at risk of developing T-cell cancer as well,” she noted.

A group of US researchers, led by US academic haematologist/oncologist Dr Rahul Banerjee**, Fred Hutchinson Cancer Center, Seattle, also urged clinicians to “cautiously reassure” any patients concerned about the potential cancer risk from CAR T treatment.

If asked by patients, clinicians should stress: that the benefits of CAR T generally outweigh the risks; that while causation is possible there are many potential confounders that need to be examined; and that active cancers are a “bigger threat” than a future, hypothetical cancer, the researchers wrote, in a commentary published in Blood.

“We suggest caution with drawing any definitive conclusions from the FDA’s statement”, they stressed. “Although further research is ongoing, the benefits of CAR T therapy clearly outweigh the risks in patients with haematologic malignancies and should not be understated”.

*Axicabtagene ciloleucel (Yescarta, Kite); Brexucabtagene autoleucel (Tecartus, Kite); Ciltacabtagene autoleucel (Carvykti, Janssen Oncology and Legend Biotech); Idecabtagene vicleucel (Abecma, Bristol Myers Squibb); Lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb); Tisagenlecleucel (Kymriah, Novartis).

**R.B. reports consulting fees from Bristol Myers Squibb (BMS), Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, and SparkCures, and research funding from Novartis and Pack Health.