FDA investigates risk of secondary malignancies with CAR T-cell therapy

Editor's Note: This story was updated 30 November to include a statement from Bristol Myers Squibb.

The US Food and Drug Administration (FDA) is investigating reports of a “serious risk” of T-cell malignancies linked to treatment with chimeric antigen receptor (CAR) T-cell therapies. The investigation includes currently approved B-cell maturation antigen (BCMA) and CD19-directed autologous CAR T-cell immunotherapies.

The investigation was prompted by 20 reports of serious adverse events, including hospitalizations and deaths associated with these therapies since the approval of the first CAR-T therapy in 2017. Fifteen of the reports came from FDA’s Adverse Event Reporting System (FAERS) and five were reported from clinical trials. An FDA spokesperson said the reports “suggest that T cell malignancy is an identified risk for approved BCMA-directed and CD19-directed genetically modified autologous CAR T cell immunotherapies.”

The warning affects six currently approved therapies:

Bristol Myers Squibb’s Abecma (idecabtagene vicleucel)
Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel)
Johnson & Johnson/Legend Biotech’s Carvykti (ciltacabtagene autoleucel)
Novartis’s Kymriah (tisagenlecleucel)
Gilead Sciences/Kite Pharma’s Tecartus (brexucabtagene autoleucel)
Gilead Sciences/Kite Pharma’s Yescarta (axicabtagene ciloleucel)

FDA said the benefits of CAR T-cell therapies “continue to outweigh their potential risks for their approved uses.” However, the agency is “evaluating the need for regulatory action.” Any patient receiving treatment with these products should be monitored for life for any new malignancies, according to FDA.

The investigation represents a potential setback to the CAR T-cell sector, which was heralded by former FDA Commissioner Scott Gottlieb as a “new medical frontier” in August 2017 when FDA approved the first CAR T-cell therapy, Novartis’s Kymriah.

All gene therapy products with integrating vectors, including lentiviral or retroviral vectors, have the potential risk to cause secondary malignancies. The US prescribing information for BCMA-directed and CD19-directed genetically modified autologous T cell immunotherapies includes the risk of secondary malignancies as a class warning.

As part of the postmarketing requirements, manufacturers of these products are required to conduct 15-year long term follow-up observational safety studies to assess the long-term risk of secondary malignancies occurring after treatment.

Novartis, which manufacturers Kymriah (tisagenlecleucel), told Focus that the company remains confident about the safety of their CAR T-cell product. “Since its first approval in the US in 2017, more than 10,000 patients have been treated with Kymriah (tisagenlecleucel) and there is no evidence to date that would change our confidence in Kymriah’s benefit/risk profile. As part of our continuous safety monitoring, Novartis has not identified a causal relationship between Kymriah and secondary malignancies. We are fully committed to patient safety and will continue to work with the US Food and Drug Administration (FDA),” according to Novartis.

BMS, which manufacturers two approved CAR T-therapies, told Focus the company "has treated more than 4,700 patients across clinical and commercial settings with Abecma and Breyanzi, which use only lentiviral vector. To date, BMS has not observed any CAR-positive T-cell malignancy cases and therefore, we have not found a causal relationship between our products and secondary malignancies."

The company said "patient safety is a top priority for BMS, and we remain confident in the safety profile and clinical value of our cell therapies. We are collaborating with the FDA in its ongoing investigation and are responding to FDA’s requests for information."

FDA Announcement

FDA investigates risk of secondary malignancies with CAR T-cell therapy

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