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The FDA has launched an investigation into what it called a "serious risk" of T-cell malignancies in patients treated with autologous chimeric antigen receptor (CAR) T-cell therapies targeting B-cell maturation antigen (BCMA) or CD19.

The agency has received multiple reports of T-cell malignancies, including CAR-positive lymphomas, from clinical trials and postmarketing adverse event data sources, according to a posted on the FDA website. Serious outcomes of these secondary malignancies have included hospitalization and death. The notice and investigation pertain to all currently approved BCMA- and CD19-targeted CAR T-cell products:

• Axicabtagene ciloleucel (Yescarta)
• Brexucabtagene autoleucel (Tecartus)
• Ciltacabtagene autoleucel (Carvykti)
• Lisocabtagene maraleucel (Breyanzi)
• Tisagenlecleucel (Kymriah)

"Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalizations and death, and is evaluating the need for regulatory action," agency officials said in the statement. "As with all gene therapy products with integrating vectors (lentiviral or retroviral vectors), the potential risk of developing secondary malignancies is labeled as a class warning in the U.S. prescribing information for approved BCMA-directed and CD19-directed genetically modified autologous T-cell immunotherapies."

According to an FDA spokesperson, the agency has received 19 reports of CAR-associated T-cell malignancies, five from clinical trials and 14 from the FDA's adverse event reporting system. The agency is investigating "the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death," but no specific numbers were provided for those outcomes.

A principal investigator in trials of CAR T-cell therapies said he is unaware of any peer-reviewed reports of T-cell malignancies associated with the approved therapies.

"That said, it is not out of the realm of possibility that one or two out of 10,000 patients could develop T-cell lymphoma," Frederick Locke, MD, of the Moffitt Cancer Center in Tampa, Florida, told MedPage Today via email. "We know that the CAR gene, in at least one case, has mediated disruption of the TET2 gene, which enhanced clonal proliferation and effectiveness of CAR-T for leukemia."

"In addition, several patients previously developed CAR-positive T-cell lymphoma after receiving an investigational CAR that utilized transposon technology, which is not used with FDA-approved CAR T cells," he added. "Finally, we know that cancer immunotherapy such as checkpoint blockade for solid tumors, which does not rely on gene therapy, can very rarely result in T-cell lymphomas."

Locke said he looks forward to learning more about whether patients "have truly developed CAR-positive T-cell lymphoma" after treatment with the approved therapies, and if so, how many. He echoed the FDA position that the therapies' benefits outweigh the risks, as reflected in the clinical experience involving thousands of patients.

"I firmly believe that these therapies offer tremendous value to patients, curing those without other viable treatment options and improving survival in the case of lymphoma," he noted.

In response to the FDA safety notice, Bristol Myers Squibb (BMS) issued the following statement:

"Bristol Myers Squibb 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."

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

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