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FDA Requires Boxed Warning of Secondary Cancer Risk for Autologous CAR T-Cell Therapies

NEW YORK – The US Food and Drug Administration on Thursday said it is officially requiring the manufacturers of CD19- and B-cell maturation antigen (BCMA)-directed CAR T-cell therapies to update the boxed warnings on their products to include secondary T-cell cancer risks.

The requirement applies to all currently approved autologous CAR T-cell therapies that target these antigens, including Novartis' Kymriah (tisagenlecleucel); Gilead's Yescarta (axicabtagene ciloleucel) and Tecartus (brexucabtagene autoleucel); Bristol Myers Squibb's Abecma (idecabtagene vicleucel) and Breyanzi (lisocabtagene maraleucel); and Janssen's Carvykti (ciltacabtagene autoleucel).

The news comes after the FDA issued a safety warning about reported risks of secondary T-cell malignancies in late 2023. At the time, the FDA said it was undertaking an investigation of postmarketing data and clinical trial reports, though it said that the benefits of these treatments still outweighed the risks. The investigation showed that patients treated with these cell therapies can indeed develop secondary T-cell malignancies, including CAR-positive tumors, as soon as a few weeks after they receive the autologous treatments. These secondary cancers can sometimes be fatal, the FDA warned.

Along with requiring manufacturers to update the boxed warnings, the FDA is requiring these drugmakers to update other parts of these treatments' labels, including the sections detailing warnings and precautions, postmarketing experience, patient counseling information, and medication guide.

The FDA is also requesting lifelong monitoring for any patient who receives an autologous CAR T-cell therapy, and that any post-treatment T-cell malignancies be reported to the manufacturer. For patients who do develop these secondary cancers, samples should be collected and tested for CAR transgenes, the agency said.

In January, representatives from numerous professional organizations, including the International Society for Cell and Gene Therapy (ISCT), the American Society of Transplantation and Cellular Therapy, the European Society for Blood Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the Parker Institute of Cancer Immunotherapy, published a commentary in Nature Medicine responding to the FDA's warnings and investigation. In the commentary, the groups further emphasized their position that CAR T-cell therapy's benefits outweigh the secondary malignancy risks. They also called into question whether there was truly a causal relationship between the secondary malignancies the FDA observed and the CAR T-cell treatments.