CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY, a personalized form of immunotherapy that modifies a patient’s immune system to target and kill cancer cells, has been lifesaving for many people with blood cancers.

But new safety concerns reported in late 2023 led the Food and Drug Administration (FDA) to require a warning with all CAR T-cell treatments given in the U.S. about the risk of developing secondary T-cell cancers.

CAR T-cell therapy starts with removing T cells from the patient’s blood. Those cells are sent to a manufacturer for genetic engineering to insert the chimeric antigen receptor (CAR) into the T cells, a process that takes three to four weeks. Patients receive low doses of two types of chemotherapy for three days before receiving a single infusion of their personalized CAR T cells.

“The one-and-done aspect of CAR T-cell therapy is very appealing to patients,” says Michael Jain, a hematologist-oncologist at the Moffitt Cancer Center department of blood and marrow transplant and cellular immunotherapy in Tampa, Florida.

Results from the U.S. Lymphoma CAR-T Consortium, which includes 17 academic centers that contribute data about their patients who had CAR-T cell therapy, reported that nearly 30% of patients with diffuse large cell lymphoma were alive without relapse five years after treatment. “It’s a lifesaving treatment for patients with lymphomas,” Jain says.

Starting in 2023, the FDA shared reports of secondary T-cell cancers that developed in a handful of patients. As of Dec. 31, 2023, the FDA was aware of 22 cases of T-cell cancers that occurred after treatment with CAR T-cell products. In response, the FDA now requires CAR T-cell manufacturers to include a boxed warning—the highest safety warning for medications—on CAR T-cell product labels stating that CAR T-cell treatments may cause cancers, including CAR-positive tumors.

What the CAR T-cell Therapy Boxed Warning Means

With more than 34,400 doses of the six approved CAR T-cell products administered in the U.S. since the treatment was introduced in 2017, the overall rate of T-cell cancers among people receiving CAR T-cell therapies is less than one in 1,000.

“That’s not a zero risk, but it is very small,” says Aaron P. Rapoport, a hematologist-oncologist at the University of Maryland Medical System in Baltimore. Still, it’s a risk to discuss with your doctor if you are considering CAR T-cell therapy. “We now mention that there are a small number of cases of T-cell malignancies after CAR T-cell therapy as part of our patient consent process,” Rapaport says.

Your doctor is also likely to mention the risks of CAR T-cell therapy that are more established, which include low immunoglobin levels, infections and other secondary cancers, including myelodysplastic syndrome (MDS). Jain estimates that 5% to 10% of patients will develop secondary leukemia or MDS after CAR T-cell therapy, but he says chemotherapy, radiation and stem cell transplants also increase the risk for leukemia and MDS, and doctors don’t know which treatment may be the cause in any individual case.

Currently, there are six CAR T-cell therapy products approved for relapsed or refractory B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma and multiple myeloma. Patients with lymphoma or leukemia must have failed one previous line of therapy to be eligible for CAR T-cell therapy. Patients with multiple myeloma must have failed four prior lines of therapy. All CAR T-cell products must carry the boxed warning.

Overall, though, Jain says the boxed warning shouldn’t stop or delay patients eligible for CAR T-cell therapy from undergoing the highly specialized treatment. “The risk of a T-cell malignancy is important and something we need to learn more about, but it’s extremely rare and not clinically frequent enough to warrant concern for patients,” he says. “The magnitude of the benefit of CAR T-cell therapy far outweighs the concern of T-cell malignancies. Patients are at a much higher risk of their cancer progressing or dying from their cancer.”

Meanwhile, clinical trials are underway investigating whether giving CAR T-cell therapy sooner, thereby reducing a patient’s exposure to chemotherapy and radiation, may reduce the risk of MDS and secondary leukemia. “It’s possible that the risks of CAR T-cell therapy may be less when used earlier in the course of treatment,” Rapoport says. “Already, the use of CAR T-cell therapy for lymphoma can be used after patients have failed one line of prior therapy,” Rapoport says. Previously, patients with lymphoma were required to fail two lines of treatment before receiving CAR T-cell therapy.

Sandra Gordon is a medical writer in Stamford, Connecticut.