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May 22, 2024

June 2024

Yes, experts agree with the FDA’s decision to require a black box warning on CAR T-cell therapies and say the treatment outweighs the risk of patients developing a secondary malignancy.

Emma Yasinski

Emma Yasinski is a science and medical journalist based in South Florida.

As of late January, 22 of 34,400 patients being treated with chimeric antigen receptor (CAR) T-cell therapy for certain blood cancers had developed a secondary T-cell malignancy.1 As a result, the U.S. Food and Drug Administration (FDA) directed the manufacturers of six CAR T-cell treatments to include a black box warning to alert patients and physicians to the drug’s potential cancer risk.2,3 However, the FDA has acknowledged that the benefits of CAR T-cell treatment continue to outweigh the risks.4

“It’s an unusual finding that patients who are receiving a T-cell therapy develop a T-cell malignancy, so it’s certainly of scientific and clinical interest,” said Robert Negrin, MD, a hematologist at Stanford Medicine in California and vice president of the American Society of Hematology (ASH). “It’s something that cannot be ignored, but the frequency of these events seems quite low.” He and other experts emphasized that it will be crucial to follow the events, but providers shouldn’t hesitate to prescribe the treatments because of the risk.

ASH Clinical News reached out to Dr. Negrin and other experts to learn more about the FDA’s decision to require a black box warning and what it means for patients, doctors, and researchers.

Scope of the Problem

CAR T-cell therapy, also referred to as CAR-T, is a type of immunotherapy in which scientists harvest T cells from the patient, genetically engineer them in the lab to recognize certain receptors on the surface of the patient’s cancer, and infuse them back into the patient so they can multiply and attack the cancer cells.5

CAR-T is currently used to treat blood cancers like leukemia, lymphoma, and multiple myeloma (MM). The first therapy was approved by the FDA in the summer of 2017.6 Over the next seven years, another five forms were approved. The treatments are expensive and come with risks of serious side effects, so the therapy wasn’t being recommended unless a patient had exhausted all other treatment options.4 Recently, it has become more commonly used as the result of a number of trials and completed studies that have investigated the utility of CAR T-cell–based therapy in earlier lines of treatment.

In November 2023, the FDA announced it had received reports of patients developing secondary T-cell malignancies after receiving CAR-T and the agency would be investigating in case regulatory action was needed.7 By January 2024, the agency had received 20 reports of T-cell malignancies in patients who had received the treatments.1

Mikkael Sekeres, MD, MS, a professor of medicine and chief of the Division of Hematology at the University of Miami’s Sylvester Comprehensive Cancer Center in Florida who is also chair of ASH’s Committee on Communications, wrote an op-ed for MedPage Today in January highlighting the low risk of secondary cancers from the treatment but applauding the FDA for warning doctors to be vigilant.8

“Based on the current data, the risk is very low,” said Mary Horowitz, MD, MS, deputy cancer center director at the Medical College of Wisconsin and scientific director emeritus of the Center for International Blood and Marrow Transplant Research (CIBMTR), both in Milwaukee. “It’s not high enough to affect the risk-benefit ratio for the patients who were being considered for this therapy. The risk from the diseases for which they are being treated is much higher than the risk of developing a T-cell malignancy.”

So far, most of the malignancies developed within one to 19 months after treatment, a time frame that Kenneth Anderson, MD, a medical oncologist at Dana-Farber Cancer Institute in Boston, called a broad range.

Drs. Negrin and Anderson pointed out that the patients who receive CAR-T are already at high risk.

“We know that, for example, in myeloma, just by virtue of the disease, the risk of having a second cancer is 10%,” said Dr. Anderson.

Dr. Negrin added that “many of these patients who have gone through chemotherapy may have gone through a bone marrow transplant, so they’ve been exposed to a lot of things that can impact risk of malignancy.”

The FDA’s Take

The experts all agreed that the FDA was right to raise the warning. The agency’s job is to evaluate the safety and efficacy of medications, so even if an event is rare, patients and doctors should be alerted so they can make the best decisions for treatment. The alert also lets practitioners know the importance of tracking and reporting the event.

Still, the FDA has repeatedly stated that the benefits of CAR-T cell therapy outweigh the risks for the time being.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) met on March 15, and during the meeting, scientists described results from a clinical trial of ciltacabtagene autoleucel (cilta-cel), a type of CAR-T therapy used to treat patients with relapsed or refractory (R/R) MM. The study reported that one patient out of 188 in the CAR-T group developed a secondary T-cell malignancy. Back in 2022, the FDA approved cilta-cel but only recommended its use if a patient had already had four unsuccessful treatments. During the meeting, experts considered whether it was reasonable to use the treatment earlier in the process.

“Right now, the approval is for patients who have received four or more prior treatments,” Dr. Anderson said. “I say this because as you move this up earlier, you may need to again evaluate the relative benefit-risk ratio.”

ASH submitted a comment before the ODAC meeting as part of the public comment docket emphasizing the importance of long-term follow-​up on patients who receive CAR-T and stating that it plans to convene key stakeholders to advance understanding of CAR-T effects.9 Additionally, ASH wrote, “We were pleased that the FDA has repeatedly acknowledged that the overall benefits of CAR-T outweigh the potential risks, and it will be important to continue to make sure those risks are placed in the context of therapies administered prior to cellular therapies, which may also be associated with secondary malignancies.”

After deliberation, the advisory committee voted unanimously to recommend approval of cilta-​cel for patients with R/R MM if two prior treatments have failed.10

Where to Go From Here

The hematologists interviewed said they will continue to use the treatments, but it will be important to monitor outcomes for a longer time. “I think one of the major concerns of the FDA is the question of ‘Is this the tip of an iceberg?’ Is there a lot of underreporting?” Dr. Negrin said. He added that he thinks the situation is not likely to be underreported. “Most of the centers that are doing these treatments are collecting the data and reporting the outcomes to CIBMTR.”

Dr. Horowitz, who works with CIBMTR, added one caveat: The center that is following the patient long-term may not be the same center that did the CAR-T therapy. She emphasized that if a T-cell malignancy does develop, whoever is treating the patient should inform the initial treating center, which is responsible for reporting to CIBMTR promptly. “What we really need is for people to be more aware of the potential risk and to evaluate and report post-treatment lymphomas and leukemias in their patients in a way that will allow us to determine whether they are related to the CAR-T or not,” she said.

ASH encourages providers to be vigilant with long-term follow-up and reporting toxicities. The Society urges its members who use CAR-T treatments to accurately identify the underlying cause of the secondary malignancy when one develops and stay current on how to effectively manage patients with secondary malignancies.9

Open Questions

There is still a lot to learn about the rare complication. First, scientists say researchers need to determine how prevalent secondary malignancies are. “We just don’t have the long-term data we need to evaluate the risk of second malignancies in absolute terms,” Dr. Horowitz said. “To understand uncommon late effects, you have to follow a lot of people for a long time. With more data, it may also be possible to understand whether some patients are at higher risk than others.” The FDA is recommending lifelong surveillance for these patients.

Another big question is how many of these secondary malignancies actually express the CAR. “In these 22 cases, there were three patients in whom there was detection of the actual CAR in the T-cell lymphoma. That does not mean that the CAR caused or is driving the lymphoma, but it does suggest, at least in those three cases, that the lymphoma does contain the CAR. Further studies are needed to understand the actual mechanism underlying development of these T-cell lymphomas in patients,” Dr. Anderson said.

It’s possible that the CAR causes a mutation in the T cell that leads to malignancy, Dr. Negrin explained. However, the CAR could also be causing changes in the environment, such as immunosuppression that allows the malignancy to grow. “We as a field need to distinguish those possibilities,” he said.

As of right now, treating a T-cell malignancy that emerges after CAR-T is no different than treating a T-cell malignancy under any other circumstances, experts said, but Dr. Negrin noted that could change in the future. “We don’t know the natural history of these cases yet, how sensitive or not they are to other forms of therapy.”

In the meantime, Dr. Negrin said, “Let’s not forget that this therapy has resulted in incredible responses in patients who often have no other options.”


  1. Levine BL, Pasquini MC, Connolly JE, et al. Unanswered questions following reports of secondary malignancies after CAR-T cell therapy. Nat Med. 2024;30(2):338-341.
  2. Deswal P. Gilead’s Tecartus escapes harsher classwide boxed warning for CAR-T therapies. Pharmaceutical Technology. January 25, 2024. Accessed February 8, 2024.
  3. U.S. Food and Drug Administration. 2024 safety and availability communications. Accessed February 8, 2024.
  4. O’Bier T. FDA says cancer treatment CAR-T therapy may cause cancer itself. Scripps News. January 20, 2024. Accessed February 8, 2024.
  5. CAR T cells: engineering patients’ immune cells to treat their cancers. National Cancer Institute. March 10, 2022. Accessed February 8, 2024.
  6. Mitra A., Barua A., Huang L., et al. From bench to bedside: the history and progress of CAR T cell therapy. Front Immunol. 2023;14:1188049.
  7. S. Food and Drug Administration. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. November 28, 2023. Accessed February 8, 2024.
  8. Sekeres, MA. When a revolutionary cancer treatment causes cancer. MedPage Today. January 27, 2024. Accessed February 8, 2024.
  9. Narla M, Percival ME M. Letter to Robert M. Califf, MD, commissioner, U.S. Food and Drug Administration. 2024. Accessed April 11, 2024.
  10. Ryan, C. FDA ODAC committee votes unanimously in favor of benefit-risk profile of cilta-cel in early R/R myeloma. OncLive. March 15, 2024. Accessed March 16, 2024.

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