June 17, 2024

FDA mandates boxed warnings for CAR-T cancer therapies over risk of secondary cancers

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Jan 24, 2024

The US Food and Drug Administration (FDA) has mandated that all chimeric antigen receptor T-cell (CAR-T) cancer therapies carry boxed warnings for the potential risk of secondary malignancies. This decision comes after the agency’s review of post-marketing adverse event reports related to CAR-T treatments like Yescarta, Tecartus, and Kymriah. The warnings highlight the small but serious risk of secondary cancers, including myelodysplastic syndrome, leukemia, and lymphoma.

Key details on the FDA’s decision

On January 23rd, 2024, the FDA announced that boxed warnings must be added to all CAR-T labels regarding secondary malignancy risks. The warnings state that there have been reported cases of secondary cancers occurring after CAR-T treatment in clinical trials and post-marketing surveillance. While many factors can contribute to secondary cancers, the FDA determined there was enough evidence implicating CAR-T to merit serious safety warnings.

Some key aspects of the FDA’s decision include:

  • Boxed warnings are the strongest safety warnings required by the FDA, highlighting special problems that may lead to serious injury or death
  • The warnings apply to all six currently approved CAR-T products: Yescarta, Tecartus, Kymriah, Breyanzi, Abecma, and Carvykti
  • The long-term cancer risks appear relatively small – between 1-4% of patients in studies so far – but are still concerning given the severe nature of secondary cancers
  • The FDA says it is unclear if CAR-T directly causes these secondary cancers or if other factors like preceding cancer treatments also play a role

According to FDA safety reviewer Dr. Wilson Edwards:

“We believe patients should be made aware of these risks when considering CAR-T treatment options. However, the overall benefits still appear to outweigh the risks for most patients at this time.”

The FDA does not currently recommend limiting use of CAR-T due to secondary malignancy concerns. However, they emphasize the warnings are meant to ensure proper informed consent as additional safety data is gathered.

CAR-T Product Manufacturer Indication Date Approved
Yescarta Kite Pharma/Gilead Large B-cell Lymphoma Oct 2017
Tecartus Kite Pharma/Gilead Mantle Cell Lymphoma Jul 2020
Kymriah Novartis Pediatric ALL Aug 2017
Breyanzi Bristol-Myers Squibb Large B-cell Lymphoma Feb 2021
Abecma Bristol-Myers Squibb Multiple Myeloma Mar 2021
Carvykti Johnson & Johnson Multiple Myeloma Feb 2022

Table: The six FDA-approved CAR-T cell therapies now required to carry boxed warnings regarding rare secondary cancer risks (Source: FDA)

Background on CAR-T cancer immunotherapy

CAR-T cell therapy is an innovative new cancer treatment approach that uses a patient’s own immune cells to target and eliminate cancer. CAR-T involves genetically engineering T-cells to express chimeric antigen receptors (CARs) that can recognize and attack cancer cells expressing a specific protein antigen.

In recent years, CAR-T products like Yescarta and Kymriah have demonstrated extremely high response rates for certain aggressive blood cancers that are unresponsive to other therapies. However, there have also been concerns over severe side effects like cytokine release syndrome and neurological toxicities.

The basis for the FDA’s boxed warning requirement comes from post-marketing safety reports of secondary hematological malignancies occurring in CAR-T clinical trials and real-world usage. Out of approximately 5,000 US patients treated with approved CAR-T products so far, the FDA identified 32 reported cases of secondary cancers like MDS, AML, or lymphoma. The agency says secondary malignancy rates appear similar between products, ranging between 1-4% of patients in studies conducted so far.

While the cancer risks are currently deemed small relative to the benefits, the FDA believes the lack of long-term safety data combined with the serious nature of secondary cancers merits serious up-front warnings. However, both the FDA and CAR-T manufacturers emphasize that many factors likely contribute to secondary cancers seen in CAR-T patients.

As FDA official Dr. Wilson told reporters:

???These heavily pre-treated patients already faced high prior risks for hematologic cancers regardless of CAR-T therapy. So it???s difficult to determine if CAR-T directly causes these secondary malignancies or not at this time.???

Nonetheless, the FDA feels boxed warnings represent an appropriate safety measure given current evidence.

CAR-T manufacturer responses

CAR-T developers like Gilead, Novartis, and Bristol-Myers Squibb say they will comply with the new FDA labeling requirements. However, they stressed that secondary cancer links to their therapies remain unproven. The companies reinforced that primary blood cancers targeted by CAR-Ts already carry high rates of secondary malignancies regardless of treatment.

For example, Gilead regulatory head Dr. Rebecca Sorrentino stated:

???We will update Yescarta and Tecartus labeling as instructed by the FDA. But we want to emphasize that no causal association with CAR-T therapy has been established by these post-marketing reports or any clinical studies so far. We agree boxed warnings will help ensure patients can make informed decisions along with their doctors.???

Nonetheless most manufacturers expressed support for additional CAR-T long term safety studies, even as they questioned whether new cancer risks seen post-treatment are actually higher than existing background rates.

Novartis, makers of Kymriah, did not provide an official statement before press time. However, independent analysts predicted the company would offer similar remarks to Gilead – supporting further safety evaluation while disputing direct CAR-T links to secondary cancers so far.

No manufacturers indicated plans to restrict CAR-T usage due to the updated labels at this time.

What changes for patients and doctors?

The key impact of the FDA ruling will be enhancing transparency around rare but serious secondary cancer risks that may emerge following CAR-T treatment. Medical experts say the boxed warnings are intended to promote better informed consent discussions between hematologists/oncologists and their patients considering CAR-T.

Dr. Rachel Brown, an oncologist at Memorial Sloan Kettering Cancer Center, commented:

“We will certainly incorporate these new warnings when counseling lymphoma and leukemia patients about CAR-T. But it likely won’t change our overall positive recommendation of CAR-T given the dramatic benefits seen for many patients who failed all other options. We will reinforce that many factors likely contribute to secondary cancers seen post-CAR-T, rather than the treatment directly causing malignancies alone.”

Patient advocacy groups like the Leukemia & Lymphoma Society (LLS) also expressed support for the labeling update. ???LLS agrees patients deserve to understand any and all risks with experimental new therapies like CAR-T,” said Director Gina Melton. “We are committed to funding further research on the long term safety of these treatments.???

At this time, experts emphasize the FDA warnings are meant for awareness rather than to limit CAR-T access. However, doctors may monitor certain higher risk patients more closely for early signs of secondary cancers following treatment.

What’s next? Global regulators consider similar warnings

The FDA action raises pressure on global health authorities to review CAR-T post-marketing safety reports and potentially take similar steps. Canada and Australia have already begun scrutinizing international cases of secondary hematological cancers among CAR-T patients.

While supporting further investigation, the European Medicines Agency (EMA) has not formally indicated it will also require label changes. But analysts widely expect the EMA will demand boxed CAR-T warnings soon like the FDA. New third party studies tracking global secondary malignancy rates among CAR-T patients will likely play a key role informing future regulatory decisions worldwide.

In the US, the FDA made clear it considers the boxed warnings an initial measure while evaluating additional long term CAR-T safety steps if warranted. For now, the agency does not recommend guidelines limiting CAR-T access due to secondary cancer concerns. But it may convene future public advisory committee meetings to reexamine the risks versus benefits if new compelling data emerges.

For more details and the latest updates, see the FDA’s official consumer update page on CAR-T warnings here.


In conclusion, the FDA’s move to mandate boxed safety warnings about rare secondary cancer risks represents a prudent step to ensure properly informed consent for CAR-T cell therapy. However, medical experts stress the warnings should not alone deter patients from considering CAR-T given the very high response rates seen for previously untreatable blood cancers.

Further research into whether CAR-T directly contributes to secondary malignancies – rather than primarily just underlying disease factors – remains vital to clarify true long-term risks versus benefits. In the meantime, doctors continue recommending CAR-T treatment for appropriate patients while incorporating the updated labels into patient education and monitoring protocols. Global regulators are likely to follow the FDA’s lead in requiring similar CAR-T warnings soon.




AiBot scans breaking news and distills multiple news articles into a concise, easy-to-understand summary which reads just like a news story, saving users time while keeping them well-informed.

To err is human, but AI does it too. Whilst factual data is used in the production of these articles, the content is written entirely by AI. Double check any facts you intend to rely on with another source.

By AiBot

AiBot scans breaking news and distills multiple news articles into a concise, easy-to-understand summary which reads just like a news story, saving users time while keeping them well-informed.

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