Banerjee Discusses FDA Call for Secondary Malignancies Boxed Warning on CAR T-cell Therapies


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Rahul Banerjee, MD FACP, discusses the FDA’s decision to add a class-wide boxed warning for secondary malignancies on all approved CAR T-cell therapies.

Rahul Banerjee, MD FACP

Rahul Banerjee, MD FACP

In late January 2024, the FDA called to add a class-wide boxed warning for secondary malignancies to all approved CAR T-cell agents following a safety probe.1 However, there are still many unanswered questions regarding this issue, including whether the CAR T-cell agents are the primary cause of these secondary malignancies and how frequent these secondary malignancies truly are, according to Rahul Banerjee, MD FACP.

The announcement affected all 6 FDA-approved CAR T-cell therapies which are indicated by the agency for patients with hematologic malignancies, and include ciltacabtagene autoleucel (cilta-cel; Carvykti), tisagenlecleucel (Kymriah), idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), axicabtagene ciloleucel (Yescarta), and brexucabtagene autoleucel (Tecartus). On January 19, 2024, the FDA sent 6 letters to the manufacturers of the approved CAR T-cell agents, noting that this class of drugs had been deemed to be associated with the risk of developing secondary malignancies. The manufacturers were given 30 days to submit proposed changes to their agents’ safety labels or file a rebuttal if they do not agree with the FDA.2

“We have become aware of the risk of T-cell malignancies, with serious outcomes, including hospitalization and death, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies. [The] FDA identified postmarketing adverse effect and clinical trial reports describing [the] occurrence of mature T-cell malignancies, including CAR-positive tumors, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies,” the FDA wrote in all of the letters.2

“This particular boxed warning didn’t come as a surprise, but the specificity of the initial FDA statement in November absolutely did,” Banerjee said. “The risk of secondary malignancies is already something I discuss with patients routinely for many therapies, including with CAR-T, but also with stem cell transplantation and lenalidomide [Revlimid]. Going forward, I’ll mention the boxed warning briefly as an extra detail in these discussions but won’t change the gist of what I describe.”

In an interview with OncLive, Banerjee, an assistant professor in the Clinical Research Division at Fred Hutch Cancer Center and an assistant professor in the Division of Hematology and Oncology at the University of Washington, both in Seattle, discussed factors beyond the CAR T-cell therapy itself that could be contributing to the secondary malignancies and whether the benefits of the treatment still outweigh the potential risks. He also highlighted a commentary piece he published with colleagues in Blood Advances.3

OncLive: In your estimation, how great is the risk of secondary malignancies following treatment with CAR T-cell agents?

Banerjee: Both our commentary and a recently published commentary by Bruce L. Levine, PhD, and colleagues suggest that this is quite rare-below 0.1% and likely lower. I’m often asked whether it’s possible that T-cell malignancies are being underreported in the post-CAR T setting, and I believe that’s extremely unlikely. We follow these patients carefully for 15 years after [receival of] CAR T-cell therapy-our center has a dedicated coordinator and nurse practitioner to review their charts and contact their local doctors to evaluate for late toxicities just like this.

Furthermore, T-cell malignancies are quite rare and often treated at academic centers. Cases like this would be noticed rather quickly and published if physicians suspected a link between prior CAR T therapy and a current malignancy.

What steps can clinicians take to minimize the risk of secondary malignancies when using CAR T-cell agents?

As of now, I’d strongly advise against trying to screen patients to minimize the risk of secondary cancers. There’s so much we don’t know about the real risk factors at play here. Is it the CAR T-cell therapy itself, or is it the patient’s prior therapies received and the fact that they’re now living longer?

In the recently reported ASH abstract describing a cilta-cel recipient who developed a secondary T-cell lymphoma, the patient’s T cells were indeed found to have other mutations that predated CAR T infusion. But screening T cells ahead of CAR T infusion is not something we routinely do, and I’d argue that the benefits of CAR T would still outweigh the risks, even in a patient who had clonal hematopoiesis of indeterminate potential or low-level T-cell abnormalities beforehand.

What factors outside of CAR T-cell therapy may be causing some of these secondary malignancies?

Many therapies that these patients receive [such as] transplantation, bendamustine, and lenalidomide [Revlimid], have been associated with secondary cancers. Cilta-cel’s package insert in myeloma was also recently updated to include the risk of secondary myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML], but many of these patients had received years of prior lenalidomide, a drug that is well known to predispose patients to secondary MDS or AML.

To take things a step further, I have no doubt that future analyses will show that patients who receive CAR T-[cell] therapy [will] have higher rates of secondary cancers [compared with] those who don’t. Why? Because of a principle similar to immortal time bias, whereby certain complications can only develop if the patient is alive to develop them. This has been well shown in multiple myeloma; patients who develop secondary malignancies after their myeloma diagnosis are paradoxically more likely to have had deep responses to therapy and to have lived longer.

In the [phase 1/2] CARTITUDE-1 trial [NCT03548207] of cilta-cel, for example, I suspect that many of these patients would otherwise only have lived for 6 to 12 months with conventional therapies before dying of myeloma. If CAR T-[cell therapy] put the myeloma into remission and patients stayed alive for another 3 years, this is 3 further years where the risk of second cancers from previous therapies like lenalidomide can become a reality.

Do the benefits of CAR T-cell agents still outweigh the potential risks for patients?

Absolutely. CAR T offers patients the potential for deep and durable remissions. Compared with other novel immune effector cell-based therapies such as bispecific antibodies, CAR T-cell therapy is a single infusion with much less time toxicity from continued drug administration every few weeks.

In [patients with] multiple myeloma, the median progression-free survival in the CARTITUDE-1 trial was almost 3 years without any maintenance therapy. This would have been unimaginable to tell patients even just a few years ago.

What is your takeaway message for your colleagues following this news—how does this affect clinical practice?

We will continue to be vigilant about this potential risk, but I do not advise any changes to our practice. If our hypotheses are true about prior therapies like bendamustine or lenalidomide being the real risk factors, then the risk of secondary malignancies may actually be lower as CAR T-cell therapy is moved into earlier lines of therapy. We will continue to watch for these toxicities very carefully as a field with this point in mind.

For community oncologists, I would encourage them to read our brief Blood Advances commentary about this piece, “Answering the ‘Doctor, can CAR-T therapy cause cancer?’ question in clinic.” It’s open-access, only 1500 words, and hopefully will provide a nice framework for them to use to discuss this topic with patients.


  1. Manalac T. FDA calls for boxed warnings on CAR-T therapies regarding secondary cancer risks. BioSpace. January 23, 2024. Accessed March 1, 2024.
  2. 2024 safety and availability communications: January 2024. FDA. Updated January 24, 2024. Accessed March 1, 2024.
  3. Banerjee R, Poh C, Hirayama AV, et al. Answering the “Doctor, can CAR-T therapy cause cancer?” question in clinic. Blood Adv. 2024;8(4):895-898. doi:10.1182/bloodadvances
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