Following FDA’s Call for CAR T Boxed Warnings, Questions About Secondary Cancers Linger


Secondary malignancies following CAR T-cell therapy have been a known risk, but an FDA investigation and call for labeling change have renewed interest.

Microscopic photorealistic image of CAR T cells - Generated with Google Gemini AI

Microscopic photorealistic image of CAR T cells - Generated with Google Gemini AI

June is Cancer Immunotherapy Month, and Targeted Oncology is highlighting stories on this developing field of research.

Following the FDA’s investigation into secondary malignancies after chimeric antigen receptor (CAR) T-cell therapies and subsequent call for boxed warnings on BCMA- or CD19-directed agents, questions have arisen regarding the meaning and implications of these decisions.

While the risk of secondary malignancies has been a class warning for CAR T-cell therapies since the first approval of tisagenleleucel (Kymriah; tisa-cel) in 2017, reports to the FDA Adverse Event Reporting System (FAERS) of T-cell lymphoma cases prompted the agency to begin an investigation in November 2023.1 In January 2024, the FDA issued class safety labeling changes to highlight the risk of post-CAR T-cell malignancies, including boxed warnings, patient counseling information, and adverse reactions in postmarketing experience. The FDA has also called for lifelong monitoring of these patients, an extension from the 15-year mandatory monitoring that has been a stipulation of these agents’ approvals.2

However, the benefits of CAR T-cell therapy still appear to outweigh the risks, as seen in the FDA’s Oncologic Drug Advisory Committee meetings in March 2024 that voted that the risk/benefit assessments for idecabtagene vicleucel (Abecma; ide-cel)3 and ciltacabtagene autoleucel (Carvykti; cilta-cel)4 were favorable for patients with relapsed/refractory multiple myeloma. Subsequently, in April 2024, the FDA approved both agents for earlier lines of therapy in these populations.5,6

“It really, to me, has not changed prescribing patterns. It has not changed the risk/benefit ratio. I think the potential benefits still far outweigh the risks. But it does emphasize that that one needs to be very thoughtful with this or any therapy and take into account what some of those risks may be,” said David Porter, MD, director of cell therapy and transplant and Jodi Fisher Horowitz Professor in Leukemia Care Excellence at Penn Medicine, in an interview with Targeted OncologyTM.

Mechanisms of Secondary Malignancies Following CAR T-Cell Therapy

Microscopic photorealistic image of T-cell lymphoma cells - Generated with Google Gemini AI

Microscopic photorealistic image of T-cell lymphoma cells - Generated with Google Gemini AI

“We know that these patients are at risk for secondary malignancies. They typically are treated with repetitive doses of chemotherapy and sometimes radiation. Many of them have had prior autologous stem cell transplant, and all that increases [the] risk of secondary malignancies,” said Porter.

The exact mechanism of action of secondary malignancies following CAR T-cell therapy remains unknown. Rahul Banerjee, MD, FACP, proposes 3 options. The first is the possibility that CAR T is “unmasking the [adverse] effects of earlier treatments that put [patients] at risk of cancer.”

“All patients who are treated for 1 kind of cancer are elevated risk of developing other kinds of cancer,” Banerjee explained. Banerjee is an assistant professor in the clinical research division and physician-researcher at Fred Hutch Cancer Center. “Some of that is potentially genetics or immune dysregulation, and part of that is treatment. In multiple myeloma and lymphoma, we certainly give treatments that have known risks. Lenalidomide [Revlimid] absolutely has been associated with all sorts of second cancers. Studies have shown predisposition to more aggressive myeloid malignancies, such as [those] found in the CARTITUDE-1 study [NCT03548207] of cilta-celin myeloma. But transplant can often do it as well.”

In a 2-year follow-up of CARTITUDE-1, a total of 20 secondary primary malignancies were reported in 16 patients; however, investigators deemed these to be unrelated to cilta-cel. These included 9 hematologic malignancies, consisting of 1 case of B-cell lymphoma, 6 cases of myelodysplastic syndrome, and 3 cases of fatal acute myeloid leukemia.7

The second possible mechanism is that CAR T may accelerate or expedite the process of a secondary malignancy emerging.

“[P]otentially, these cells were already destined to become cancerous. These T cells, due to preexisting clonal hematopoiesis or other complications, you put a CAR in them, and that makes them grow faster, and suddenly, a T-cell lymphoma that may have taken 5 years to develop, now it takes 2 years to develop,” Banerjee said.

The third possibility—that Banerjee considers the most unlikely—is insertional mutagenesis, where the CAR is inserted into a spot that turns a normal cell into a cancerous cell.

An online publication in Blood released before the 2023 American Society of Hematology Annual Meeting that may support this theory has been the subject of controversy in the medical community since its release. The case study discussed a 51-year-old male patient who received cilta-cel; 5 months postinfusion, a nasofacial plaque developed that was identified to be T-cell lymphoma. The lesion biopsy showed that 90% to 100% of cells were CAR-positive.8

Study authors postulated that the malignancy was possibly driven by genetic mutations in TET2, NFKB2, PTPRB, and/or JAK3. However, “a potential contributory role of the CAR insertion in the 3′ untranslated region of PBX2 to TCL development remains unclear and cannot be excluded at this time,” authors wrote.

“The FDA did not say that the CAR T cells caused the cancer. Unfortunately, people on Twitter were assuming that that is not the case,” Banerjee said.

“Our guess is probably that the patient did have some clonal hematopoiesis going into this and that this patient had this pro T-cell lymphoma gene that was already there. Of course, a precancerous T cell that becomes a precancerous CAR T-cell is going to be at higher risk of becoming a cancerous CAR-positive cell. CAR T cells, as soon as they see a cognate antigen, grow. If the seed was already planted for that cell to cause problems, you are unmasking it in this regard,” Banerjee continued.

“I think on that scale of 3 possibilities that number 3, that CAR T cells cause cancer, no one is saying that. The FDA is not saying that, industry is not saying that, academia is not saying that. I do not think that is likely at all. Certainly, the studies we have seen do not support that,” Banerjee added.

“Those cases where there is good evidence, the CAR T cells involved are very few. It is a very low-risk…There always has been a concern that CAR T cells…could potentially induce new malignancies. In fact, it is why there has been a robust long-term follow-up program established.I think the boxed warning just emphasizes the concern that honestly…most people that I know, we are aware of that,” said Porter.

Investigating the Risks of CAR T

Even with the known risk, the incidence of malignancies following CAR T, especially T-cell malignancies, is notably low.

Data from the CARTITUDE-4 study (NCT04181827) showed that second primary cancers were diagnosed in 4.3% of patients (n = 9) in the cilta-cel arm and 6.7% (n = 14) in the standard-care arm, where patients received pomalidomide (Pomalyst), bortezomib, and dexamethasone or daratumumab (Darzalex), pomalidomide, and dexamethasone. Most of the cancers were hematologic or cutaneous.9

An analysis of theFAERS showed that second primary malignancies were reported in 4.3% (n = 536) of 12,394 adverse event reports following CAR T-cell therapy. Specifically, T-cell non-Hodgkin lymphoma were reported in 17 of 536 reports, making up 0.1% of all CAR T adverse event reports.10

Smaller institutional studies, like one performed at the University of Pennsylvania, show similar rates of secondary malignancies. At a median follow-up of 10.3 months, an analysis of 449 patients treated with CAR T at the University of Pennsylvania showed that 3.6% of patients (n = 16) had a secondary primary malignancy, and only 1 case of T-cell lymphoma was observed.11

“There is this worry that maybe doctors are underreporting it. I think that would be unlikely…If it was something common, maybe patients who get CAR T are at higher risk of high cholesterol, I could see that completely slipping by the radar here,” said Banerjee.

“We have our long-term follow-up program. We are required by law to follow people for 15 years. T-cell lymphoma is such a rare toxicity that when it happens, we would all be aware of it, especially now,” he added.

Implications of the Boxed Warnings

Porter and Banerjee note that the boxed warnings emphasize the seriousness of the treatment and provide more transparency for physicians and their patients. 

“I think it is more for the FDA to illustrate the seriousness of the monitoring that is needed here. Certainly, the boxed warning has been helpful to frame the discussion a bit more in terms of long-term [adverse] effects…I think here, I am able to say, for the second cancer screening, let us talk about it because the FDA has a boxed warning on these products. I think I do put that into the discussion with patients just to remind us of an important topic to bring up,” said Banerjee.

The decision also emphasizes the FDA’s refined focus on safety.

“In transplant—we use transplant all the time in myeloma—if melphalan [Evomela] had been developed today as a modern drug, it absolutely would have the same boxed warning. I think most of our patients who are getting transplants, we do remind them that after transplant, you have to see your primary care doctor, once a year, if not more, you have to do colonoscopies, mammograms, pap smears, etc.,” Banerjee added.

Microscopic photorealistic image of myeloma cells - Generated with Google Gemini AI

Microscopic photorealistic image of myeloma cells - Generated with Google Gemini AI

As CAR T-cell therapies are modified and then administered to a patient, patients likely will not see the physical boxed warning. However, Porter notes that the information on the risks is readily available for patients.

“There is a lot of information for anybody, if not even directly seeing the boxed warning, about the secondary malignancies, the T-cell lymphomas that have developed, and the fact that the FDA has issued a boxed warning, even if they are not directly seeing the bolded writing and the actual wording,” said Porter.

Importance of Long-Term Follow-Up

Along with its call for boxed warnings, the FDA noted that patients should receive lifelong monitoring for secondary malignancies.2 The approvals of CAR T therapies were contingent on 15-year observational safety follow-up, including risk assessment for secondary malignancies. As the first CAR T product was approved in 2017, the 15-year mark has not yet been hit, and what lifelong monitoring looks like practically has not been fleshed out.

“I think they vary in duration of plan follow-up. I do not know that the logistics have been worked out yet what lifetime monitoring actually means. Hopefully, for those patients who have been cured by CAR T cells, that lifetime monitoring is a long time. I think it is a laudable goal,” said Porter.

“To be fair, many patients that we treat for cancer have lifetime monitoring. They see a doctor, sometimes an oncologist, for the rest of their life…To recommend lifetime monitoring should not be confused with say, recommendations to do CT scans every year for the rest of your life. That is not what the recommendations are. But it is to continue to monitor and track these patients for long-term outcomes so that if there is an issue with problems developing now, not within 15 years, but maybe 20 or 25 years, that there is a way to understand and capture that information,” said Porter.

Long-term follow-up has been a standard for many physicians and institutions following CAR T and other therapies, including transplant, so this call for lifelong monitoring is not anticipated to be a major paradigm shift.

“Independent of this, in our [bigger] center, we have a long-term follow-up program. We have a dedicated nurse practitioner [and] a dedicated database. Most big transplant centers also have a long-term follow-up program to keep an eye on these patients. We reach out to those patients, see how they are doing, and so forth,” said Banerjee.

CAR T-cell therapy is an evolving field, and the move for CAR T in earlier lines of therapy also means that the length of monitoring will naturally be longer, as many patients who are treated with CAR T in later lines of therapy still do not have very long survival times.

“At least in myeloma, if my patients live 15 years, great. Even right now, that is a stretch for many of my patients, because they are already older at baseline. And for many lymphomas, that is also the case. I do not foresee that increasing the monitoring for 15 years to lifelong will add that much to the numerator of cases [of secondary malignancies] being caught…I think that if the FDA mandates that we have to do it, but more importantly, I think if this helps us better characterize, who should get a CAR T, who should not,” said Banerjee.

Additionally, the longer survival times will also lead to more diagnoses of secondary malignancies, according to Banerjee.

“One of the tricky things about CAR T, [is] there is a survival benefit for these patients physically, live longer. It does sound silly, but unfortunately, you have to be alive today to be diagnosed with a second cancer.With CAR T and 15-year follow-up, they are probably going to see more patients hitting that 15-year mark . You may see more of these cancers being reported year by year. That is not because they were being underreported before, but because more [patients] are physically living longer. So, do I think CAR T causes breast cancer? No. But again, if you live long enough, 1 in 8 women will get breast cancer. So, you are going to see more and more of that in these patients,” added Banerjee.

Ultimately, Banerjee and Porter agree that the FDA investigation and call for boxed warnings has not changed their prescribing patterns or patients’ views of these treatments.

“Since November, I have yet to have a patient who has declined the CAR T because of these new safety updates,” said Banerjee. “The benefits of CAR T vastly outweigh the risks. I think the most important takeaway would be that I think if a patient is even plausibly a CAR T candidate, they should be referred to talk with one of us. The [American Society for Transplantation and Cellular Therapy (ASTCT)] and the [Association of Cancer Care Centers (ACCC)] has a nice catchphrase: if it recurs, you should refer.”

1. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. News release. FDA. November 23, 2024. Accessed June 20, 2024. 
2. FDA requires boxed warning for T cell malignancies following treatment with BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. News release. FDA. April 18, 2024. Accessed June 20, 2024. 
3. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. March 15, 2024. Accessed June 20, 2024.
4. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. March 15, 2024. Accessed June 20, 2024.
5. U.S. FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb. April 5, 2024. Accessed June 20, 2024.
6. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed June 20, 2024.
7. Martin T, Usmani S, Berdeja J, et al. Ciltacabtageneautoleucel, an anti–B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J Clin Oncol. 2023;41(6):1265-1274. doi:10.1200/JCO.22.00842
8. Harrison S, Nguyen T, Rahman M, et al. CAR+ T-cell lymphoma post ciltacabtageneautoleucel therapy for relapsed refractory multiple myeloma. Blood. 2023;142(1):6939. doi:10.1182/blood-2023-178806.
9. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med.2023;389:335-347. doi:10.1056/NEJMoa2303379
10. Elsallab M, Ellithi M, Lunning MA, et al. Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA Adverse Events Reporting System. Blood. 2024;143(20):2099-2105. doi:10.1182/blood.2024024166
11. Ghilardi G, Fraietta JA, Gerson JN, et al. T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy. Nat Med. 2024;30(4):984-989. doi:10.1038/s41591-024-02826-w
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