Call for Boxed Warning for Secondary Malignancies on CAR T-Cell Therapies Raises Alarm, But Key Questions Remain

Following a safety probe, the FDA called to add a class-wide boxed warning for chimeric antigen receptor (CAR) T-cell therapies in late January 2024 to alert patients and clinicians of the potential risk of developing secondary T-cell malignancies following treatment with these agents.¹ However, some clinicians with extensive expertise administering CAR T-cell therapies are wary that these agents may not be the primary cause of these issues and insist that the benefits of these treatments for the patients who need them still far outweigh the potential risks.

The announcement affected all 6 FDA-approved CAR T-cell therapies, including ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), axicabtagene ciloleucel (Yescarta), and brexucabtagene autoleucel (Tecartus), all of which are indicated by the agency for patients with hematologic malignancies. 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.¹

“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 the letters.²

“If you look at the commercially approved products and their indicated usages, they are indicated for patients who are at a very high risk of dying of their disease without effective therapy,” David L. Porter, MD, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and the director of the Cell Therapy and Transplant Program at Penn Medicine in Philadelphia, Pennsylvania, said in an interview with OncologyLive. “Most of them have already been through just about every conventional treatment and have limited treatment options. The risk of these [secondary] lymphomas appears to be very low from what we know right now. [I believe] the potential benefit far exceeds the potential, very small risk. That doesn’t mean we should ignore the risk, [pretend] that it’s not real, or that we shouldn’t be very aware of it and consider it. But for now, the potential benefits seem to significantly outweigh the very small risk.”

“We will continue to be vigilant about this potential risk, but I do not advise any changes to practice,” Rahul Banerjee, MD, FACP, an assistant professor in the Clinical Research Division at Fred Hutchinson Cancer Center and an assistant professor in the Division of Hematology and Oncology at the University of Washington, both in Seattle, said in a statement to OncologyLive. “If our hypotheses are true about prior therapies like bendamustine or lenalidomide [Revlimid] being the real risk factors, then the risk of secondary malignancies may 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.”

FDA Investigates Relationship Between CAR T-Cell Agents and Secondary Malignancies

On November 28, 2023, the FDA announced it would be investigating the safety of CAR T-cell agents following reports of T-cell malignancies, including CAR-positive lymphoma, in patients who received treatment with BCMA- or CD19-directed autologous CAR T-cell immunotherapies. The reports stemmed from clinical trials and adverse effect data sources. The agency noted that the potential risk of secondary malignancies is labeled as a class warning in the United States prescribing information for all FDA-approved BCMA-directed and CD19-directed genetically modified autologous T-cell immunotherapies, as it is with all gene therapy products with integrating vectors.³

In its statement, the FDA also noted that the initial approvals of all CAR T-cell agents included postmarketing requirements to conduct 15-year follow-up observational safety studies to further determine the long-term safety profile and risk of secondary malignancies following treatment with these agents. At the time, the FDA wrote, “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, [the] FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action.”³

“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 second malignancies is already something I discuss with patients routinely for many therapies, including CAR T-cell therapy but also with stem cell transplantation and lenalidomide. Going forward, I’ll mention the boxed warning briefly as an extra detail in these discussions, but [I] won’t change the gist of what I describe.”

Additionally, during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in December 2023, investigators presented the clinicogenomic characterization of a patient enrolled in the phase 3 CARTITUDE-4 trial (NCT04181827) who developed CAR-positive T-cell lymphoma (TCL) following treatment with ciltacabtagene autoleucel. CARTITUDE-4 compared the anti-BCMA CAR T-cell therapy with standard of care in lenalidomide-refractory patients with multiple myeloma following 1 to 3 prior lines of therapy.⁴

The 51-year-old patient was treated with ciltacabtagene autoleucel and achieved a stringent complete response and minimal residual disease negativity at a 10-5 threshold. At 5 months post CAR T-cell infusion, the patient developed a rapidly growing erythematous nasofacial plaque and was diagnosed with TCL. The investigators noted this was a rare malignancy that was potentially driven by genetic mutations, such as TET2, NFKB2, PTPRB and/or JAK3, that could have been present as a clone with malignant potential prior to the manufacturing of ciltacabtagene autoleucel. However, they wrote that apotential contributory role of the CAR insertion in the 3 prime untranslated region of PBX2 to TCL development remains unclear and could not be excluded, emphasizing that further investigation into the etiology of the case was needed.⁴

Also during ASH 2023, investigators presented findings from a phase 1 study conducted at 4 sites (NCT04317885, NCT04655677, NCT04696432, NCT04693676) evaluating the novel anti-CD20/CD19 bispecific CAR T-cell therapy C-CAR039 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. A total of 48 patients were treated with the agent, and second primary malignancies following infusion were reported in 3 patients (2 instances of acute myeloid leukemia that occurred at 2- and 10-months post infusion and 1 case of Epstein-Barr virus–positive cytotoxic TCL at 8 months). However, tumor biopsy by quantitative polymerase chain reaction and the CAR transgene was negative, so the investigators concluded that none of these cases were related to C-CAR039 treatment.⁵

Subsequently, in a perspective piece published in the New England Journal of Medicine on February 15, 2024, the coauthors—Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, and Nicole Verdun, MD, super office director of the Center for Biologics Evaluation and Research Office of Therapeutic Products—wrote that the FDA was aware of 22 cases of T-cell cancers that occurred after treatment with CAR T-cell agents as of December 31, 2023. This included instances of T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. They noted that such cases have been reported in 5 of the 6 CAR T-cell agents—although not specifying which ones—and that of the 14 cases with adequate data available, the cancers manifested within 2 years after administration of CAR T-cell therapy (range, 1 to 19 months), with approximately 50% occurring within the first year.⁶

Marks and Verdun added that in 3 cases for which genetic sequencing data were available, the CAR transgene was detected in the malignant clone, indicating that the CAR T-cell agent was likely involved in the development of the T-cell malignancy. However, they also noted, “With more than 27,000 doses of the 6 approved products having been administered in the United States, the overall rate of T-cell cancers among people receiving CAR-T therapies appears to be quite low, even if all reported cases are assumed to be related to treatment. But relying on postmarketing reporting may lead to underestimates of such cases.”⁶

“There are very limited data on the majority of cases that have so far been reported,” Porter added. “The risk of CAR-induced malignancies, particularly T-cell lymphomas, is very low. This group of patients who get CAR T cells for B-cell malignancies [already] have a real risk of secondary cancers, and that’s been well described and reported. In most cases, it’s not at all clear that [the secondary malignancies] are related to CAR T cells. These patients get secondary malignancies even without getting CAR T cells, and the risk that these are CAR-manufacturing induced is quite low.”

Unanswered Questions Linger as CAR T-Cell Therapies Remain an Important Option

In light of the FDA looking into the relationship between CAR T-cell therapies and secondary T-cell malignancies, Porter and Banerjee coauthored commentaries with their respective colleagues outlining some of the lingering questions held by clinicians. The commentaries were published in Nature Medicine and Blood Advances, respectively.

In their commentary, Porter and colleagues wrote that, “T-cell homeostasis in vivo is controlled at the level of the T-cell receptor by clonal competition, and T cells are relatively resistant to genotoxicity. Under unusual settings, such as Janus kinase retroviral activation, and at very high insertion copy numbers using a transposon system for CAR gene delivery, T-cell lymphomas may be induced.”⁷

They outlined that the Center for International Blood and Marrow Transplant Research (CIBMTR) captured 11,345 recipients of commercial CAR T cells and that 8060 were enrolled in postauthorization safety studies. At a median follow-up of 13 months (range, 0-69), 565 secondary or subsequent malignant neoplasms were present in 485 patients who had received commercial CAR T cells and were enrolled in post-authorization studies, and 420 secondary or subsequent malignant neoplasms were present in 357 patients enrolled in postauthorization studies. The median time from CAR T-cell infusion to first subsequent neoplasm was 9 months, and the most common types of neoplasms were nonmelanomatous skin cancers and therapy-related myelodysplasia oracute myeloid leukemia which are anticipated based on the age and prior treatment profile of patients who usually receive CAR T-cell therapy. The authors noted that of the 3 instances of T-cell malignancies reported by the CIBMTR (1 T-cell large granular cell leukemia, 1 anaplastic TCL, and 1 peripheral TCL), no aberrant expression of CD19 in the tumor cells was present based on clinical immunophenotyping.⁷

The commentary authors highlighted that a total of 20 cases of T-cell malignancies have been reported out of approximately 8000 cases of adverse effects in the FDA Adverse Events Reporting System (FAERS) database. “Given that an estimated 34,400 patients have received commercially available CAR T cells so far, the rate of T-cell malignancies observed is far lower than that seen with some other treatments,” they wrote, noting that both FAERS and CIBMTR reporting is voluntary.⁷

“Patients, caregivers, and clinicians need to be aware of [this risk], and we need to continue to monitor patients for development of these complications and secondary malignancies,” Porter said. “They need to be reported because that is the only way the community can understand what the risks are. The only way you can mitigate it is to understand what the risks are. [This call for a warning] also shows that the long-term [15-year] follow-up program is working. This is why patients are followed and why there is a reporting system because this is a relatively…new therapy. We will continue to monitor it, [the secondary malignancies] will be recorded, and the whole community will benefit from understanding [the risks] better.”

In their commentary, Banerjee et al suggested other factors that could be contributing to the occurrence of secondary malignancies among patients who received CAR T-cell therapy. They wrote that pretransplant conditioning, bendamustine, and lenalidomide have all been associated with secondary primary malignancies. In addition, they noted that lenalidomide has also been shown to predispose patients to myeloid malignancies through its effects on hematopoietic progenitor cells and that the lymphodepletion with agents such as fludarabine needed for CAR T-cell therapy can increase the risk of secondary primary malignancies. They also made the point that the principle of immortal time bias could be at play—ie, patients can only develop secondary primary malignancies if they survive their initial malignancy long enough to do so, something that likely would not be possible for many without CAR T-cell therapies.⁸

The commentary authors highlighted that the risk of T-cell malignancies from ex vivo gene therapy was first identified more than 15 years ago and that discussion of secondary primary malignancies is already routine when a clinician is considering CAR T-cell therapy for a patient. They also stressed that an active cancer is almost always more pressing than the threat of developing a hypothetical cancer years later.⁸

“As of now, I’d strongly advise against trying to screen patients to minimize the risk of second cancers,” Banerjee said. “There’s so much we don’t know about the real risk factors at play here. Is it the CAR-T therapy itself, or is it the patient’s prior therapies and the fact that they’re now living longer? CAR [T-cell therapy] offers patients the potential for deep and durable remissions. Compared with other novel immune effector cell–based therapies such as bispecific antibodies, CAR T is a single infusion with much less time [and] toxicity from continued drug administration every few weeks. In multiple myeloma, the median progression-free survival in the [phase 1/2] CARTITUDE-1 trial [NCT03548207] was almost 3 years without any maintenance therapy––this would have been unimaginable to tell patients even just a few years ago.”

In response to the FDA’s investigation, similar reviews of the relationship between treatment with CAR T-cell agents and secondary malignancies are underway worldwide, including by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency, the European Union’s European Medicines Agency, and South Korea’s Ministry of Food and Drug Safety.⁹

References

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2. 2024 safety and availability communications: January 2024. FDA. Updated January 24, 2024. Accessed January 25, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/2024-safety-and-availability-communications
3. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. FDA. November 28, 2023. Accessed January 25, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous
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5. Li P, Yu WJ, Zhou L, et al. C-CAR039, a novel anti-CD20/CD19 bi-specific CAR T-cell therapy shows deep and durable clinical benefits in patients with relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL) in long term follow up. Blood. 2023;142(suppl 1):1025. doi:10.1182/blood-2023-182817
6. Verdun N, Marks P. Secondary cancers after chimeric antigen receptor T-cell therapy. N Engl J Med. 2024;390(7):584-586. doi:10.1056/NEJMp2400209
7. 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. doi:10.1038/s41591-023-02767-w
8. 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.2023012336
9. Asanga P. Global regulators increase CAR T scrutiny in wake of FDA’s investigation. BioSpace. January 22, 2024. Accessed January 25, 2024. https://www.biospace.com/article/global-regulators-increase-car-t-scrutiny-in-wake-of-fda-s-investigation-/