Black-Box Warnings for CAR-T Therapies Unlikely to Change Clinical Practice

The US Food & Drug Administration (FDA) has ordered a class-wide black box warning for all 6 approved genetically engineered BCMA- and CD-19 chimeric antigen receptor T-cell (CAR-T) autologous immunotherapies: axicabtagene ciloleucel (Yescarta®; Kite Pharma Inc), brexucabtagene autoleucel (Tecartus^TM; Kite Pharma Inc), ciltacabtagene autoleucel (Carvykti^TM; Janssen Biotech Inc), idecabtagene vicleucel (Abecma®; Bristol-Myers Squibb), lisocabtagene maraleucel (Breyanzi®; Bristol-Myers Squibb), and tisagenlecleucel (Kymriah®; Novartis Pharmaceuticals Corp). 

In letters to manufacturers dated January 19, 2024, the FDA said it had “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” and told the drugmakers to add warnings to the boxed label for patients and prescribing clinicians that potentially fatal secondary T-cell malignancies “may present as soon as weeks following infusion.”¹

The move followed a November 2023 safety notice that the FDA was investigating a possible association between these biologics and secondary T-cell blood cancers.² As of January 2024, the FDA knew of 25 cases among patients receiving 5 of the 6 approved CAR-T agents, but the agency did not specify the distribution of cases between agents.^3,4 (Bristol Myers Squibb stated in January 2024 that the company knew of no CAR-positive T-cell cancers among more than 4700 patients administered idecabtagene vicleucel.⁵)

Support for FDA’s Action

Half of the 25 cases had occurred within a year of CAR T-cell infusion.⁴ In the 3 cases with available cancer cell gene sequencing data, the malignant cells harbored CAR transgenes, implicating CAR-T therapies as at least 1 factor in the secondary T-cell cancers.⁴ 

Viruses used to introduce transgenes into patient T cells in the lab can sometimes insert those transgenes into unintended regions of the genome. If that occurs next to tumor suppressor genes or oncogenes, they could trigger up- or downregulation. Such insertional mutagenesis and resulting gene dysregulation might lead to carcinogenesis.⁵

“That’s always been the theoretical concern,” said David Porter, MD, director of Cell Therapy and Transplant and Jodi Fisher Horowitz Professor in Leukemia Care Excellence at Penn Medicine in Philadelphia. “The basic concern is that whenever you insert new genetic material into the genome, it has the potential of being inserted someplace it’s not supposed to be — and that can result in interrupting genes that are necessary for keeping a cell from becoming a cancer cell.”

The FDA’s initial approvals required 15 years of follow-up with patients to assess that risk. The first commercially available CAR-T therapy was tisagenlecleucel, approved in 2017, and detecting rare adverse events can take many years of real-world monitoring.

Despite the relatively few known cases and concern about news media headlines causing patient alarm,⁶ black box warnings were the right call, according to clinical experts contacted for this article. It is unlikely to immediately change clinical practice, they said.

“The black box warning is a way to alert clinicians and caregivers, and even patients, to this potential risk, but I don’t know that changes the decision-making process for using these therapies,” Dr Porter said.  “Anything that induces second cancers deserves attention, but I still believe strongly that for the vast majority of patients getting CAR T cells, the potential benefits far outweigh the small potential risk of T-cell lymphoma.”

“We were not surprised about the FDA’s decision … given the recent reports,” said Saad Usmani, MD, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York. The available evidence suggests the risk of developing a second primary malignancy is “very low” and the benefits of CAR-T for patients with advanced hematologic malignancies outweigh that risk, he noted, echoing the FDA’s January 2024 statement. 

Risk and Incidence of SPM Remain Low

“The second primary malignancies or SPM issue has been recognized for years in multiple myeloma and is influenced by prior transplant and use of immunomodulatory drugs as maintenance,” Dr Usmani said. “The frontline trials comparing transplants to CAR-T therapies will be the most telling [about] where the SPM risk is originating from, and if the presence or absence of clonal hematopoiesis has a role to play in its origin in an older patient population.”

Johnson & Johnson spokesman Brian Kenney said the manufacturer is working with the FDA to update its anti-BCMA ciltacabtagene autoleucel’s prescribing information (personal interview, February 2024). Two ciltacabtagene-associated T-cell lymphoma cases have been identified, Mr Kenney said: a patient with relapsed/refractory multiple myeloma, who was enrolled in the phase 3 CARTITUDE-4 study (ClinicalTrials.gov Identifier: NCT04181827), and a January 22, 2024, case reported to the postmarketing FDA Adverse Event Reporting System (FAERS) database. 

The CARTITUDE-4 case was described in an abstract presented at the 2023 American Society of Hematology (ASH) Annual Meeting.⁷ The 51-year-old male patient had achieved a stringent complete response and no minimal residual disease (MRD) at 92 days postinfusion, but at 5 months postinfusion, he developed a rapidly growing erythematous nasofacial plaque that was diagnosed as CD2- and CD3-positive T-cell lymphoma.⁷ 

“To date, more than 2000 patients have been treated with [ciltacabtagene autoleucel] worldwide,” Mr Kenney noted. “We remain confident in the favorable benefit-risk profile.”

A separate 2021 report stated that 2 of 10 patients in a phase 1 clinical trial of a piggyBac transposon-modified, CD-19-targeting CAR-T therapy developed CAR T-cell lymphomas.⁸ Despite detailed analysis, however, the authors found no evidence of insertional mutagenesis.⁸ 

Genetically engineered CAR T cells are created by modifying a patient’s own T cells to specifically target cancer antigens. Long-term outcomes following CAR-T therapy have shown robust and durable remissions among patients with B cell lymphomas.⁹ Common adverse events include cytokine release syndrome (CRS), characterized by symptoms such as high fever, chills, trouble breathing, and muscle pain, which can be life-threatening if not managed quickly and effectively. Other complications mentioned in the facts include CAR-T related encephalopathy, anemia, thrombocytopenia, and increased infection risk.¹⁰

Other Potential Causes of SPM

Some postinfusion secondary cancers may not be caused by CAR-T therapy. Patients receiving CAR-T therapies typically have relapsed or refractory hematologic cancers and have been exposed to bendamustine and other chemotherapy regimens associated with secondary cancer risk, as are stem cell transplantation and lenalidomide. Patients with B-cell cancers who do not receive CAR-T therapy sometimes develop T-cell lymphomas.⁵ And CAR-T therapies prolong patient survival, allowing secondary cancers caused by other factors time to emerge. 

Impact on Clinical Practice

The black box warnings are unlikely to deter clinicians from prescribing CAR-T therapies, largely because these patients frequently have few other options. But it remains important to describe the potential risk to patients.

“At Memorial Sloan Kettering Cancer Center, we have been following the SPM incidence in our patient population for many years, and we discuss the possibility of second malignancies with all of our multiple myeloma patients,” Dr Usmani explained. 

Widespread news coverage of the potential for secondary blood cancers following CAR-T therapy will likely leave many patients and their loved ones with serious concerns about this treatment modality. Authors from the Fred Hutchinson Cancer Center in Seattle recently suggested that patient communication about the black box warnings should focus on the relatively low risk and the overriding benefits of CAR-T therapy in the relapsed/refractory setting, and the fact that other factors might explain the reported secondary cancers.⁶ 

“Given the ‘one-and-done’ nature of CAR-T infusions coupled with their potential for rapid and durable remissions, several trials have also shown that CAR-T outperforms standard therapies in terms of meaningful improvements in quality of life,” they noted.⁶ 

Disclosure: Dr Porter has received consulting fees from Kite Pharma, and Dr Usmani has received funding from Bristol Myers Squibb and Janssen Biotech.