When it comes to CAR-T therapies, safety issues have never been an afterthought.

However, they moved out of the periphery last month and firmly into the forefront when the Food and Drug Administration called for boxed warnings for all six CAR-T drugs on the market.

“We have become aware of the risk of T cell malignancies, with serious outcomes, including hospitalization and death,” following treatment with autologous CAR-T immunotherapies, the FDA wrote in letters to manufacturers. 

The companies, too, have acknowledged the drugs’ benefit-risk profile. Still, evidence of an actual causal relationship between autologous CAR-T therapies and T-cell lymphoma (TCL) malignancies has remained something of an uncertainty. 

That is, until Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, offered his latest view at a recent industry briefing. Sharing preliminary results of an investigation, he admitted there probably is a causal link. 

“The onset of these [malignancies] was soon enough after the administration, in some cases, that it does look like there’s a causal relationship,” acknowledged Marks, who is a hematologist and oncologist by training.

As to how that admission may affect the CAR-T-zeitgeist, a brief history of the drugs’ safety profile is in order. 

CAR-T safety: a brief history

CAR-T therapies involve removing a patient’s blood, isolating their white blood cells and then genetically re-engineering them to produce a certain T cell. Once re-administered, the cells boost the immune system’s cancer-fighting ability against various blood cancers. 

Johnson & Johnson’s/Legend’s Carvykti and Bristol Myers Squibb’s Abecma are approved for use in multiple myeloma. Other indications include various types of lymphoma (Kite Gilead’s Yescarta and Tescartus, as well as BMS’s Breyanzi) and acute lymphoblastic leukemia (Tescartus, along with Novartis’ Kymriah).

The approval of the first CAR-T treatments in 2017 required drugmakers to manage through not only their complex administration process, but also some significant safety concerns, among them a life-threatening condition known as cytokine release syndrome (CRS). Besides neurological effects, CRS may cause organ failure.

Prescribing information for at least some of the drugs had included secondary malignancies in the “Warnings and Precautions” section of their label. One of them, Carvykti, had a warning for myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) in its black box.

In Carvykti’s Cartitude-1 trial, there were five cases of MDS and three cases of AML, with a further two cases of MDS progressing to AML. Ten percent of these patients developed MDS or AML, with nine out of 10 of these subjects dying.

While various side effects can and have manifested with the CAR-T therapies, most are “generally manageable,” said Marks during a presentation at a “state of the industry” briefing hosted by the Alliance for Regenerative Medicine.

However, in the months leading up to November, the FDA received 19 reports from clinical trials and from its postmarketing adverse event database pointing to a variety of different types of T-cell malignancies, prompting the agency to open its investigation. 

Three more reports came in by year’s end for a total of 22, Marks said. Sequencing is not available for all of the cases and the FDA doesn’t yet have the full data, he added. Nevertheless, he did share some of the agency’s thinking on the matter.

“We know the CAR construct is in the malignant clone, which really suggests that there was probably an association there,” said Marks, referring to a form of analysis FDA has been doing in which the agency looks at the “CAR positivity” of the malignancies. Basically, this measures whether the gene edit is observed or not in the new cancer and if yes, then it’s probably due to the product. 

About 11 days after his remarks at the January 8 briefing came FDA’s letters to the makers of the half-dozen CAR-T drugs, moving T-cell malignancies into the black-box label as a class effect.

As the letters explained, FDA determined that the T-cell malignancy safety signal “should be included in the labeling for all BCMA- and CD19-directed genetically modified autologous T cell immunotherapies.” 

Of note, one of those drugmakers, Gilead Sciences, received a revised letter urging its cell therapy unit Kite Pharma to include the language.

What the manufacturers said

Asked to comment, drugmakers underscored the class-wide nature of the labeling update, pledged to work with the FDA to make those updates to their prescribing information and emphasized the safety profile of their products. 

Unsurprisingly, none of the four acknowledged a causal connection to TCL malignancies. 

“After conducting an analysis of our data, we are not aware of evidence to date establishing that treatment with Yescarta or Tecartus has a causal role in the development of malignancies of T-cell origin,” a Gilead spokesperson said. “Our latest analysis includes more than 15,500 patients treated with Yescarta and more than 2,700 patients treated with Tecartus in our Global Safety Database and medical literature.”

Novartis echoed that “it has not found sufficient evidence to support the causal relationship between Kymriah and secondary T-cell malignancies to date and remains confident in the favorable benefit/risk profile of Kymriah.”

That’s against a backdrop of more than 10,000 patients treated with Kymriah worldwide in clinical studies and the post-marketing setting since Kymriah’s August 2017 U.S. approval, the drugmaker said.

Ditto for BMS, which said it “has treated more than 6,500 patients with hematologic malignancies across clinical and commercial settings with Abecma and Breyanzi, and we have not found a causal relationship between our products and secondary T cell malignancies.” 

For its part, J&J said, “We remain confident in the favorable benefit-risk profile of Carvykti,” adding that to date, more than 2,000 patients have been treated with the drug worldwide. 

Real-world impact unlikely

Nevertheless, as Marks noted, having identified the CAR construct in the new cancer does seem to be substantial evidence – a “smoking gun,” perhaps – that the drug did in fact cause the malignancies seen.

However, revelation or no, this is not likely to have an impact on real-world use of the drugs. In fact, T-cell malignancy is “a non-issue and does not factor…in clinical practice decisions,” wrote UBS analyst Ashwani Verma, in a recent investor note.

Summing up a conversation he had with a KOL-level oncologist focused on multiple myeloma, Verma added, “Our KOL noted that the AML/MDS associated with Carvykti is likely due to the longer survival of patients after treatment with Carvykti vs. other therapies.”

Indeed, one has to weigh the benefits versus risks. These drugs treat diseases that are otherwise fatal. In their currently marketed settings, patients are virtually guaranteed death from these cancers. So, while the drugs can cause secondary cancer, they also substantially increase life expectancy.

Also, consider that standard CAR-T treatment protocols incorporate a preconditioning regimen of chemotherapy prior to the CAR T-cell infusion. This preconditioning is damaging to DNA and can cause cancer at some low rate. Additionally, lentiviral vectors used in the T-cell engineering process can integrate into genes in a way that makes them oncogenic, or mutate them to cause cancer.

Thus, despite the FDA labeling change, there has been no change to the agency’s position that the overall benefits of CAR-T therapies continue to outweigh the potential risks. 

‘No concerns’

As Marks put it, “the rate of a few of these cases…it’s not overly concerning to us in this malignant setting right now,” he concluded, given that some 27,000 people have been treated with the drugs so far in the U.S. 

Despite the agency’s safety investigation, “one has to take a step back,” suggested Marks, and keep in mind that “the other way to try to salvage people is to give them combination chemotherapy with cytotoxic agents that have secondary malignancy rates measured in the low-percent range. So this is a risk-benefit balance.”

The agency is still trying to understand the frequency of the events, Marks cautioned, and said it’s asking providers to monitor the situation closely and report any T-cell malignancies. 

“But make no mistake,” he said, “the overall risk-benefit profile is still incredibly beneficial. For all of the approved uses, we don’t have any concerns with continued use of these products.”

For a March 2024 article about CAR-T makers questing to scale the drugs’ production, click here.