Chimeric antigen receptor (CAR)-T cell therapies have always carried a risk of causing secondary malignancies, but until now that risk has been somewhat theoretical. In the last two months, since the FDA launched an investigation into the risk of developing secondary cancers following the administration of CAR-T cell therapies, a volley of safety updates has increased the scrutiny of these innovative therapies. 

One month after the FDA opened its investigation, Johnson and Johnson and Legend Biotech reported data from the Phase II CARTITUDE-1 trial (NCT03548207) showing that myeloid neoplasms occurred in 10 out of 97 patients following treatment with its CAR-T cell therapy Carvykti (ciltacabtagene autoleucel; cilta-cel). Nine of these 10 patients died after developing myeloid neoplasms. In December, the companies added a boxed warning stating the risk of developing secondary hematological malignancies following treatment with Carvykti. 

Then, on 19 January, the FDA sought to add boxed warnings for secondary T-cell malignancies to all approved CAR-T therapies, including Carvykti. A few days later, the agency updated the proposed label for Gilead Sciences’ CAR-T treatment Tecartus (brexucabtagene autoleucel) to a general class-wide boxed warning instead of the specific warning that was previously issued.

While there is potential for correlation, there is not enough information to infer any causation, says Dr. Bruce Levine, Barbara and Edward Netter Professor in Cancer Gene Therapy at the Perelman School of Medicine at the University of Pennsylvania. Levine is credited as a co-inventor of the first CAR T to get an FDA nod: Novartis’s Kymriah (tisagenlecleucel). “Although there have been cases with T-cell lymphomas and other secondary T-cell malignancies, some of these were positive for the CAR transgene and there are multiple unknowns.” 

Difficulty in defining a causal relationship

Dr. Rahul Banerjee, oncologist and assistant professor at Fred Hutchinson Cancer Center, explains that many of the patients who have developed secondary T-cell malignancies in the CARTITUDE-1 trial have been on other treatments that are known to predispose patients to secondary cancers, including chemotherapies like lenalidomide, bendamustine, and fludarabine. Given the fact that these patients may have received other therapies in prior years that could be coming to the forefront, it is hard to say what effects are due to a CAR T and what are not, he adds.

Banerjee highlights a discussion surrounding this issue at the premier haematology meeting—American Society of Hematology (ASH) Annual Meeting & Exposition—which took place in December 2023, shortly after the news of the FDA investigation broke. In one case of a patient from the Phase III CARTITUDE-4 study (NCT04181827) with relapsed/refractory (R/R) multiple myeloma being treated with Carvykti, a CAR-T cell lymphoma, was observed. However, Banerjee says it appeared as if the cells were potentially predisposed and destined to become a T-cell lymphoma, even before CAR-T therapy was administered. In that particular case, those T cells had many risk factors, including a genetic predisposition that probably meant that they were destined to become T cell lymphoma cells in that patient’s lifetime, Banerjee adds.

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Levine says longer survival because of patients receiving CAR-T therapies creates an “immortal time bias” in this specific population. Often, patients receiving CAR-T therapies are in the R/R setting and have no other good options. However, “patients are now surviving, and we don’t know the frequency of secondary malignancies that would ordinarily occur in this population,” Levine adds.

Moreover, Banerjee points to a population-wide Medicare data analysis that was conducted before the era of CAR-T therapies, which found that patients who had B cell lymphomas had a five-times higher risk of secondary T-cell lymphomas compared to the general population. While some of that is due to treatment, transdifferentiation—where the B cell lymphoma itself starts to behave as if it is a T-cell lymphoma—could also contribute to it, he adds.

While the underlying mechanisms are not well understood, the same risk factors that put an individual at risk of one type of blood cancer could put them at risk of a second kind of blood cancer later, says Banerjee.

The benefits outweigh the risks

“Even if all 22 cases of T-cell malignancies currently being investigated by the FDA are CAR transgene positive, and in every one of them, there was a determinative link of causality, even then, the risk is many, many, many times lower than the chemotherapy that these patients would have ordinarily received,” says Levine.

As recently as five years ago, the life expectancy of triple class refractory multiple myeloma patients was one year or less, says Banerjee. “Even if there’s a 0.1% chance of developing a second cancer, I would say that getting the myeloma in remission is a far bigger threat,” Banerjee adds.

This risk-benefit calculation can be trickier in lymphoma, where CAR-T therapies like Kymriah are approved. “There, therapies are considered to be curative for up to 50% of patients depending on the specific study,” says Banerjee. Calling it “a balancing act”, he goes on to say that the same principle of considering available alternatives that are used in multiple myeloma is applicable here. There are some bispecific antibodies, but they have their toxicities along with the inconvenience of indefinite clinic visits, he says. Patients can be offered a hematopoietic stem cell transplant, but autologous transplant also carries a risk of secondary cancers and so forth, he adds.

In a commentary on this subject published in Nature Medicine, Levine states that the T-cell malignancy reports should be investigated, but existing data suggests a low risk compared with other cancer treatments. Levine goes on to say that this is also the consensus of various organizations like the International Society for Cell Gene Therapy, the American Society for Transplantation and Cellular Therapy, and others. When asked for a comment, an ASH spokesperson said the organization was unable to take a stance on CAR-T therapies at this time.

Changes going forwards

Currently, CAR-T cell therapies are approved as a fourth-line or later treatment, but multiple companies are seeking their approval as an earlier line of therapy. Levine and Banerjee believe that the investigation of CAR-T therapies as an earlier line treatment may help to prove or disprove the hypothesis of a causal relationship between T-cell malignancies and CAR-T therapies. “CAR-T cell therapies are relatively new treatments and have room to grow. So even if they take a hit in, let’s say, the fifth line of therapy sales in multiple myeloma, they still have room to grow in other diseases, and there’s going to be more approvals,” says Sakis Paliouras, associate director for oncology research and analysis at GlobalData.

GlobalData is the parent company of Pharmaceutical Technology.

One potential effect could be on investments in other immuno-oncology modalities, and other CAR-T technologies like in vivo CAR-T cells or those that can bypass or minimize the risk for T-cell malignancies, Paliouras adds.

Although research into the causal relationship between CAR-T therapies and T-cell malignancies is ongoing, the CAR-T cell therapy market is expected to grow. Banerjee proposes that identifying and validating risk factors could help tailor therapies for patients with high secondary cancer risks, while not denying them access to CAR-T therapies.