T Cell Lymphoma After CAR-T

I may get back to a couple more ASCO presentations, but for now I want to write about three articles in the New England Journal of Medicine this week. You probably remember that in January, the FDA issued a warning about CAR-T. There seemed to be an increased risk of developing secondary cancers, especially T Cell Lymphoma, after CAR-T. Some research a few months later looked at how common those T Cell Lymphomas were.

Now the NEJM has published more research on this topic. Two studies looked at groups of CAR-T patients who developed T Cell Lymphoma after treatment. The researchers in both studies were especially interested in where the secondary T Cell Lymphomas came from. There had still been some uncertainty about whether the new cancers came from the manipulated T Cells. (Remember that CAR-T involves removing T Cells, a kind of immune cell, from the patient; then changing the cells so they can recognize cancer cells; then putting them back into the patient.) The concern is that changing the T Cells makes them more likely to become cancerous themselves.

I'll give you the bottom line -- it's possible that the treatment can lead to the secondary cancer.

One of the studies, "Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy," looked at 724 patients who had received CAR-T at their center. Only one of them developed T Cell cancer -- a patient with Diffuse Large B Cell Lymphoma. The researchers performed a number of tests on samples of the two lymphomas, and found that they were genetically unrelated. However, both were positive for Epstein-Barr Virus, a very common virus that does have a connection to some cancers, including Burkeit's Lymphoma and Hodgkin's Lymphoma. The study isn't suggesting that DLBCL is caused by Epstein-Barr, but there may be some issue that ultimately leads to cancer forming -- in this case, independently of one another. In other words, the T Cell Lymphoma might have come about from the same general conditions as the B Cell Lymphoma, but they are genetically unrelated to one another.

In the other study, "Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy," researchers looked at a different group of patients who were given a different type of CAR-T. This study looked at a single patient who had received CAR-T as a treatment for Multiple Myeloma, a different type of blood cancer. In this case, the researchers did find a genetic connection between the new T Cell Lymphoma and the T Cells that had been changed as part of the treatment. The researchers looked deeply at the samples and seem to have found the genetic alternations that resulted in the T Cell turning cancerous.

To be clear, these two studies weren't comparing the same samples or the same patients -- or even the same CAR-T treatments. And while I say it is possible, I mean that they aren't coming right out and saying CAR-T will definitely lead to cancer, because that's just not true.There have been thousands of patients who received CAR-T who have not had any issues with secondary cancers. They're saying there's a possibility -- but they still don't know why or how.

That's why the third article that issue of NEJM, "T-Cell Cancer after CAR T-Cell Therapy," tries to bring together what the two studies say and add it to what we already know. They point out that there is a connection between the treatment and the new cancer in that second study, but still don't know how it arises. That single case of T Cell Lymphoma came from a pool of 587 B Cell Lymphoma patients, making the rate of incidence 0.17%. That's in line with the data that the FDA reviewed, which identified 354 cases of T-cell lymphoma in 288,478 patients with B-cell lymphoma, an incidence rate of 0.12%.

The important part of these studies is their attempt to identify whether or not the treatment causes the secondary cancer. Patients (like us) with B Cell Lymphomas are about 5 times more likely than the general population to develop a T Cell Lymphoma, meaning the conditions for someone receiving CAR-T are already greater.

In the end, I can't imagine that this research will cause the FDA to change its recommendation about CAR-T. The Black Box Warning will remain, and patients will still need to have that conversation with their oncologists. But the FDA will likely conclude that the benefits of CAR-T far outweigh the risks.