Who Should Get CAR-T?

A few days ago, a video was released called "Who Should Receive CAR-T Therapy for Lymphoma."

It's a presentation by Dr. Caron Jacobson, from the Harvard Medical School and Dana-Farber Cancer Institute in Boston. She gave the presentation as part of the Great Debates and Updates in Hematalogical Malignancies virtual conference this past summer.

In the presentation, Dr. Jacobson goes through the results of some of the clinical trials for CAR-T use for lymphoma patients, as well as some "real world" studies of CAR-T that happened after it was approved by the FDA. Based on that data, she has some suggestions for which lymphoma patients might benefit from CAR-T.

I'm not going to go too deep into the data -- the video does that well, and it's fairly dense in the material presented, and a lot of packed into the 22 minute video. But I'll offer some highlights.

The message that I think Dr. Jacobson wants to get across is that CAR-T is "quite revolutionary" and more patients should be encouraged to try it. The message that I am getting is sightly less positive. More on that below.

Dr. Jacobson first looks at three trials, two of which (the Zuma-1 trial and the Transcend-CORE trial) involved patients with B-cell lymphomas. (The other involved patients with T-cell lymphomas, so I'm going to ignore that, since Follicular Lymphoma is a B cell lymphoma). Both trials involved patients with aggressive lymphomas (like transformed FL).

The Zuma-1 trial's CAR-T was Axi-cell, and 82% of patients in the trial had a Response, with 54% having a Complete Response. After 6 months, 41% maintained that Response, including 36% that has a CR.

The numbers for the Transcend-CORE trial, which used the CAR-T treatment called Liso-cel, 73% of patients had a Response, and 53% had a CR. There was not enough data to give a 6 month follow-up.

Dr. Jacobson also commented on the Zuma-5 trial, which looks at patients with Relapsed/Refractory indolent FL -- not aggressive or transformed, but just your regular old FL, the kind that most of us probably have. That data was presented at ASCO over the summer.  Results are great. After about a year of follow-up, 93% of patients had a Response, with 80% having a Complete Response. Of the FL patients in the trial, the response was even better -- 95% Overall Response, with 81% getting a Complete Response.

Those numbers stayed roughly the same in "real world" studies -- doctors who kept track of how patients were doing outside of clinical trials, after FDA approval. See the video for more on the actual studies, but the Overall Response/Complete Response for them were 70/50, 82/64, and 74/54, with one of them finding 41% of patients maintaining the response after 6 months (same as the Zuma-1 trial).

All of this sounds excellent, and it is. However, it gets trickier when we look at  toxicity -- the side effects that come with CAR-T.

In the Zuma-1 trial (the trial for aggressive FL), 93% of patients experienced Cytokine Release Syndrome, with 16% having grade 3 or higher (that is, very serious). 70% experienced neurological toxicities, or nerve issues, with 35% at grade 3 or higher. In the Transcend-CORE trial, 83% had CRS (9% grade 3 or higher), and 53% had neurological toxicities (17% grade 3 or higher).

As with all treatments, there were side effects, and sometimes very serious side effects. The good news, according to Dr. Jacobson, is that doctors have learned how to manage those side effects much better, and those numbers seem to be going down.

Dr. Jacobson also looked at data from patients who were not included in the trial. They received CAR-T, but the results weren't included in the data for lots of reasons, including that they had a "bridging therapy" -- that is, in between the time their T cells were collected and the time they were put back into their bodies, they received another treatment. This makes sense to not include them -- they got something "extra" that might have messed with showing how well the CAR-T worked. 

Those patients who received a bridging therapy were tracked anyway, and the data shows that the CAR-T didn't work as well for them, though it worked better than lots of other treatments. This might have been because their disease was already very far along, and the CAR-T was getting to them too late to hep as much as it could have.

That's really important information to have.

So, based on all of the data, which lymphoma patients should get CAR-T?

Well, CAR-T gave a durable remission (one that lasted longer than 6 months) to about 41% of patients with aggressive lymphomas. Among the reasons it didn't work? Patients has elevated LDH (the disease was behaving aggressively) or had co-morbidities (other health issues that might have influenced the outcome). 

So it seems like CAR-T works well for many patients with aggressive FL, but not too aggressive or too advanced. 

And for patients in the Zuma-5 trial (relapsed/refractory FL), 83% had a response that remained after 15 months. Longer follow-ups and a larger study are necessary, but it seems kind of intuitive here -- CAR-T works better on disease that isn't too aggressive, so maybe indolent, slow-growing FL is an even better target than aggressive FL? [That's a complete guess by me, someone who, I should remind you, is not a doctor or a cancer researcher.]

Dr. Jacobson is calling for more "real world" study of CAR-T, beyond trials, because trials can sometimes be too restrictive. That makes sense -- to compare patient responses accurately, you need clinical trial participants to be as alike as possible. But outside of a trial, after a treatment has been approved, it's easier to pay attention to other variables. Expanding access makes a lot of sense.

OK, so my take on all of this (again, recognizing that I am not an expert, just a patient who reads a lot):

I agree with Dr. Jacobson that CAR-T is "quite revolutionary," and has the potential to really change things for Follicular Lymphoma patients. I look forward to seeing what the FDA thinks about CAR-T for R/R FL patients, those with less-aggressive disease. I know my oncologist s excited about this, too, and thinks it could be a game-changer for FL.

However, we can't ignore a bunch of things: there needs to be more long-term follow-up for the Zuma-5 trial. Side effects of CAR-T, while becoming more manageable, can still be very serious. CAR-T is really expensive, and some health insurers may not like the idea of paying almost a half-million dollars for a treatment when cheaper options exist.

I'm saying this from a patient advocate perspective. I see lots of patients online who think CAR-T will solve all of our problems. And you know, it just might. But we have lots of hurdles to overcome until then. It might not work for everyone, it might not remain working for everyone, and it might not be available to everyone. 

That said, there is lots to be excited about, if we can keep a long-term perspective on things. 

(And since I plan to be around for a very long time, I think I can do that. I hope you can, too.)