Emerging therapies in CAR T as seen in the TRANSCEND NHL 001 trial for the treatment of relapsed/refractory large B-cell lymphomas and the future role of CAR T in lymphoma.

Transcript

Bruce Feinberg, DO: Michael, you get to talk about next-generation CAR T-cells, we anticipate that they’re going to be learning. And we’re going to see refinements of those already in the market andnew agents released. Tell us what’s emerging?

Michael Diaz, MD: One of the things we’re always trying to do in medicine is, as we evolve and reinvent things, we want to make things better, we want to make things less toxic. There was a trial that was done with a Juno product. It was, a phase 1 study released and discussed at the American Society of Hematology this past December. And it was interesting. This study was different in design in that they allowed a larger, broader spectrum of patients to enroll and participate in the trial. That’s one of the criticisms about the previous trials. They didn’t always let what would be considered to be a normal population enrolled in the trial. Patients with a lower performance status that weren’t pristine but still strong and healthy could also participate in the trial. And just as well, they could have some acceptable degree of organ dysfunction, as well as low blood counts such as low white blood cell counts, anemia, low platelet counts. And they let the patients participate in this study. One of the things that was interesting is that overall, it seems like there was a reasonable response rate. Now, we’re comparing apples, oranges, and grapes, but patients did respond well. To a certain extent there may even have been a lower degree of severe toxicities, such to the point that even in this clinical trial, a certain number of patients, maybe around 10% was even treated as an outpatient which is pretty remarkable given the fact that the majority of the time these patients are treated in an inpatient setting. And that helps us understand that maybe this is a lesser toxic approach which deserves more, merits more investigation to see if we can still achieve remission with lesser toxicity to the patients because the easier part is infusing the medicine. The hard part is identifying the patient and then making sure that they are safe after they’ve received it by staying ahead and identifying potential toxicities and making sure that you intervene at the right time.

Bruce Feinberg, DO: Ian, the trial that Michael’s referring to is the TRANSCEND trial, is that the trial, Michael?

Michael Diaz, MD: Yes.

Bruce Feinberg, DO: When you start to see trials that are being done expanding the potential eligibility, what are you thinking down the road three years, five years? What is that role that CAR-T will play in lymphoma?

Ian W. Flinn, MD, PhD: If you look at the constellation of all the trials that are being conducted and where the field is going in general, the realization is that we’re going to have the best outcome for the most patients. We need to make it easier to give, easier to use, and more applicable. A lot of that is in the outpatient setting. We have trials, many of our trials now allow for patients to receive it in an outpatient setting in large cell lymphoma, in multiple myeloma, in solid tumors where that’s definitely the trend. The trial that Mike was talking about, that product tends to have different safety profile that perhaps lends itself, at least that’s what the manufacturer is hoping, lends itself to being used more often in the outpatient world. In the big picture, if we’re going to make the most, we’re going to improve the outcomes for patient, we have to be able to treat more people with this. We have to have a safety profile that can be done more readily and more easily accessible.

Bruce Feinberg, DO: Michael, I’m going to go back to you because even in the setting of relapsed/refractory disease, in most cases when that patient presents back to the office, either they were found at routine restaging or they developed symptomatic relapse, in most cases while you’re waiting for that evaluation to be done by a transplanter in your practice or at a research center, you’re initiating salvage chemotherapy. And maybe it’s R-ICE but you can elaborate on what’s being used. Those treatments themselves are inherently toxic and I’d like to get some understanding about that.

Michael Diaz, MD: That’s a good point. Whenever someone relapses with a large B-cell lymphoma, it can be aggressive and extremely quick-growing cancer that can cause a lot of medical complications quickly if it’s not treated in a timely fashion. Unfortunately, sometimes there is a window of time that is necessary just to be able to get in to see a transplanter. You must start patients on treatment as soon as you can effectively and quickly work them up. And a lot of the times you’re paralleling that.

Some of the standard treatments have been around for several years. They are toxic. You mentioned one that’s called rituxan or R-ICE is one of the things we like to call. There’s even versions using the Gemzar [gemcitabine] and oxaliplatin as well as rituxan. Nonetheless, they all are aggressive regimens. They’re toxic. They can half the time, get a patient into some form of remission to help buy you that time to be able to get them in to see the transplanter. Usually, a patient will have at least one cycle, sometimes unfortunately two cycles before they can get in to see these specialists. Why? Because sometimes it just takes time which patients don’t have.

Bruce Feinberg, DO: Ed, similar? Are you using GEM/OX, RICE, ESHAP, EDAP? Is there a standard within the practice?

Edward J. Licitra, MD, PhD: Most people use R-ICE. That’s the standard if you think they’re going to transplant. This brings a critically important aspect of ultimately getting people to CAR T-cells. To Mike’s point, quite often these patients have been through multiple lines of therapy potentially, they have aggressive disease. We know that the generation of a CAR T-cell takes several weeks from the time we harvest their cells to the time we can infuse. A lot of things must happen during that period, so their care has to be highly coordinated and planned out. It’s which chemotherapy regimen to pick, when to harvest their cells, when to ultimately bring them back, how many cycles of therapy they get. Getting one of these patients who’s been through multiple lines of therapy to a CAR T-cell is challenging, but ultimately in those cases the CAR T-cell may give them the best option for a long-term durable response.

Bruce Feinberg, DO: Ian, as the transplanter, do you have a preference over which regimen?

Ian W. Flinn, MD, PhD: We generally recommend RICE as well. It’s a very aggressive regimen given over three days. We use it as an outpatient, but some centers, they admit patients for it. It’s similar to a litmus test. If they can’t take RICE, then they’re not going to be able to withstand an autologous transplant.

Bruce Feinberg, DO: In a patient who was already determined to be transplant ineligible, are you doing something different?

Ian W. Flinn, MD, PhD: Someone who is transplant ineligible, depending on what the long-term goals are. If you’re transplant ineligible because of organ dysfunction and then you’re just trying to palliate them, then we’re talking about the new CD19 antibody lenalidomide, we’re talking about BR+ polatuzumab, we’re talking about these types of regimens. But, if we’re trying to get them to CAR T-cell, then I wouldn’t do another salvage. You take them directly and try to harvest the cells before further damage is done to their T-cells, so that you have an effective product.