Treating Patients Who Relapse or Progress on CAR T-Cell Therapy


Drs Nowakowski and Gordon discuss treatment options after disease relapse on CAR T-cell therapy.

Leo Gordon, MD: We’re talking about CAR [chimeric antigen receptor] T cells and how the responses are great and the durability looks great. But when it doesn’t work, when patients relapse or don’t respond, it reminds me a little of the [Henry Wadsworth] Longfellow poem about the little girl with the curl on her forehead. “When she was good, she was very, very good. But when she was bad, she was horrid.” What do we do about CAR T cells that are horrid, when they aren’t working? What’s our next step? Is it all these things that we’ve talked about? Is there anything that anyone favors? That’s a question that comes to me.

Grzegorz S. Nowakowski, MD: That’s an excellent question. In addition to those relapses after CAR T cells, which can happen relatively early, those patients frequently have profound cytopenia from lymphodepleting therapy, which makes another candidate for many of the therapies that we use in this setting. It’s a very challenging population. Multiple reports show that survival of those patients is extremely poor, particularly if they have cytopenia, because it corresponds to more aggressive relapse. What do we do for those patients? What do you do in your practice?

Caron Jacobson, MD: I like bispecifics in this setting, but obviously that means trying to find them on a clinical trial. I also like second cellular therapy trials, either CARs that target more than 1 tumor antigen or CARs that target a different tumor antigen. With allogeneic CAR T cells, we’ve seen some activity post autologous CAR failure. Those are my preferences, but I’m always trying to get those patients to an allotransplant because they’ve already proven to us that their remission isn’t going to be durable to an immunologic therapy.

When a trial isn’t available to me, or the patient isn’t a candidate for a trial, this is where I go to with or without bendamustine and Rituxan [rituximab]. As I said before, I’d also use tafasitamab and lenalidomide if the patient is still CD19 positive. It’s going to be interesting when more patients get polatuzumab in the front line. That isn’t going to be an option for either bridging before CAR or relapse after CAR, so it’ll be interesting to see how the landscape changes with new approvals.

Frederick Locke, MD: We don’t know the best treatment after failure of CAR T cells. That’s a huge unmet need because we’re seeing CAR T cells move up earlier. I agree with Caron. Getting them into remission is key. If you’re able to do an allogeneic transplant, that’s how I try to do it. But I’d also add that as we move them into the second line, there’s an outstanding question. After we’ve done CAR T, maybe in the second line for a patient, could they benefit from an autologous transplant if they progress on CAR T? We don’t know the answer to that.

Leo Gordon, MD: It’s similar. For example, we’ve had patients on the PILOT study, which was designed for people who aren’t candidates for stem cell transplant. But we’ve had people on that trial who progressed then had a transplant. We said, “You’re 73, which is the reason you went to CAR T first, but the performance status is good now, and we’ll try a transplant,” and we’ve had people who have had long remissions. We also try allotransplant in younger patients. I explain to patients that CAR T was derived from the idea of allotransplant, but now we’re talking about an educated T cell that’s going to treat their lymphoma. An allotransplant is an uneducated T cell that’s going to treat [their lymphoma]. Why is that going to be better? We try it, but I have this thing in the back of my head that says, “Why does that make sense?”

Caron Jacobson, MD: In Hodgkin lymphoma, there’s some evidence to support sequencing an autologous transplant or going back to chemotherapy after CAR T-cell therapy in the second line that either led to partial response and then relapse or led to a complete response followed by a relapse. We definitely see that after patients get immune checkpoint inhibitors, they can respond to chemotherapy regimens that they didn’t respond to before the immune checkpoint inhibitors. There’s clearly a chemotherapy resensitization following immunologic therapies. I recently had a patient who relapsed a year after liso-cel [lisocabtagene maraleucel] in the second line, and she was primary refractory. She responded beautifully to chemotherapy and had an autologous transplant and did great. There’s a valid reason to try that approach.

Grzegorz S. Nowakowski, MD: You’re touching on something very important with the sequencing of therapy and how the choice of therapy can affect subsequent therapies, or some of the gains in progression-free survival resensitize patients to therapy as well.

Transcript edited for clarity.

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