Therapeutic Sequencing and Bridging in DLBCL


Optimizing approaches to therapeutic sequencing in relapsed/refractory DLBCL.

Grzegorz S. Nowakowski, MD: Let’s start from the beginning of the relapse and discuss sequencing the therapy. With this prolonged brain-to-vein time, a lot of patients are left behind or progressing before they can get to the CAR [chimeric antigen receptor] T cells. What do you typically use in those patients? How do you stabilize them before CAR T cells?

Leo Gordon, MD: You’re talking about bridging basically. For me, it depends. We’ve sometimes used Revlimid [lenalidomide] combinations. I’ve been concerned about tafasitamab and lenalidomide, only because I’m then planning a CAR and I don’t know that occupying the CD19 is what that’s going to do. I have a little concern about that, even though there are some data saying it isn’t a problem. It’s often a Revlimid-type regimen. In people who haven’t had a D-HAP [dexamethasone, cytarabine, cisplatin] or R-ICE [rituximab, ifosfamide, carboplatin, etoposide]—in other words, in the second line—I might do that for a cycle. It depends on the situation.

To me, LDH [lactate dehydrogenase] is still the most important clinical factor, going back to data that we did years ago. If the LDH is 3 times normal, I’m not going to sit back. I’m going to treat with a more aggressive regimen. But if it’s just a recurrence with a normal or minimally abnormal LDH, I might look at a Revlimid-containing regimen.

Grzegorz S. Nowakowski, MD: This targeting of CD19 multiple times is very controversial in this setting. There’s some anecdotal evidence that patients did well with CAR T cells for lenalidomide-tafasitamab exposure or other CD19-directed therapy. We also know that expression of CD19 is quite robust on the cells, and you probably don’t need all the CD19 to form the antibodies and the CAR T cells to express its activity. In fact, there are some preclinical data that show that dosing with CD19 maybe can reduce a bit of early activation of CAR T cells, which then leads to apoptosis from overactivation and then better expansion over time. But this is all preclinical data.

Matthew Lunning, DO, FACP: Yes, it’s more our anxieties within a relatively in vivo data-free zone. The in vitro data are very interesting, especially the over-recovery at day 100. That’s what your laboratory showed. In some cases, the community may force our hand. If they gave tafasitamab and lenalidomide and then the patient progressed and they come for a CAR T or lymphoma consultation, is that going to hold me back? No, it’s going to be an asterisk in the chart to say that this person had CD19 exposure before CAR T and let’s see what happens.

Caron Jacobson, MD: Matt, this is where you mentioned earlier that sometimes it’s about the amount of time between therapies. If someone who’s had tafasitamab comes to me and is relapsing, I treat them with 1 or 2 cycles of polatuzumab, just to give them a little time from the tafasitamab because there may be a receptor occupancy issue. We don’t know what epitope tafasitamab binds to. We don’t know if it competes with the binding site for CAR T cells.

Matthew Lunning, DO, FACP: That time is going to be needed anyway, because the odds are fairly low that you’re going to get the CAR T cell on Monday outside of a clinical trial and that a slot magically opens up.

Frederick Locke, MD: A couple of things. One is regarding the question about bridging. There are 2 things here. One is what we call holding therapy, which is when we haven’t collected or done the apheresis but we have time barrier issues. If the patient urgently needs treatment, that usually means I see some symptoms. Maybe high LDH triggers that for me. But if I think that patient can wait the week or two to get the leukapheresis, then I won’t give them any of that holding therapy.

We prefer polatuzumab without bendamustine for the holding therapy, but also sometimes for bridging, which I define as after the apheresis when you know of a defined 4-week, whatever it is, turnaround time to get your CARs back. It’s the same thing. Are they going to need active therapy within that 4-week timeframe? That’s where single-agent corticosteroids or a lenalidomide-based regimen [come in]. Sometimes we use GemOx [gemcitabine, oxaliplatin], something that we can give and hold the tide. But we only do that at our center if we think that patient needs the treatment.

The other thing I’ll say is we don’t recommend CD19, like tafasitamab or lenalidomide, for these patients if we intend to go to CAR. There are emerging data in vivo in patients. I presented this at ASCO [American Society of Clinical Oncology annual meeting]. In ZUMA-7, if you look at CD19 expression by IHC [immunohistochemistry], by H-score—a quantitative score of CD19 expression on the tumor cells prior to treatment—if CD19 expression was low, it was associated with worse EFS [event-free survival] in the CAR T-cell–treated patients. They still did better than the standard of care.

That also matches data from Stanford [University], where they used a bispecific CAR and found that if you look very carefully, using fresh biopsies by flow cytometry, where you quantify the CD19 protein on the cells themselves, that lower amounts—not disappearance—of CD19 on the surface of the tumor cell may be associated with lack of durable response and may go down, even at relapse. We’re still figuring out the role of CD19 target expression, but that gives me even more pause to think carefully about how we sequence these.

Leo Gordon, MD: We do pretty much the same.

Matthew Lunning, DO, FACP: One modality that we haven’t spoken about is radiation. That can be a game-changer in very select patient populations that are going to be problems.

Leo Gordon, MD: Sure.

Matthew Lunning, DO, FACP: Whether it’s “boom, boom, bam, bam” or multiple different fractionation strategies, if you have a chemorefractory tumor in an area of importance—like next to the liver, kidneys, or airway—radiation in the holding, or what I call pre-apheresis period of time, or in the vein-to-vein time may be appropriate. Fred, you guys presented data at a past ASTRO [American Society for Radiation Oncology annual meeting].

Frederick Locke, MD: We have a series of papers in the Red Journal using it exactly as you’re saying, as a holding or bridging therapy.

Caron Jacobson, MD: Yes, and there are data to support radiation affecting the peripheral T-cell compartment, so it’s great to use before you collect the T cells and then to use it right before you give the CAR T cells because it may enhance the immunologic effects. We use radiation whenever we can as well. It’s an important point.

Leo Gordon, MD: We’ve done that as well. It’s an important modality.

Frederick Locke, MD: Thank you for reminding me of that. We published on that; it’s a good idea.

Transcript edited for clarity.

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