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Bridging Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma
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Before closing out their discussion on the relapsed/refractory setting of diffuse large B-cell lymphoma, panelists identify best practices in bridging therapy.
Transcript:
Matthew A. Lunning, DO, FACP: Dr Rhodes, let’s rewind a bit and talk about the operationalization of CAR T-cell [therapy] because we know in the second line, we’re treating primary refractory patients, they are coming in hot. They have rapidly progressing disease. Dr Westin doesn’t like to use bridging therapy unless he absolutely must, but you sometimes must. What is your go-to bridging? I think this is an important point. I think there are 2 bridges. There’s the pre-apheresis bridging time, I call it the brain to vein time, but a lot of others call it holding time when you want to do CAR T cell, but you haven’t pulled the T cells out. Then you have the clinical trial vein to vein time, which is after you’ve pulled the T cells out, when sprinkling a little bendamustine isn’t going to hurt the T cells. But if you did it before, you’re going to be getting a little phone call talking about out of spec type of situation. How are you navigating this space right now in a very fluid environment?
Joanna M. Rhodes, MD, MSCE: It’s a challenging space. We all know is that, like Dr Westin said, the majority of patients who are CAR T-cell eligible are probably not getting them. Part of that has to do with the fact that there are only so many centers that are doing it. The big issue I think is the time from when you declare someone you want to give CAR T cells to when they actually get apheresis, and that time period can be quite long, depending on whether there are insurance issues, how long it takes the patient to get an appointment with Dr Westin or someone at a CAR T-cell center, a CAR T-cell-ologist, so to speak. Those factors, when it’s 1 week and 1 week and 1 week, suddenly that’s a 6-week period. Especially with the work-up that’s needed for insurance companies, things like pulmonary function tests, which are probably useless, echocardiograms, and LPs [lumbar punctures], depending on what product you’re using. That time becomes quite long. In someone who is primary refractory, with 3 to 4 weeks before you can do anything, you can’t wait that long.
I do use bridging therapy. I think the challenge is what are you going to give, when is that going to start, and how can you pause it? If you give something antibody based, you have to wait, there must be a washout period before you can do apheresis. It’s like a game of chess, trying to figure out all the dates and how that lines up appropriately. I think the other issue is [getting] apheresis spots, because there are so many people who are now CAR T eligible, they’re gold, and that can take time as well.
Matthew A. Lunning, DO, FACP: We often have people calling looking for a cancellation spot to try to move people up, and trying to play that, if I give them therapy, then what now? What is a regimen you would use? I’m going to go to the gentleman to the left of me and talk about radiation as a means of bridging. But if you aren’t going to use radiation, what is your go-to pre-apheresis bridging strategy?
Joanna M. Rhodes, MD, MSCE: At my old institution, we were doing a lot of Pola-R [polatuzumab and rituximab] and then playing the apheresis game, just because, again, you don’t want to give anything that’s going to damage T cells. It’s a Q3 [every 3]-week regimen, so it buys you a bit of time for insurance, pulmonary function tests, etc. That’s what we’ve done. You can use any of the other CD19-directed [therapies] in this scenario as well. You just have to be mindful of the timing of everything in terms of apheresis. Post-apheresis, it’s dealer’s choice, I feel like.
Matthew A. Lunning, DO, FACP: It’s a reset button.
Joanna M. Rhodes, MD, MSCE: You get the reset button.
Matthew A. Lunning, DO, FACP: Very good. Dr Westin, let’s talk about what the role of radiation is in this timeframe. I think it is a very effective lymphoma therapy. Your institution has shown some data on this, all the way from a couple of fractions to definitive therapy. Would you care to comment on your utilization of radiation in the bridging period?
Jason Westin, MD, MS, FACP: Thank you. Radiation is a great tool against lymphomas in the right setting. There is a right patient that radiation might benefit, and often that’s a patient who has a single or maybe 2 hotspots that need to be touched up a bit before the patient can get ready for CAR T-cell therapy. Chelsea Pinnix, [MD, PhD,] from [The University of Texas] MD Anderson [Cancer Center] published an article a few years ago showing that [radiation] bridging therapy, including all disease sites, may do better than other bridging options. There’s perhaps a little bias in that, of which patients get radiation as bridging therapy, they’re going to probably have lower tumor burden overall because they’re eligible for radiation, as opposed to somebody who’s got lymphoma coming out of their ears, may not be someone who gets radiation. I think it’s an important tool to use for the patient who’s got 1 site that’s painful, or 1 site that’s growing rapidly, 1 site that’s putting pressure on some organ that needs to be reduced in size. And maybe you don’t treat everything, but you might treat that 1 area just to hold.
As you mentioned, sometimes you can even use a lower dose or fewer fractions of radiation. Bouthaina Dabaja, [MD, FASTRO,] from our team has coined the term, “boom, boom,” basically giving 2 gray twice, 2 days in a row. That can be very effective to hold the disease for a few weeks to get to CAR T cell. Radiation is something not to forget about when you’re considering a patient who’s got 1 or 2 areas that are getting them into trouble while you’re waiting for CAR T cells to come back.
Matthew A. Lunning, DO, FACP: Dr Flinn, do you have any secret sauce, secret regimen you utilize in the bridging periods?
Ian W. Flinn, MD, PhD: It’s similar to what we’ve already heard. For a long time we’ve used R-Pola [rituximab and polatuzumab] mostly in the bridging after you acquire the cells to keep someone cooled off until they get the T cells. Jason’s presentation earlier today brought home the importance of trying not to have to bridge people. There’s a survival difference if you must give someone another therapy. We have all these logistical issues, we have the same problems with getting patients apheresis, the same insurance barriers as everyone does, but trying to get the referring doctors to realize they need call you quickly to get that patient in immediately, so that perhaps you can avoid this, ultimately translates into better outcomes for patients.
Matthew A. Lunning, DO, FACP: Every day matters in this regard. One of the things we must keep in mind is that size matters of the disease. Now that we have all these fairly effective therapies, when do we employ bridging? The bridging we were talking about years ago was chemotherapy bridging, but now we’re talking about bridging with drugs that have a chance of controlling the disease burden or even shrinking it. Are we at a point, Dr Westin, where we must start rethinking the paradigm around pre-apheresis, post-apheresis and cellular therapy?
Jason Westin, MD, MS, FACP: Absolutely. I think with the old paradigm, many referring physicians would start R-ICE [rituximab, ifosfamide, carboplatin, etoposide] or R-DAP [rituximab, dexamethasone, cytarabine, platinum] and then send the patient to the transplant center. That wasn’t done as bridging, that was done in chemotherapy testing to see if somebody could go to a transplant. Basically, can you give high-dose therapy in autologous transplant? And that still is a muscle memory move that many people will consider to do. “My patient’s progressing, I’m going to just give them a couple cycles of R-ICE, and then I’ll send them to the CAR T-cell center.” What we’ve seen in the ZUMA-7 trial is that delaying CAR T-cell therapy effectively to the third line, if you’ve given someone 2 cycles of R-ICE and they didn’t respond, now you’re in the third line, that’s an inferior approach. I agree with Dr Flinn, sending the patient to the CAR T-cell center as early as possible is absolutely critical. Avoid using bridging platinum-based chemotherapy to try to hold someone when we know response rates are relatively bad, toxicities are relatively high; don’t do that. Send the patient to the CAR T-cell center as quickly as possible.
Transcript edited for clarity.
