How Should CAR-T Be Used in Diffuse Large B-Cell Lymphoma?

CAR T-cell therapy has proven to be a widely adopted treatment across many disease states in oncology, and lymphoma is among one of the most prevalent. At the same time, many unique challenges emerge that providers may be more unfamiliar with compared with some of its alternatives. In this Satellite Session program hosted by CancerNetwork®, a panel of community oncologists, an institutional oncologist, a nurse practitioner, and a pharmacist, spoke about the full CAR-T journey in patients with diffuse large B-cell lymphoma (DLBCL).

The panel was led by Brian Hill, MD, the director of the Lymphoid Malignancies Program and a staff physician in the Cleveland Clinic Taussig Cancer Institute. He was joined by Samir Abraskia, MD, a hematologist-oncologist at South Point Community Oncology of Cleveland Clinic; Katie Mohr, CNP, a nurse practitioner in the lymphoma group at the Cleveland Clinic’s main campus; Omer Koc, MD, a hematologist-oncologist at the Cleveland Clinic Beachwood Family Health and Surgery Center; Joel Saltzman, MD, a hematologist-oncologist at Cleveland Clinic Hillcrest Hospital and Taussig Cancer Center; Bachar Dergham, MD, a hematologist-oncologist at Cleveland Clinic Independence Family Health Center; and Jack Kissam, PharmD, BCOP, a pharmacist at Cleveland Clinic Taussig Cancer Center.

Decision-Making in Second Line Treatment

Hill: Where along the way do you most often refer patients for CAR-T?

Abraskia: [At] 12 months is where we decide if this is a patient who we're going to do transplant or we can. We go mostly with the timing of less than 12 months or more than 12 months. No. 2, if you have a patient who [received a] transplant but then relapsed, you might think about that too, CAR T. The third option would be probably a patient who you're considering for transplant but is not fit for transplant. Those are the 3 [cases] I can see for that.

Hill: In what line of therapy? Let's say they had R-CHOP [rituximab (Rituxan) plus cyclophosphamide, doxorubicin, and vincristine] and now they're relapsing. When are you thinking about making that referral before, during, or after second line or third line?

Abraskia: Now, as I’ve changed lately, I would try to do my best to refer patients very early. With the guidelines and the situation changing, I don't have enough experience in CAR-T per se as a community oncologist. I'd like to see how the people who see lymphomas more decide if that's the right approach or not.

Mohr: We typically see CAR-T referrals for second and third line, or if someone has previously declined and [later], they decided [to receive it]. Then we have a lot of trial CAR-T options as well. It can be even later.

Koc: In addition to that, there are these transformed patients. They have Richter’s [syndrome] and have relapsed multiple times.

Hill: Let's say they had follicular [disease], got bendamustine, and now they're coming in 3 years later with a diffuse large B-cell [disease].

Koc: The issue is how do you sequence bispecifics vs CAR-T? Obviously, a lot can go into that. The advantage of CAR-T is [the one-and-done treatment], as opposed to protracted therapy and the associated issues with that. That makes it attractive for eligible patients.

Saltzman: At this point I would have to take Abraskia’s point that pretty much the minute someone recurs I'm referring them for an opinion from a lymphoma expert. The only ones that I'm not [referring] are the frail 80-plus [years old patients] who look at me and say, “I barely want any treatment.” Then I'm thinking about some [other] options.

Hill: If you're truly in the palliative mode, then you're off [CAR-T]?

Saltzman: Exactly.

Hill: What proportion of patients out of 10 who relapse are palliative only?

Saltzman: In my practice, I would say it's probably better than 50% because that’s the nature of who I choose to keep in my practice.

Dergham: Going back to those who relapse after less than 12 months, they're chemotherapy-refractory. Even thinking about transplant, it's [not] a wise thing because in the past, that's what we've done. We give them salvage [treatment] — they each [receive] DHAP [dexamethasone, etoposide, high-dose cytarabine, and cisplatin] — then send them for transplant, and we know they don't do well. You can argue half of those patients treated with CHOP, R-CHOP, or Pola-R-CHP are still doing fine years later. We're curing some, no doubt about it.

With any relapse, early relapse, I lose faith with the chemotherapy and automatically start thinking about bispecifics or CAR-T. It doesn't matter what age because we've always stuck in our minds that those who are eligible for transplant will be eligible for CAR-T, and vice versa. With CAR-T, we can still treat elderly and frail patients. Sometimes dialysis and cardiomyopathy may not be an issue. I also [like] CAR T up-front… anyone who relapsed, I'd like to consult with the CAR-T team downtown after first relapse because you can argue, even beyond the year, and I know with NCCN guidelines, unless it's 4 or 5 years out, anyone who relapsed, I'd like to see if I can go with CAR-T. It's one-time treatment and then they're done. On bispecifics, they may go [indefinitely]. In someone who relapsed 5 or 6 years out, you can reach out with the CHOP argument, but why would I do that nowadays? We have all those good options.

Hill: Out of the last 10 relapses, how many would you say in your practice are in palliative mode, where CAR T on main campus is never going to happen?

Dergham: Maybe one…. I refer them. That doesn't necessarily mean they would get it. Let's put it that way.

Hill: [Kissam], I know every day you come in and hear about the last relapse and the next chemotherapy or the next regimen we want to build because these second-line regimens are constantly evolving. But what have you seen on the pharmacy side of things? The people that you are prepping orders for, have they already had multiple lines [of treatment] or are they typically already in their second line?

Kissam: I see a lot in the second line. The main patients I get involved in are the ones who get admitted, like the relapsing [patients]. Then we have to give them some sort of bridging therapy, whether that just be Pola-R -GemOx [polatuzumab vedotin plus rituximab (Pola-R) plus gemcitabine and oxaliplatin (GemOx)]. Or maybe we start them on glofitamab (Columvi)-GemOx and then give them the CAR-T once we can get that ready. Those are the patients I see a lot.

ZUMA-7 Findings

Hill: We're coming up on the 10-year anniversary of the first CAR-T patient treated at Cleveland Clinic. It was actually my patient on the ZUMA-1 trial, 9 years ago now. Since the ZUMA-1 trial led to third-line approval, a lot of things have happened. Probably the most important was ZUMA-7.

In the event-free survival [EFS] by either investigator assessment or the blinded central review there was a dramatic and substantial benefit to immediate CAR-T over the approach of platinum-based chemotherapy and transplant…. What you can see in second line is basically that we're curing half of all comers as opposed to 25% of all comers. That translates into a statistically significant overall survival [OS] advantage. Now we're really curing people or they're surviving longer, and the hazard ratio here of 0.7 was significantly different.

Abraskia: I like the progression-free survival; the EFS is very impressive. But for this group of patients, the refractory disease group didn't do as well as the [patients] who are relapsed for less than 12 months. I like the idea that you have an OS [advantage]. That's nice. I like the idea of the flattening [curve], which is hopefully some of [the patients] cured. As far as the adverse effects [AEs], we understand it very well in the community now, mostly because of our [patients with multiple myeloma].

Hill: Katie used to work on the inpatient [Bone Marrow Transplant] unit quite a bit. You lived and breathed autologous transplant, and you took care of the patients receiving axicabtagene ciloleucel (axi-cel; Yescarta) and lisocabtagene maraleucel (liso-cel; Breyanzi). What were your impressions of the tolerability of the 2 approaches?

Mohr: On the inpatient side, it seemed like axi-cel had a tougher AE profile. We tended to see more neurotoxicity and more cytokine release syndrome [CRS]. Liso-cel was a bit better tolerated, at least from what I saw in the immediate inpatient side of things.

Hill: How does it compare to [autologous] transplant [using abemaciclib (Verzenio) as the preparative regimen]?

Mohr: [It] was probably similar. If people had no toxicity, it was easier. If people had severe CRS, obviously it was a bit harder. When we used [busulfan, ifosfamide, and VP16], that was much tougher.

Hill: How about the duration of stay in the hospital?

Mohr: It was shorter for CAR-T.

Hill: [Kos], you have experience with transplant and have [treated] many patients who've gone through CAR-T. What are your general impressions of tolerability?

Koc: I think certainly better tolerated in terms of the immediate, post-treatment [toxicity].

Survivorship

Hill: Now we're going to address delayed toxicities following CAR T. We have Marcus; he got his CAR-T of axi-cel 3 weeks ago, and had some grade 2 CRS, so that means fever and some hypotension, tachycardia, or hypoxia. It resolved after a few days. Then, no other toxicities or neurologic events. He's been discharged. He's home. He's ready to go back to his community [oncologist]. How long after CAR-T are patients typically transitioned back to the satellite center?

I'll just answer this and say that we hold on to them for at least 30 days to get that 30-day response assessment. I don't think we've done you any favors if we do the CAR-T, then 2 weeks later send them to you to order the PET scan and find out that it didn't work. Certainly, we want to get them — especially the people who are really attached to their primary oncologist — back in to see you. What have you all on the receiving end experienced?

Dergham: Early on, I used to freak out. With my first CAR-T patient, they called me and said, “We’re sending [them] back to you.” I said, “Seriously?” Because we did not know what to do. I told them the other day: the first time I heard about ICANS [immune-effector cell associated neurotoxicity syndrome], I had to Google it to know what it stood for. It was very new to us. Now we're more comfortable seeing those patients. We always have the backup in case we have any concern or question; I can make a quick phone call and address it. Giving the prophylactic antibiotic, intravenous immunoglobulin, if needed, we became [increasingly] trained how to [address it]. But early on, I hated when I got the phone call and I tried to push it off as far as I could.

Abraskia: I share what [Dergham] said. Initially we were confused, but now we know what to do. Most of them have been seen by specialists in the main campus, like infectious disease — I have a few patients with cytomegalovirus titers, and they gave me guidance about what to do with that. We always get guidance before the follow-up plan. We share patients. Every 2 to 3 months, [the patient will] go back to the main campus and see their lymphoma specialist, while I'm doing the work in the community.

Hill: [Kissam], what have you seen in terms of low [neutrophil] counts and the need for growth factor?

Kissam: I get involved with the low counts a lot with trying to get approval for like filgrastim or pegfilgrastim for patients, then the intravenous immunoglobulin [IVIG] a lot. I've seen problems with insurance specifically…. A lot of time they want to do what they call white bagging….

Essentially, we won't provide the IVIG. [The patient will] get it from another pharmacy and they'll bring the IVIG to main campus and get infused there, where we lose a lot of money from it. We try to avoid that if possible. There's a lot of fighting with insurance on that.