John M. Burke, MD

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 We talked about loncastuximab and LOTIS data, LOTIS-1. There’s 1 more thing that’s out there to be aware of. LOTIS-8 is being tested in newly diagnosed patients, but I haven’t reviewed that yet. Be on the lookout for that to be reported. Of course, when I introduce myself, I always say I’m a recovering stem cell transplanter, and neither 1 of us is an actual cellular therapy prescriber. We’re referring physicians for cellular therapy. With that in mind, take our insights with a grain of salt. We represent—I wouldn’t say community, because Dr. Burke is amazing and impressive. I love this discussion learning. You know the data so well, but we’re not the ones managing toxicities, grading the ICANS [immune effector cell-associated neurotoxicity syndrome] score for neurotoxicity, cytokine release, and stuff like that. We come to this discussion from a prescriber’s perspective.

That being said, the other big area for all of us is where does CAR [chimeric antigen receptor] T-cell therapy fit in? We’ve talked about it a little in the beginning in our fit vs unfit. I will just say that if somebody is eligible for a curative therapy, they need to be referred and considered for that therapy. Loncastuximab, tafasitamab-lenalidomide, polatuzumab, and all these other new things are not curative therapies. Looking at all the major products, we have the ZUMA trial, JULIET, and TRANSCEND NHL 001, which is the liso-cel [lisocabtagene maraleucel]—I call it the Kite, the Novartis, and the Juno. These are the 3 options. If you look at big picture from a prescriber standpoint, of those patients, maybe 40% to 50% can be cured from CAR T in this setting, and it’s currently for third line. My general perspective is that anybody who can be considered for that should not be deprived of potentially curative therapy. What do you think, John?

Liso-cel, tisa-cel [tisagenlecleucel], and axi-cel [axicabtagene ciloleucel]. You made an important point earlier that very few patients who are eligible for CAR T-cell therapy receive it. It was in 1 of the ASH [American Society of Hematology] journals within the last year. Since CAR T was approved for DLBCL [diffuse large B-cell lymphoma], about 2000 patients have been treated with it. Within the last year I saw that in writing, so that’s not many if you think about how many relapsed large cell lymphomas have happened in the United States over the last 2 years since CAR T became available. It’s important, as you say, to think about it, to offer that to patients as a potentially curative option, and to make every effort you can to get your patients to it.

There’s a reason that not that many patients have gotten it or many reasons, including all the barriers—the insurance hurdles, the cost, the potential toxicities might scare some patients away, the need to travel to selected centers, the lack of wide availability, many potential barriers to it. That does open the door for some of these newer therapies that, as you say, may not be curative. I’m a little cautious on saying that because chemotherapy alone can be curative. If you go back and look at the old PARMA trial, there’s a tail on that curve even in the chemotherapy arm. Tafasitamab-lenalidomide sure has pretty good PFS going out at 3 or 4 years. Even polatuzumab-bendamustine-rituximab has a percentage of patients who haven’t relapsed after getting that treatment. CAR T-cell therapy does appear to be the leader in terms of potential for cure in relapsed DLBCL.

 I don’t think either 1 of us wants to look in depth at axi-cel, tisa-cel, and liso-cel. We all seen those trials out there for a while. The new kid on the block is the liso-cel, and that FDA approval was almost 2 years after the other 2. That may be interesting in terms of outpatient because they have a lot more data there. Steve Schuster, 1 of my mentors from fellowship, did try to compare tisa-cel and liso-cel. There was no real measure; it was not prospective. Looking at the data, there was no significant difference in outcomes between those 2 products. More data are needed in terms of comparing these head-to-head.

I’m excited about the allogeneic ones as well, maybe having an off-the-shelf version that decreases the processing time. That may be more accessible to people in the community or who aren’t able to travel. My dream is to not need FACT [Foundation for the Accreditation of Cellular Therapy] certification to do that because my background is as a transplanter. It would be good for remote areas if that could be a product in the future. The [University of Texas] MD Anderson [Cancer Center] data looking at those NK [natural killer] allogeneic products look really exciting.

We have these 3 available, and the hope is that No. 1, in my opinion, we can move up to second line for those wham-bam-thank-you-ma’am, chemotherapy-refractory patients who you know aren’t going to be cured with an autotransplant, and then getting people fast enough and bridging them to CAR T. You don’t disagree, John, that if somebody is potentially a candidate, they should try to get it if possible.

Videos

Experts discuss recommendations to increase the uptake of CAR T-cell therapies into clinical practice and relapsed/refractory diffuse large B-cell lymphoma.

Increasing CAR T-cell Use in R/R DLBC Lymphoma: Marin F. Xavier, MD; John M. Burke, MD

 When you have a patient who’s fit who has relapsed, the million-dollar question is, do you refer over and try to avoid CD19? Obviously, for relapsed large cell lymphoma, you don’t have a lot of time to get referrals. Oftentimes they need to be treated right away. In fit patients, do you go with an R [rituximab]–salvage chemotherapy approach until you know if they’re going to get CAR [chimeric antigen receptor] T cells or auto transplant? How is your clinical pathway for a fit patient with relapse large cell?

 Historically, I’ve administered salvage chemotherapy. For fit, transplant-eligible patients, I’ve initiated the salvage chemotherapy, and then I get on the phone. I’m not a transplanter, so I do refer those out. I’ve gotten on the phone and arranged for a referral to a transplanter. That’s how it has worked in my practice. I’ll deliver the salvage chemotherapy, typically R-ICE [rituximab, ifosfamide, carboplatin, etoposide], arrange for them to see the transplanter, and have that ready to go if they’ve achieved a response after a couple of cycles.

It will be interesting to see how the world changes because we have in press release form only that 2 of 3 trials, comparing CAR T in the second-line setting with salvage chemotherapy and transplant, have improved event-free survival. What will be interesting is seeing those data at an upcoming meeting. Then also teasing out why did 2 of them work, but not the third 1? How should we all be practicing in the second line? Assuming that the decision is made that the best way to go is CAR T-cell therapy as a second-line therapy instead of salvage chemotherapy and transplant, a lot of questions come up. How are we going to get everyone to that? Do we have enough CAR T-cell centers to do that for the patients we have? Are there a lot of patients who won’t be able to travel to a center for CAR T-cell therapy, and can we expand CAR T-cell therapy and make it more widely available? What do you do after that? The experiences of patients who relapse after CAR T can be hard to treat. A lot of times they have cytopenias that prevent further therapy or make further therapy more difficult. What becomes your best third-line therapy after CAR T cells? There are a lot of questions, and the field may change dramatically in the next year as we see some data emerge. It’s a very exciting time.

 At the ICML [International Conference on Malignant Lymphoma], they did report out the ZUMA-7 and BELINDA trials for the second line.

 ZUMA-7 would be for the Kite product, and BELINDA for Novartis. Maybe it’s because I’ve been doing lymphoma for 20 years, but I get this gut feeling when I know that a salvage transplant is not going to cure someone. What goes through my mind is, how long did they have their remissions? If it’s truly chemo-refractory disease, I try to push my patients onto those trials. We’re lucky to have centers that we partner with that offer them. Or do we fudge it, give a bridge, and then call it standard third-line therapy? If I know somebody is not going to be cured with high-dose chemotherapy and stem cell rescue, I find myself in that situation a lot: the bad ones recur soon after their frontline therapy or double or triple hits. I’m trying to get them on a fast track to cellular therapy. I work within a transplant group, but I don’t do transplant anymore. It’s still hard to get authorization for CAR T. It’s easier to do an auto transplant, especially if they’re Medicare. Most of our patients are Medicare, so there are financial barriers. They changed some of the reimbursements for that a year ago. It should make it easier, but it’s not easy to get it coordinated. Very few patients end up getting CAR T in any setting.

 That’s an important point for practitioners to realize. It takes awhile to get it set up, to get them referred and get the insurance authorization. Most people by now have some experience with that and the delays. In a rapidly progressive disease, that can turn out not so well. When you have a patient with relapsed large cell lymphoma, getting on the phone early with your transplant CAR T-cell provider is important.

Experts discussed using newer targeted treatment approaches as frontline therapy  instead of transplant in patients with relapsed/refractory diffuse large B-cell lymphoma.



CAR T or Transplant in DLBC Lymphoma: John M. Burke, MD; Marin F. Xavier, MD

 What are the greatest unmet needs for the available frontline options?

We have R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] plus drug X. As we said in the beginning, we’ve had a hard time establishing a practice change based on the many attempts. Who knows if the data for polatuzumab are going to change practice. So far, we have a pretty decent 1. R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is less toxic than everything else in the chemotherapy land that they compared it with, even before the rituximab era.

Let’s move on to the meat of the discussion, which is CD19 as a target. This is a hot topic because while there was no drug approval, we had polatuzumab approved in the third-line setting with bendamustine and rituximab. For the longest time, the only other thing approved was CD19 CAR [chimeric antigen receptor] T-cell therapy a couple of years back. Now we have 2 other CD19-targeted therapies that are on the shelf for us to use. Tell me, Dr. Burke, what are the characteristics of a good therapeutic target in diffuse large B-cell lymphoma [DLBCL]? How does it function in healthy cells, and how does it differ from CD20?

 For a targeted DLBCL, you want the target to be present on the cells. That’s 1 key feature. You don’t want a target that’s present or partially present. CD19 is a transmembrane protein that’s expressed on pretty much all B cells, perhaps more reliably than a CD20, which we’re all used to targeting in DLBCL and many other lymphomas. To my understanding, its function is to modulate B-cell receptor signaling, so that’s what it does in normal B cells. It’s been proven to be a really useful target in DLBCL and many other lymphomas with the advent of various types of drugs, from naked monoclonal antibodies in the form of tafasitamab, to antibody-drug conjugates with loncastuximab, to several CAR T-cell therapies. It’s very clear that CD19 is an excellent target in DLBCL.

 Yeah. My short answer would have been saying it’s just a pan–B-cell marker. I’m glad you tried to dig up some of that transmembrane B-cell–signaling science. For a clinician, we see it as a pan–B-cell marker. I agree that it’s more pervasive than CD20, especially in B-cell lymphomas.

One thing is that there could be different isotopes that some of these anti-CD19 therapies target. The CAR-T CD19 epitope may be different from the naked antibody and antibody-drug conjugate. We’re starting to see some data about it being effective to use another anti-CD19 as a bridge to CAR T, or that CAR-T failures still respond to CD19 therapy, non–CAR T after. We’re starting to get a little more data about that, mainly from tafasitamab. Because that was the first naked antibody available, we’re starting to have some real-world data emerge on that. Any thoughts about different targets for CD19? What do you know about using CD19 and then being able to do CD19 CAR T vs vice versa?

 As you said, we’re starting to get some information on that, but we certainly don’t have the level of evidence that we’d love to have. There are some laboratory data from the Mayo Clinic suggesting that 1 does not necessarily lose sensitivity to CD19-targeting therapy between tafasitamab and CAR T-cell therapy. When tafasitamab was approved, I was hearing about a couple of case reports of patients getting 1 treatment after another and doing reasonably well. In the loncastuximab trial, they report patients—I forget exactly how many; I think it’s 9—who received loncastuximab and then went on to receive CAR T-cell therapy. They reported on the response rates in those patients, and it looked similar to the overall response rate of patients on the trial, something like in the 40s. So far there haven’t been a lot of clinical data suggesting that patients can’t respond to 1 treatment after the other. But there’s concern about that in the field.

 We haven’t been charged with talking about bispecifics, but that’s another exciting area that has CD20 and CD19. I’m looking forward to looking at that. Bispecifics work really well after CAR T failures in certain situations.

Experts discussed using CD19-targeted agents in patients with various subtypes of diffuse large B-cell lymphoma.



CD19 CAR T and Therapies in LBC Lymphoma: Marin F. Xavier, MD; John M. Burke, MD

 [Let’s] talk about relapsed/refractory [R/R] [diffuse large B-cell lymphoma (DLBCL)]. Can you tell us about your current treatment approach at The University of Texas MD Anderson Cancer Center for patients with relapsed disease, and how frequently do you see patients relapsing?

 Generally, when we counsel patients even at frontline, we anticipate that we may see treatment failures as high as 40% after using R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate (Oncovin), prednisone] or CHOP-like frontline approaches. There are different time points when [treatment] can fail, and [these] inform some of our second-line approaches. [We’re particularly nervous about] patients with primary refractory disease who progress in the midst of frontline CHOP-like therapy or generally within 6 months of completing frontline therapy. We also have learned from the CORAL study, which looked at the preferred salvage regimen for patients—R-ICE [rituximab, ifosfamide, carboplatin, etoposide] versus R-DHAP [rituximab, dexamethasone, high-dose cytarabine (Ara-C), cisplatin (Platinol)], and the takeaway was that patients who [had progressive disease] within 12 months of frontline rituximab-containing therapy generally had a poor prognosis. For patients who [have progressive disease] beyond that 12-month interval, it's still not a good factor for R/R large cell lymphoma. Generally, my anxiety surrounding their prognosis is slightly less. With that in mind, [we’re quick to try to enroll] our primary R/R patients on a novel-based approach.

We had had 3 of the randomized studies looking at CAR [chimeric antigen receptor] T-cell therapy in that second-line space, [which] was our preferred trial option for patients with primary R/R disease or those [with disease] that progressed within 12 months. Outside of a trial, that's where we probably could spend some time discussing, “What is the best approach for these patients?” I generally will assess their fitness level, and if I have patients who I think are going to tolerate intensive therapy and potentially go on to targeted stem-cell transplant and high-dose therapy, I generally will still pursue salvage, even if my expectation is lower that they'll respond. That's been our traditional route to date. However, for patients who are unfit or frail, or I'm concerned they're not going to get to transplant, I might consider a more novel approach.

[Based on the L-MIND study data], we have tafasitamab and lenalidomide as a reasonable second-line option right for transplant-ineligible patients, whether [because] of comorbidities or frailty. Where I'm struggling the most is for those patients who are refractory to frontline therapy. My optimism surrounding salvage chemotherapy is low. But if they are fit and could potentially tolerate salvage chemotherapy, should I be altering treatment and pursuing tafasitamab/ lenalidomide because it has a novel mechanism of action? That's where I've been struggling, because those patients were also excluded from the L-MIND study. But I think that's an interesting area to discuss. What do you do?

 My overall approach is similar. I think it's fairly well-established that we think about these relapse patients in two main groups—either they're transplant-eligible, or they're transplant-ineligible. In someone who's considered to be eligible for transplant, it's generally accepted that that's the most likely way to cure that patient, and that's the route you should go. Certainly, the times may be changing. We heard in a press release that there may be some data forthcoming, that one of those three trials you mentioned regarding CAR T-cell therapy may be demonstrating improved outcomes, or, apparently, is demonstrating improved outcomes.

That is hot off the press, and I'm not aware that many people have seen that data. Historically, our standard for those folks has been salvage chemotherapy followed by transplant. Then you consider how quickly a relapse is occurring after initial therapy, and you're more comfortable with giving chemotherapy to patients [with relapsed disease that] occurs at least 6, but preferably 12, months later. Those who have so-called “primary refractory disease” have a much less favorable outcome, because their cancer has relapsed really quickly. Then you have [patients] who are considered to be transplant-ineligible, possibly because of their comorbidities, performance status, age, personal preference, or distance from a transplant center. In those patients, we just had conventional chemotherapy. Over the last couple of years, a lot has changed.

Many new targeted drugs [have] become available, and those include polatuzumab in combination with chemotherapy, tafasitamab, and lenalidomide. Selinexor was approved last year, and, just recently, we have loncastuximab tesirine, a new antibody-drug conjugate. We suddenly have this plethora of options to offer patients who are not eligible for transplant or who experience relapse after transplant or CAR T-cell therapy. It is one of the challenges of managing these folks these days. But then, how do you do that, and how do you sequence these things?

Loretta Nastoupil, MD, and John Burke, MD, discussed treating relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

CAR T and Other Approaches for Patients with R/R DLBC Lymphoma

John M. Burke, MD, associate chair of the Hematology Research Program for US Oncology and medical oncologist and hematologist at Rocky Mountain Cancer Centers, discusses the potential benefits of time-limited therapy with BTK inhibitors in B-cell malignancies.

Whether BTK inhibitors have to be given continuously to maintain their efficacy remains unanswered, says Burke. Moreover, the majority of trials to date have evaluated indefinite BTK inhibitor therapy. 

However, continuous BTK inhibitor treatment can cause additive toxicities over years, as well as added cost to the health care system, Burke explains. Additionally, many patients prefer to stop therapy rather than continue on the drug indefinitely. 

Stopping therapy after patients achieve an early clinical benefit appears to be an ideal approach to BTK inhibitor treatment, Burke says.

Currently, trials are evaluating novel combinations to see if patients can achieve deeper remissions and then stop therapy with favorable outcomes, Burke concludes.

John M. Burke, MD, discusses the potential benefits of time-limited therapy with BTK inhibitors in B-cell malignancies.  



John M. Burke, MD

Articles

Increasing CAR T-cell Use in R/R DLBC Lymphoma: Marin F. Xavier, MD; John M. Burke, MD

CAR T or Transplant in DLBC Lymphoma: John M. Burke, MD; Marin F. Xavier, MD

CD19 CAR T and Therapies in LBC Lymphoma: Marin F. Xavier, MD; John M. Burke, MD

CAR T and Other Approaches for Patients with R/R DLBC Lymphoma

Dr. Burke on the Potential of Time-Limited BTK Inhibitor Therapy in B-Cell Malignancies