Marin F. Xavier, MD

We’ve covered most of the clinically important stuff. We have some questions about the lymphodepletion and promising up-front therapies. We already discussed what’s most clinically important. We talked about the sequencing. Let’s move on to the future options in terms of what you’re excited about. I already hinted about what I’m excited about, and you’ve educated a lot about some trials that are going to be reporting out, especially for front line. Anything that excites you for large cell lymphoma in the coming months to years?

As you mentioned, the bispecific antibodies are probably first on most everyone’s minds. We saw 4 or 5 of them reported out at ASH [American Society of Hematology Annual Meeting] last year and some more follow-up from the summer meeting, so it will be exciting to hear more at ASH this year. That’s probably No. 1. High up there, as you mentioned, are some of the off-the-shelf cellular therapy products: T-cell and even NK [natural killer]–cell therapies. I hope it’s as easy as just seeing great efficacy of those things and then making cellular therapy more available to more people. That would solve a lot of problems, especially with some of the reduced toxicity problems that are being seen. It seems that’s a potential therapy that could be delivered more widely than CAR [chimeric antigen receptor] T. The biggest problem with CAR T is that it’s hard to get. It’s hard to get patients there and hard to get patients that treatment. There are a number of other novel therapies out there. One that’s crossed my radar screen is targeting the CD47-SIRPα interaction. There are antibodies being developed at both of those targets showing some potential for promise, particularly in combination. We’ll see how that turns out. How about you? Anything else high on your radar?

Yeah, CD47 is interesting in many malignancies as a different type of immunotherapy using phagocytosis. Thanks for bringing that up. I’m excited to see how that pans out in terms of will that be another tool in our toolbox. You and I mentioned previously bispecifics. There’s 1 that’s also a subcutaneous and that seems to be pretty manageable. I’m comfortable doing bispecifics even in the ALL [acute lymphocytic leukemia] setting, even not being a transplant center. That’s really promising as a salvage therapy and also in combination with front line. They’re both going to have some potential improvements on our standards and be fairly accessible in the community.

What are your pearls for the community hematologist-oncologists who may see diffuse large B-cell lymphoma [DLBCL]? That’s our final question.

The pearl is that we have long-term disease control and a lot more therapies that work for a significant duration of time in the second- and third-line settings. That’s my mantra. It’s no longer life and death, and it’s possible to live with decent quality of life with relapsed diffuse large B-cell lymphoma. That’s where I find a lot of hope. I see a lot of geriatrics, so it’s been fun to have this new role to palliate.

I can’t say it any better than that. The other thing I’ll add is that, all of a sudden, we have all these new agents. That’s a fairly uncommon scenario for us oncologists to be facing relapsed DLBCL. We have more treatment options now than you can possibly use as a community doctor. It’s hard to be an expert on all these and to get experience with all these. Nobody can use a ton of tafasitamab, a ton of loncastuximab, and a ton of selinexor and polatuzumab. Going back to a point you made earlier about contacting your local or regional expert in the field and finding somebody you can trust and work with to help manage these patients is important to make sure your patients are getting the right treatment.

Thank you so much. They chose both of us for a reason. We’re community doctors who happen to see a lot of lymphomas, and not depriving the opportunity for cure and working with your cellular therapy programs is quite important. This has been extremely informative for me. I hope our audience agrees. Dr. Burke, you’ve been such a wonderful discussant. Thank you so much to the audience for watching this 

™presentation of “CD19 as a Target in the Treatment of Diffuse Large B-cell Lymphoma.”We hope you found this to be useful, as I did, and we thank you for inviting us for this opportunity.

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The future of combined treatment approaches with anti-CD19 therapies for diffuse large B-cell lymphoma.

Next Steps Using Anti-CD19 Therapies in DLBCL

These are chimeric antigen receptor [CAR] T cells, and the most common of the 3. They’re all CD19, which is the important point. That’s why we raised these questions about sequencing with other targeted anti-CD19 therapies and the unknown questions. Yes, we have some data emerging about people going on to receive CD19 CAR T post-loncastuximab in the LOTIS registrational trial. They reported out a subset of those outcomes and then looked at tafasitamab before and after tafasitamab CAR T. From the toxicity scales to mitigation.

The 2 of us are not consenting our patients, but they’re coming back to us for guidance. They have this scary discussion, and they want us to tell them what to do. So we do need to know a little about the risks of the procedures. I’ve had probably a dozen or 2 that were on a lot of the trials, and BCMA [B-cell maturation antigen] and CAR T for myeloma. The neurotoxicity can be long-standing: long-standing cytopenias, long-standing B-cell depletion.

I talked to David Porter, who’s 1 of my mentors, from the University of Pennsylvania. Using CD19 for CLL [chronic lymphocytic leukemia], we’ve been doing initial studies at the University of Pennsylvania. Those patients are now over 10 years out, but a lot of them are still requiring IVIG [intravenous immune globulin]. There’s a cost to that potential cure. In my 75 year-olds who are very skittish, I say, “The stakes are high, but the outcome can be long-term remission and cure.” I do heavily push the youngsters, for sure. But those geriatric patients get in this category who are not fit enough for autotransplant but may be fit enough for CAR T. That’s a gray zone.

From a clinical perspective, let’s talk about that group. When they come back to you, are you enthusiastic about pushing them toward that, or do you say we have some other alternatives?

You’re talking about the group, post? Which group again?

The group of patients who relapse who are not fit enough for autotransplant but are considered fit enough for cellular therapy. That’s where I struggle the most on pushing people toward cellular therapy when we have some very effective alternatives that we never had before.

Those are borderline and not that healthy. It’s tough. I’ve heard people who do a lot of CAR T-cell therapy treatment say almost no one is not a candidate for CAR T-cell therapy. I’ve heard different perspectives. Not being a CAR T-cell treater, I’m not the 1 who usually makes that decision. You made a really good point earlier. Community doctors have got to be able to talk to patients. You haven’t even sent them off yet and you find out they have a relapse. You’ve got to be able to tell them about some of the risks and benefits of CAR T-cell therapy and help them make a decision about the right thing to do. It is important to know a bit about cytokine release syndrome, and neurological toxicities. Talk your patients through a bit about how it works, just as you do about transplant, and share that with them. Then help them make a decision: is that consult something they want to do? As you said, it’s important to give as many patients as possible that option because it’s potentially curative therapy where previously we had no such thing, right? Third-line DLBCL, especially post-transplant, was a death sentence. Nowadays that’s not necessarily the case.

Suggestions to hematologist-oncologists when talking to patients with relapsed/refractory diffuse large B-cell lymphoma about the potential benefits of CAR T-cell therapy and toxicities.

R/R DLBCL: Educating Patients About CAR T Cells

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.

Recommendations to increase the uptake of CAR T-cell therapies into clinical practice when managing patients with relapsed/refractory diffuse large B-cell lymphoma.

CAR T Cells in R/R DLBCL

The duration of response that we see is about 10.3 months, and the time to response was 1.3 months. In the past, 10.3 months was excellent. It still is, but it seems that perhaps the tafasitamab may be a little longer for those responders. Any comments on that? I know those were no head-to-head comparisons, but that’s my impression.

I interpret that with caution because sometimes those median durations of response change with longer follow-up, so it’s possible that will happen. It did already change once from 10 to 13 months if I’m not mistaken. Another comment is that it stops after a year. As you pointed out earlier, tafasitamab is a continuous therapy. We don’t know, but maybe an important feature of tafasitamab is that it continues on. Maybe there’s some benefit to that. My understanding is that there may be some studies of duration of tafasitamab in the future, even just retrospective ones. We don’t know the right answer in terms of, do you need to keep the tafasitamab going for those long responders?

That’s an excellent point. The LOTIS trial was fixed duration, John?

That’s an important point. Of course if you have somebody who’s responding to therapy, I could imagine them not wanting to stop as we see sometimes in our patients with CLL [chronic lymphocytic leukemia].

I’m correct, the PBD-dimer is an alkylating agent. It binds to the DNA minor groove and forms highly cytotoxic DNA interstrand crosslinks. I still don’t know how that relates to the edema. That’s unique. In general, most of the toxicities were fairly low grade. I’m excited to use this drug. I did a cost analysis, and it’s pretty much on par with tafasitamab-lenalidomide, so they must have strategically priced it like that. A lot of our Medicare beneficiaries or a lot of our patients don’t have access to orals, so I can see this having a place for some people who have really high co-pays or access issues for the lenalidomide.

Yeah. Another comment about duration of response that you’ve got to interpret with caution is that it’s not the same patient population in this study as in tafasitamab-lenalidomide, right? Because this study required at least 2 prior lines of therapy. This is only third line and beyond, whereas tafasitamab-lenalidomide included second line and beyond. We saw from subset analysis of L-MIND that tafasitamab-lenalidomide works better and longer in the second-line setting than in the third-line setting. If you start weighting PFS [progression-free survival] curves and duration-of-response curves with those second-line patients, it’s going to make your drug look better.

That’s why it’s also not like apples to apples because we’re talking about a second- and third-line approval.They’re going to be competing because they’re in a similar space, but upon relapse an unfit patient would not go straight into loncastuximab. They’d have to be third line to stay on label. We don’t know a lot about if they progressed on the tafasitamab-lenalidomide, if that’s going to be an effective strategy to have a targeted antibody-drug conjugate with a payload that’s different from that immunomodulatory mechanism that the tafasitamab-lenalidomide has. I don’t know if, once we get bispecifics, if that’s going to kick it all out of the ballpark for both of those. But this is going to be great especially for our less fit patients or our patients who do relapse post salvage and autotransplant.

Variables that are likely to impact the use of loncastuximab vs a combination approach with tafasitamab and lenalidomide to treat relapsed/refractory diffuse large B-cell lymphoma.

Anti-CD19 Therapy for DLBCL: Treatment Selection

Should we move on to loncastuximab? We know it’s a CD19, an antibody-drug conjugate. The drug that’s linked to it is an alkylator, is it not?

It’s a PBD dimer, so it’s pyrrolobenzodiazepine PBD dimer cytotoxin. That’s the drug in the antibody-drug conjugate.

I thought for some reason that had alkylating properties.

I confess that I’m not sure. You might be right.

It’s a newer payload that we’re not used to in our ADCCs [antibody-dependent cell cytotoxicities]. We’re more used to the MMAE [monomethyl auristatin E] and maybe MMAF [monomethyl auristatin F]. This is a new 1. Some of its toxicity relates to that payload. Why don’t you talk a little, John, about the LOTIS-1 trial. Then I’m going to try to nail down some of the other data that I’m getting a little foggy on because I haven’t looked at it in a couple of days.

There was a phase 1 trial in all comers with relapsed B-cell non-Hodgkin lymphoma that demonstrated activity. Then they did a phase 2 trial, which is now published. In the phase 2, the eligible patients had relapsed/refractory DLBCL [diffuse large B-cell lymphoma] and had received at least 2 prior therapies. It’s important to talk about the dosage. The way this drug was dosed in the phase 2 was 150 µg/kg IV [intravenous] every 3 weeks for 2 doses, but then you drop the dose to 75 µg/kg thereafter. It’s 2 doses, and they get 150 µg/kg every 3 weeks and thereafter it’s 75 µg/kg every 3 weeks, and the drug was continued for up to a year.

The efficacy results were an overall response rate of 48% and a CR [complete response] rate exactly half that, so it’s easy to remember: 24% CR and overall response rate 48%. It’s still fairly early, so we’re getting a little duration of response with longer follow-up. The last 1 I saw as a median was 13 months. It does appear to be effective in all groups. I stand corrected—it was 15 patients. I forgot the number earlier. Fifteen patients went on to receive CAR [chimeric antigen receptor] T-cell therapy after loncastuximab and had an overall response rate of 47%, and 9 patients got a stem cell transplant after loncastuximab.

The toxicities of the drug are to some degree a unique and, as you mentioned, probably related to that PBD dimer. One thing reported that no one quite knew what to make of were these elevated GGT levels, which were tracked on the study. That did not seem to correlate with real liver toxicity. My understanding is that the prescribing information does not recommend that we all follow GGT levels or act on GGT levels. That was just a phenomenon that was observed. Another unique toxicity was fluid retention and edema, which apparently can be a problem for some patients. It’s important to keep that in mind in managing folks. The anecdotes were that spironolactone does seem to have some benefit in helping control the edema. The other toxicities were basic cytopenias that we’re all used to dealing with: neutropenia, thrombocytopenia, anemia, and fatigue. Those were the main toxicities to be aware of. Particularly the fluid retention and edema are something to keep an eye out for those who are using the drug.

Those are unique toxicities, and edema may have to do with the payloadbecause we know that other CD19 agents don’t have that.

That GGT issue is residual from how the studies were designed because that’s not something, in this country at least, we tend to measure. That’s a quirky thing about the toxicity and what made it into the package insert, which is a little different from what we do in regular clinical practice.

An overview of the LOTIS-1 clinical trial and the rationale for the accelerated approval of loncastuximab for relapsed/refractory diffuse large B-cell lymphoma.

Loncastuximab for R/R DLBCL

You were really good [talking about] the ADCC [antibody-dependent cell cytotoxicity] and ADCT [antibody-drug conjugate toxicity] tafasitamab with the mechanism of action. We went through that and went through the L-MIND, the First-MIND, and the Re-MIND trials. That covers tafasitamab-lenalidomide. Also, you were very kind to discuss the frontMIND study and what to look out for granted that we had early phase and not a lot of randomized data to report out for long-term follow-up.

We’ve got some efficacy response rates and safety information. I mentioned safety a little in that most of my experience with tafasitamab has been toxicity related to lenalidomide. There’s a 6% or 8% infusion reaction rate. I haven’t held the infusion for anything. I have to try to train my pharmacists that I’m getting the labs for the lenalidomide, don’t hold up to wait for the results for the tafasitamab. There are very few things that I’m holding the tafasitamab for. Of course, it’s a pan–B-cell depleter, and we want patients to get response from their vaccines for COVID-19, although maybe it’s moot in this population. I haven’t held it to get a COVID-19 shot. Do you have the same experience clinically with your toxicity and management of that for the combination?

I agree with everything you said, but I think a lot of the toxicity is from lenalidomide.

Recommendations for managing patients with diffuse large B-cell lymphoma on tafasitamab.

Marin F. Xavier, MD | Authors

Articles

Next Steps Using Anti-CD19 Therapies in DLBCL

R/R DLBCL: Educating Patients About CAR T Cells

CAR T Cells in R/R DLBCL

Anti-CD19 Therapy for DLBCL: Treatment Selection

Loncastuximab for R/R DLBCL

Anti-CD19 Targeted Therapy for DLBCL: Safety and Efficacy