Future Directions in the Treatment of DLBCL


Loretta Nastoupil, MD, and John Burke, MD, discuss the future of the therapeutic landscape for patients with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma.

Loretta Nastoupil, MD: We’ve covered some of the CD19-targeted therapies. What emerging options are you particularly excited about? We just had ASCO [American Society of Clinical Oncology Annual Meeting]. Lugano [International Conference on Malignant Lymphoma] is underway. What are you excited about?

John Burke, MD: The bispecific antibodies are the first thing that come to my mind. We saw a fair number of these reported at ASH [American Society of Hematology Annual Meeting]. Well, at least 4 were reported at ASH: mosunetuzumab, odronextamab, epcoritamab, and glofitamab. All these are in phase 1 trials with escalation of doses and then dose expansions. Some are a little further along in development than others. At Lugano, I saw a presentation on glofitamab and epcoritamab in diffuse large B-cell lymphoma [DLBCL]. They’re still relatively young in their development, but we’re seeing response rates that get your attention in the order of 50% to 70%, with CR [complete response] rates pretty high.

At the early looks we’re seeing—the caveat is that these are phase 1 studies with dose escalation, but they look close to, probably not as highly effective as CAR [chimeric antigen receptor] T cell therapy, but pretty darn close—these are treatments that you might be able to get in somebody pretty quickly. I can see somebody on a Monday and then have him going on a treatment pretty quickly, maybe Thursday or Friday. Definitely, there’s that attractiveness to them where you can get somebody on a pretty effective treatment soon. There is definitely, a lot of hope in my mind that those will make their way into the clinic. How about you? Are there any others? What are your thoughts on the bispecifics?

Loretta Nastoupil, MD: I totally agree. The other potential advantage of the bispecific fold is that they probably will move into combination strategies. We saw some of those data emerge recently where mosunetuzumab is being combined with polatuzumab. Without a randomized comparison if a double is better than a single, it doesn’t look to me that it can be done feasibly. The responses look pretty impressive. The questions everyone wants to know is, how can we mitigate some of the CRS [cytokine release syndrome]? Is a subcutaneous injection going to be the best approach? Is it more aggressive premeds? Do we need to bind up the target with predose of obinutuzumab? All these strategies are employed in some of these studies. But as you said, it’s impossible to draw conclusions that there’s 1 that’s clearly better or 1 strategy that’s clearly better. The duration in the dosing frequency is quite variable from 1 to the other.

You brought up a good point. Some of these patients, particularly with how they’re being introduced into the clinic, have failed multiple lines of therapy. They’re trying to resume some form of normalcy and fewer visits to the clinic would be well received. Do you think we’re ever going to get to a point where we would just omit chemotherapy altogether?

John Burke, MD: I’m not seeing that. We’re still dealing with a disease for which we use chemotherapy and chemotherapy-immunotherapy as the main way to cure it. I don’t see that we’re going to completely eliminate chemotherapy for these patients. Even CAR T-cell therapy uses chemotherapy as lymphodepletion. I would be a little surprised if things move that quickly. My vision of the future in how to advance cures for this disease is to take some of these effective treatments that we’re seeing and move them forward—so what you just said, which is taking something like a bispecific antibody and moving it earlier.

That is to increase the effectiveness of the immunotherapy component of our treatment. Likewise, we alluded to the press release about CAR T-cell therapy being superior to autologous stem cell transplant in relapsed patients. That’s a huge step forward because if that’s confirmed in these other trials and we see the data, a stem cell transplant and a high-dose chemotherapy has been the staple of our treatment for relapsed disease for more than a couple of decades, or my whole career.

To be able to replace that with immunotherapy would be a major step forward. Moving the immunotherapy forward earlier and moving some of these novel agents forward so we’re using them in the first line and certainly in the second line and beyond is going to increase that 60% cure rate number that we currently have been stuck with for a long time. I don’t know. What about you? Any other thoughts on how to advance the field forward and what’s going to move the needle?

Loretta Nastoupil, MD: Even in the front line, for older, frail patients who are poor candidates for anthracycline-based approaches, now that we have many more effective options that also have a favorable toxicity profile, that group of patients is the next frontier. Can we improve their outcomes? Oftentimes, they’ve been approached with rituximab, or rituximab and steroids, and we know their outcomes are very poor. This expanding treatment landscape in the relapsed setting does lend itself well to these nonchemotherapy approaches in those patients where chemotherapy is not the answer. I completely agree: for those patients where CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] has performed well, the many years [trying] to dethrone it have been unsuccessful because we’ve cured a large portion of patients.

It’s hard to approach them with a nonchemotherapy approach for the sake of novelty and avoiding chemotherapy-related toxicity. But as technologies emerge, there might be potential to further slice that pie and define those patients for whom chemotherapy is not justifiable. Then you could proceed trying a nonchemotherapy approach. CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is going to stay with us for a little while. In the meantime, we’ve got great options for patients who fail frontline chemotherapy-immunotherapy, and many more options than we had just a year ago.

John Burke, MD: I totally agree about how older patients are left out of these trials. Either they’re excluded, or they’re too frail, or they’re too sick, and they don’t go on the trials and don’t do as well. That’s a big need in management of this disease, for us to improve how we take care of those folks and to standardize something for them because there’s no standard. As you point out, developing a nonchemotherapy approach might be helpful for those patients, definitely as a way forward for some of these novel agents.

Loretta Nastoupil, MD: This has been extremely informative. Thank you, Dr Burke, for your insightful discussion. Thank you to our audience for watching this Targeted Oncology presentation on CD19 as a therapeutic target in DLBCL. We hope you found this discussion to be useful and informative.

Transcript edited for clarity.

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