The Future of DLBCL Treatment

Grzegorz S. Nowakowski, MD: All of us have anecdotal experience, and these real-world data from studies can help us capture some information on how to choose the best therapies clinically. In the last 15 minutes, let’s talk a little about the future of diffuse large B-cell lymphoma. Matt, I’ll start with you. What’s the most exciting development for you?

Matthew Lunning, DO, FACP: For me, it’s in the frontline space. We have a trial that met its primary end point, when you can go to the chalkboard and list all the other regimens that have gone up against R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and have failed to meet their primary end point. We’re at an impasse regarding whether the frontline therapy in diffuse large B-cell lymphoma is going to change. If it does and there’s adoption of the frontline setting, then the chips fall into the second and third lines. There’s going to be a grace period where people haven’t seen polatuzumab, so it’s still going to be there. But on the heels are bispecific therapies, which will intercalate into the second and third lines.

But how do you position them in the second line with combination chemotherapies and other partners, such as lenalidomide, that have an interesting mechanisms of action, or the next-generation CELMoDs [cereblon E3 ligase modulator] in that regard? With CAR [chimeric antigen receptor] T cells, you’re making a decision at your institution: Are you taking CAR T cells that are commercially available and trying to make them better? Or are you a center that’s trying to find the next CAR T cell that’s going to be better than the CAR T cells that are commercially available? There are a lot of adjunctive trials trying to make the current commercial CAR T cells work better. There’s a lot of area above the PFS [progression-free survival] or EFS [event-free survival] curve in cellular therapy to improve on, and that’s the charge that all of us are trying to do: raise the PFS and EFS curves in that high-risk poor prognosis population.

Leo Gordon, MD: Let me tell you a slightly different view on polatuzumab, partly because I’ve been there before. Just to remind everyone, we didn’t find anything comparing CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] vs mBACOP [methotrexate, bleomycin, hydroxydaunorubicin hydrochloride, cyclophosphamide, vincristine, prednisolone]. Richard Fisher didn’t find anything adding ProMACE-CytaBOM [prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine] and MACOP-B [methotrexate, hydroxydaunorubicin hydrochloride, cyclophosphamide, vincristine, prednisone, bleomycin]. But Bertrand Coiffier did find a difference in ACVBP [doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone] with transplant in CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. The German group found that CHOPE [cyclophosphamide, hydroxydaunorubicin hydrochloride, prednisone, etoposide] was better than CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. There have been studies. They didn’t catch on for a variety of reasons. There were flaws in all those studies. In some ways, we’ve been there before.

There are a couple of questions I had about polatuzumab. Caron, we may have talked about this once at an advisory board. If you look at the supplemental figure 4 in that paper, which is next treatment, it probably had something to do with the data cutoff. I’m wondering why only 20% to 30% of patients who progressed after either CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or polatuzumab–CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] didn’t have any treatment. It may have been that the cutoff was such that they didn’t have time, but it’s a little surprising. Also, there was no improvement in younger patients, patients with bulkier disease if you look at the forest plot. It’s good that there was a slight progression-free survival difference. I haven’t adopted that as first-line treatment, but maybe I will in time. It takes awhile to convince me.

The other thing is that if you look at the PHOENIX study, it was certainly a negative study, but I’m impressed with Louis Staudt’s and Wyndham Wilson’s reanalysis of that trial in the younger patients. Granted, there were only about 30 patients in that cohort, but the differences in outcome in the people who got ibrutinib who were in the MCD [MYD88 and CD79B] and N1 [NOTCH1] group were fairly striking. It’s worth following up on that. There are some other studies. Reem Karmali in our group is looking at a SYK inhibitor, TAK-659. It’s a small group of patients looking at nivolumab. People are looking at acalabrutinib. There’s less toxicity than ibrutinib, although it might be less effective on T cells. I’m excited about looking at some of these new things.

Grzegorz S. Nowakowski, MD: So you’re betting some of the future developments are still molecular profiling?

Leo Gordon, MD: I’m thinking the science is going to ultimately drive this. I’m waiting for the cell-of-origin 20 years later to have made a difference, but it’s going to get there.

Caron Jacobson, MD: There are a lot of parallels between the POLARIX trial and the results in ECHELON-1 in Hodgkin lymphoma with brentuximab. Initially, there was a lot of discussion after ECHELON first came out regarding whether this was going to be practice changing. Then people looked at those forest plots and said, “Maybe this will be practice changing for this select patient population but not for everyone.” Then all of a sudden we’re in a phase where there’s a randomized trial and it’s the standard-of-care backbone.

To your point, we’re all slow to adopt new things, but I suspect that the magnitude of difference is going to be big enough that it’s going to become a standard of care. The biggest difference between that and some of the other randomized trials you referenced is that the toxicity profile and the logistical administration is identical to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], so it isn’t more taxing for the patient or provider.

Matthew Lunning, DO, FACP: Right. And that was different from E1, with the toxicity profile.

Transcript edited for clarity.