Beyond R-CHOP: The Future of Targeted Therapies in DLBCL

Thomas Habermann, MD

While rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a highly effective therapy for diffuse large B-cell lymphoma (DLBCL). However, major unmet clinical needs still exist for patients with advanced disease.

According to Thomas Habermann, MD, a hematologist with the Mayo Clinic, the rituximab era has caused major progress. However, since it’s development, little has been done about trying to improve R-CHOP. Progress has been made in the management of toxicities, but not in treatment development. However, the addition of polatuzumab vedotin (Polivy) may help to improve outcomes.

Targeted therapies and immunotherapy have also shown promise, according to Habermann. While R-CHOP remains the biological approach, the future may lie with targeted therapies and chimeric antigen receptor (CAR) T-cell therapy, says Habermann.

In an interview with Targeted Oncology™, Habermann discusses the current unmet needs in the DLBCL space, along with the future of targeted therapies.

TARGETED ONCOLOGYTM: What does the current DLBCL landscape look like?

HABERMANN: There's been a rather interesting evolution over time, where we've moved away from radiation therapy up front. And the rituximab era has changed things. But what's also changed things is the strategy of PET-adapted therapeutic approaches nationally and internationally.

The current landscape is interesting. Since the development of R-CHOP, there really has been about 25 trials trying to improve upon R-CHOP. And essentially, we really have not gained ground over time. In this particular area, what we've done has been able to move to less therapy. There are less short-term toxicities and potentially long-term toxicities with extremely favorable outcomes.

Do you think R-CHOP is an outdated method?

So, the interesting part of R-CHOP immunochemotherapy is we're going to hear some updates in the ASH meeting this year. And whether or not that will change the landscape, I think it'd be critical to understand the details. But polatuzumab in addition to R-CHOP, there's an improvement in outcomes. We've not seen the data. And that will be critical. If one looks at the current NCCN guidelines, it's still not outdated. Were really looking for other newer, better therapeutic interventions that improve outcomes and overall survival. I had the privilege back in the 90s of chairing the North American trial, which then led to the regulatory approval of R-CHOP. We know that we're getting better with interventions that we can implement with relapse, but in the upfront management, we still are not there in randomized clinical trials to prove that we've beaten the standard of care at this point in time.

What do you think the future of immunotherapy and targeted therapies be in DLBCL management?

I think it's definitely the future. The more biologic approach is, rituximab was the first monoclonal antibody. And then the other interventions that have come along to look at and address the microenvironment such as in CAR T-cell therapeutic interventions, or the bispecific antibodies, I think have great potential to change things. But we need to analyze and get data on the upfront approaches in newly diagnosed patients.

What do you think the next 5 to 10 years is going to look like in the development of new treatments for DLBCL?

My short answer to you is I have no idea, but I think it's going to be very exciting. I think the genomic landscape to date has not brought us to the level we had all hoped over the last 5 to 10 years. But things are moving. And we're developing concepts of trials to utilize that approach. There are now companies that have developed approaches and assays and machines that we can get genomic information back soon. We reported a few years ago that one of the issues in randomized trials was if there was a delay in the diagnosis to treatment of 28 days or greater in that range, then those patients had a more favorable outcome. And it was because they had less aggressive disease, at least by standards that we understand, such as the International prognostic index and a couple of other indications. So, we've learned a lot of stuff that way. Technology is catching up, the world of lymphoma and the genomic era. By 2018, there were 3 major publications that were very elegantly done, that have laid out a landscape for potential exploration and then implementation. And those have been built upon since there continues to be an incredible amount of information that's come out, come forward and will continue to come forward. And I think that's what's really going to help ultimately change the landscape 10 years from now. So, when I'm asked about any lymphoma right now, where do you think things will be in 10 years for patients? I literally use the sentence, I don't know. But I've never been so optimistic and hopeful about how the way things are moving forward. And the pace of change is extraordinarily right now.

What unmet clinical needs still exist in this patient population?

Well, in DLBCL the unmet need is we need to cure 100% of patients. And until we get there, we can't be satisfied. If you take R-CHOP alone in advanced disease, beyond the limited stage up front, if you take all comers, we can cure about 65% of patients. If you took other tumors and looked at it well that's pretty good. But that really isn't good enough. If you take the data that we presented on limited stage disease, we still have issues.

We've come a long way in this disease, in both limited stage disease and advanced disease, but in limited stage disease there is a long way to go. We've decreased the toxicity and exposures and decrease the risk of developing secondary malignancies with less chemotherapy potentially, we've also decreased the risk of secondary malignancies as a result of radiation therapy. Now radiation therapy approaches have been also changing with proton beams and other approaches. And so, it'll be very fascinating to see the whole evolution of where things are going to end up.