Relapsed and Refractory Diffuse Large B-Cell Lymphoma


A panel of diffuse large B-cell lymphoma experts discuss patient criteria and treatment selection in relapsed/refractory DLBCL.


Kami Maddocks, MD: While we know that we cure probably a little over 60% of people with R [rituximab (Rituxan)]-CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], it remains to be seen if we’ll cure more with polatuzumab [Polivy] in the frontline. We’d like to talk a lot about relapsed/refractory diffuse large B-cell lymphoma. First, to get into a discussion, Dr Maziarz, is there a difference in patients who relapse from R-CHOP vs those who are refractory to it? Do you approach these patients differently? Do you treat them the same? Do they present differently? Walk us through a little about both relapsed and refractory patients.

Richard T. Maziarz, MD: I always look back at some data from Dr Moskowitz when he and Memorial Sloan Kettering presented a big global picture of large cell lymphoma. Within the rituximab era, if there were 100 patients, he would point out that 35 would be refractory and 65 would go into remission with R-CHOP. Of those who go into remission, 20 will have a late relapse and 45 will possibly be cured. Patients who have refractory disease tend to do far worse than those who have relapsed. What we’re going to talk about over time is the timing of when patients relapse. This will be highlighted significantly at the presentations from ASH [American Society of Hematology Annual Meeting]. Do you relapse early or late?

That’s what we learned from the CORAL trial. This was a study from Europe. It was very well designed and it taught us many lessons. First, for patients who relapsed, the use of 2 different well-designed platinum-based regimens didn’t appear in a randomized trial to be positive. This is rituximab with DHAP [dexamethasone, high dose cytarabine, cisplatin] vs rituximab with the ICE [ifosfamide (Ifex), carboplatin, etoposide] regimen. There’s a subset of patients that may have done better with high dose cytarabine that came out in analysis, but they didn’t say that 1 salvage regimen was better than the other.

They did then go on to look at the question of patients who go to transplant and rituximab maintenance. Rituximab maintenance didn’t prove to be providing an additional benefit for patients who relapsed. What did show to be very relevant is when you relapsed. Patients who relapsed within 12 months of rituximab exposure universally did poorly vs those who relapsed later. The refractory patients are in that same group of patients these days who failed rituximab upfront, similar to early relapse.

There’s also a lot of attention to the SCHOLAR study, which is a retrospective analysis that also incorporates data from CORAL and [The University ofTexas] MD Anderson, which points out that these patients could probably anticipate prior to the very modern era a 15% long-term overall survival and a less than 10% likelihood of being in remission at 2 years. It’s important.

And as we address the concept of the likelihood of being someone who’s salvaged, it’s important to understand what our tools are that can salvage a patient. Like Dr Miklos, I’m a transplant physician. I’ve been doing transplant for many years. I grew up in the world of, “How high can you go?” We certainly don’t use age as a factor. Transplant is often in the eyes of the beholder. I’m always struck by studies that say patients are transplant ineligible, and when I go through that population of patients listed, I see 50% to 70% of patients sometimes in various studies who I’d say are transplant eligible. It’s an important characteristic for us to understand. We need to not look at age. We need to look at the presence of comorbidities.

We could identify patients with refractory disease with early relapse, for whom we need to do something else, but that something else is going to be determined by what they came to the plate with. We always look at disease. That’s what we’re going to talk about. There’s double-hit and triple-hit. That’s a disease-specific factor that may influence decisions. We’re going to look at patient-specific factors, which is where we talk about organ function and performance status. Then we’re going to finally talk about the tools we have. Most of the focus of large cell lymphoma is on autologous transplantation, but we can’t neglect that allogeneic transplantation is also an acceptable therapy, because we get a graft-vs-lymphoma effect. It’s dissecting the patient population and the appropriate patient for the appropriate tool.

David Miklos, MD, PhD: While we think we have all these clever exams and ways to cut off what’s acceptable, I bring this back to the eligibility requirements to go forward with these therapeutic CAR [chimeric antigen receptor] T-cell therapies, which in the original studies were very strict. But as we went into the real-world studies—we all did this in 2018—real-world CAR T showed that 50% of the patients could be outside of the eligibility criteria for a study. This time, I saw a mantle cell presentation that showed I believe 80-plus percent outside of what was going to be eligible. What is a clinical trial eligible patient? Why are we being so strict? Why do these trials frequently represent the patients who we don’t treat as opposed to the patients we’re faced with in our clinics?

I want to emphasize the importance of the physician, because maybe some of us thought that everybody gets R-CHOP and 1 therapy fits all, but that’s not the way it is. We have to tailor the therapy. We have to sometimes put in radiation. We have to truncate the number of cycles. We have to pull back on Adriamycin [doxorubicin]. And we have to provide outstanding supportive care with our nurses, teams, colleagues, and these other specialties.

Jason Westin, MD: I’d add that what we’ve seen in a lot of these real-world studies is that the outcomes of some of these novel targeted therapies that have a different toxicity profile than chemotherapy are as good as what you’d see on a clinical trial. They’re not always as good, but they’re still really good. I agree with my colleagues that if we’re seeing these great outcomes in patients who are ineligible for trials, the question we have to ask is, “Are we doing the right trials? Should we have different eligibility criteria that aren’t copied and pasted from the old studies, but are actually reflective of what we expect the toxicity profile to look like?”

Kami Maddocks, MD: There are probably 2 great points there. One, we need to think about the eligibility and who we’re including and not including in these trials. But there’s also an important aspect to the real-world data: making sure we’re collecting and reporting it so that we know what’s going on in patients who weren’t eligible or weren’t able to access trials. But expanding trial access is certainly important.

Transcript edited for clarity.

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