Prognosis of R/R DLBCL


John P. Leonard, MD: Nathan, we have people who relapse after frontline therapy and, to some degree, lack-of-cure meeting relapse is the biggest unmet need that we more or less decided. Patients are either refractory or relapsed, so in your experience, how does that break out from some patients in the double-hit group who progress in the middle of their treatment or soon thereafter, who tend to relapse? How do you shake out the relapse setting as far as patients who have relapsed disease and their presentation and the timing of such?

Nathan H. Fowler, MD: Those are 2 very different populations, John. Patients who are refractory, meaning they’re progressing during treatment and soon thereafter, and patients who progressed after some interval, somewhere around 18 months to 2 years. Patients who are primary refractory often do very poorly regardless of outcome with regard to standard treatment option. That’s been seen again and again in different types of trials, patients who are either primary refractory or progressing very early. Unfortunately, they do poorly with standard treatment, and that brings up questions. Is this a population for whom we should be thinking of alternative approaches, either some type of cellular therapy or enrollment in a clinical trial? Those are the patients for whom I’m really thinking of novel approaches before trial referral, patients who are refractory to their first line of treatment. I’ve talked to Wyndham Wilson MD, PhD and he’ll tell you patients who are refractory to EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] in the frontline setting do poorly, which is not surprising since it’s a pretty aggressive regimen. That in my mind makes up somewhere around 10% to 15% of all patients. The other 20% to 25% of patients who relapse 2 to 5 or 6 years later I consider re-exposing to chemotherapy with stem cell transplant as consolidation, assuming that with standard frontline therapy there will be long-term remissions around 60%. There are a lot of data to suggest that those patients actually do well. You can cure about 50% of patients who have a late relapse that you can get into remission and go to transplant. Those are the 2 big buckets. In general, even in those early relapses, I will re-expose them to chemotherapy. The outcomes are much worse than patients who have an interval that’s significant without disease.

How can we identify those patients de novo? That’s a much more difficult question. Are there prognostic markers? Are there genomic findings that can uniformly predict these early relapsed patients? I don’t think so. We talk about double hit, MYC, ABC [activated B cell-like], GC [germinal center B cell-like], and other kinds of prognostic systems coming out of multiple places on the East Coast. Even within those systems, there are groups of patients who do well, such as double-hit patients who do well with CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and EPOCH. I don’t think we have a uniform way to identify those patients with biological markers de novo. Is there a scoring system that tells me I should have treated this patient differently in the frontline? To me, no. As Kami and Matt mentioned, double hit is probably the only thing I use routinely to stratify patients in the different treatment groups. And that would be something like EPOCH.

John P. Leonard, MD: Kami, when you see a relapse DLBCL [diffuse large B-cell lymphoma] patient, what are the things that come to your mind as to prognosis in that setting and how you’re going to approach the patient?

Kami Maddocks, MD: Two things come to mind. One, are they primary refractory, or did they get some response to their initial chemotherapy? Second, are they in good shape, and how old are they? What are they going to be a candidate for moving forward with treatment? The first thing I think about at this time is bad outcomes for patients if they’re primary refractory, although we don’t necessarily have, outside clinical trials, any great answer other than giving them more chemotherapy and trying to get them to transplant.

Our randomized studies are ongoing. Look at the use of cellular therapy with chimeric antigen receptor CAR T cells right now, but that’s not something available in the second-line setting. The biggest decision is if they’re a candidate for more aggressive chemotherapy, to try to get them to transplant. Or if the patient is not a candidate for more aggressive therapy, even because of their age, their intolerability to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] and their other medical comorbidities, or if the patient is just not interested in that kind of aggressive approach.

Most of the time, regardless of whether a patient is a candidate for transplant, they’ll be offered a second-line chemotherapy-immunotherapy regimen. We know in patients who are refractory to the first-line regimen they don’t respond very well to that chemotherapy. We also know that even patients who respond to the chemotherapy get much less of a response if they have had previous rituximab, which in this era is pretty much going to be every patient.

John P. Leonard, MD: We’re going to get into the run-of-the-mill patients and how we standardly approach them. But I want to ask you, Matt, are there any patients you would re-treat with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or give a second-line regimen and not transplant them, even if they’re a candidate? I’ve had a couple of people recently who’ve had more or less 7- or 8-year remissions to R-CHOP and have relapsed with large-cell lymphoma again. It crosses my mind, should I just treat them again and not transplant them? Assuming they’re a candidate for transplant, is there any case in which you would try to get away with a less aggressive approach?

Matthew Lunning, DO: If the intent is curative, I would have difficulty not going down a second-line platinum-based regimen and trying to consolidate with an autotransplant. You have to go back to the R-CHOP question and you’re looking at doxorubicin at about 300 mg/m2 of cumulative dosing with 6 cycles of R-CHOP. I can’t say I’ve come across a situation where I’ve said I’m going to give you a second time of R-CHOP.

From that standpoint, the unique ones are the localized relapses that have long durability. If people don’t want to take chemotherapy or don’t want to do a transplant, are you then trying to find some other short-course therapy you could consolidate with radiotherapy? I don’t think that that’s necessarily standard, but everybody on the screen here has always seen those cases that just don’t fit the textbooks.

And they’re trying to figure out some way or some data to explain why you didn’t go down the platinum and transplant route in what would otherwise be perceived on paper as a person who could go to transplant. If you’re in those situations, you’re documenting very heavily what your discussions were and rationalizing why you chose the course you went down. Because anything short of that, unless data show us in the second line CAR T-cell setting, I’m not sure I’m having a curative intent discussion in that setting.

Nathan H. Fowler, MD: I’m just wondering, John, is there a patient where you think they could have a second large-cell lymphoma, not a relapse, for whatever that risk was that led to the initial large cell? Is there a select group of patients where the relapse is long enough to weed treatments that it’s a new clone? This is something I struggle with, and we hear about these cases in tumor board. In our setting, I’ve treated these patients a couple of times with CHOP and if they’re at 300 mg/m², I’ll do 2 or 3 cycles of CHOP and then 2 or 3 cycles of COP [cyclophosphamide, vincristine, prednisone]. Whether that’s right or wrong, everything is anecdotal because some of them do well and some of them don’t.

Matthew Lunning, DO: You really have to go searching to pathology reports to pull those out. The first was CD5 positive, then relapse, CD10 positive. And then that asks you, do you spend the money proving that the first and the second clones were different? Even in those situations, that clone that’s arising, you have to think it has seen anthracycline and it’s ontogeny of development of the second large cell. Would you even then you re-expose them to it an anthracycline-containing regimen?

Transcript Edited for Clarity

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