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Management of Relapsed/Refractory DLBCL

Panelists: Julio Chavez, MD, Moffitt Cancer Center; Nathan H. Fowler, MD, The University of Texas MD Anderson Cancer Center; Andre Goy, MD, MS, John Theurer Cancer Center - Hackensack University Medical Center; Kami Maddocks, MD, The Ohio State University; Peter Martin, MD, Weill Cornell Medicine; Grzegorz S. Nowakowski, MD, Mayo Clinic
Published: Thursday, Feb 13, 2020



Transcript: 

Andre Goy, MD, MS: We’re going to switch now into the relapsed/refractory setting. Obviously, this is something that is very important because 80% of the relapse…will occur within the first 18 months, and it’s really challenging.

Salvage and high-dose therapy as well as auto was the standard of care. We know that patients who fail early do very poorly. One of the questions that comes up is regarding how we are starting to understand better the molecular diversity at baseline. What becomes this molecular diversity, and what molecular factors matter to predict the outcome in the relapsed setting? Grzeg?

Grzegorz S. Nowakowski, MD: It’s a very interesting question. What we found, for example, that cell of origin that is predictive of the outcome of the initial diagnosis appears to be not as prognostic at the time of relapse. Relapse seems to be an equalizer of the outcome, at least for cell of origin. There are more data emerging in terms of the molecular clusters and how they look at the time of relapse. As you would expect, some of them are enriched in certain mutations. But at this point, apart from maybe double-hit lymphoma, there is no clear-cut evidence, to my knowledge, that any of those particular subtypes would have worse outcome in the relapsed/refractory setting. All those patients relapsed early, unfortunately.

Andre Goy, MD, MS: Peter, what’s your take on how you manage those patients in relapsed large-cell lymphoma? Obviously, it depends when it happened. How do you manage them?

Peter Martin, MD: I think Grzeg is on the money, and that’s the old victim that the proof of the pudding is in the eating. If somebody has chemotherapy-refractory lymphoma, the fact is chemotherapy didn’t work, and we have to look outside the standard toolbox. I think historically, standard second-line therapy has been R-ICE [rituximab, ifosfamide, carboplatin, etoposide] at our institution. The CORAL study suggested that potentially R-DHAP [rituximab, dexamethasone, high-dose cytarabine, cisplatin] would be better in the germinal center subtype. Occasionally, I’ve done that. I admit that anecdotally I don’t feel like there’s a huge difference.

We have, at our institution, a clinical trial with selinexor and R-ICE, and I think other institutions have done similar trials in that space. We’ll hear more about CAR [chimeric antigen receptor] T cells in that space. Clearly there’s a need for improvement.

Andre Goy, MD, MS: This is definitely a population that is a challenge still, right? Then it depends if the early failure, primary-refractory early failure within 12 months do very poorly, even if they go in to… after salvage, typically they soon…auto. But this is not the majority definitely of the patients. Dr Chavez, how do you manage the patients when they have an early relapse?

Julio Chavez, MD: An early relapse?

Andre Goy, MD, MS: Early relapse.

Julio Chavez, MD: Your early relapser is very challenging. This CORAL study data show that the overall response rate is about 25%, 26% CR [complete response] is less than 10%, and the overall survival is about 6 months. This is a very poor prognosis for the patient, so what we usually recommend is to consider a clinical trial. One of the important clinical trials actually recently completed was the ZUMA-7, and they were looking at seeing if we can improve the outcomes. But in the absence of a trial, unfortunately there is nothing other than the standard of care.

Andre Goy, MD, MS: ZUMA-7, for our audience we should mention that this is a CAR T-cell approach versus a salvage therapy. In order to go to an auto and then obviously if they fail the salvage, they’re going to go into a CAR T commercial for the ZUMA-7 and other studies that cross over.

Julio Chavez, MD: It’s a very challenging population. In the absence of trials, we recommend the approach of a standard salvage chemotherapy. If the patient had that chemotherapy-sensitive disease, as soon as possible we can send them to autologous transplant. That’s probably not the case for double-hit lymphoma because double-hit lymphoma is early relapse, and we had remission after salvage chemotherapy. We typically consider an allogeneic transplant.

Andre Goy, MD, MS: Sorry, go ahead.

Nathan H. Fowler, MD: I just want to add 1 thing to that. In early relapses, especially patients who are primary refractory, I always try to repeat a biopsy. Sometimes you can learn additional things, especially if their first biopsy was needle only. These patients, as you mentioned, they don’t do well. So I’m looking for things like CD30 positivity. I’m looking for ALK status and obviously checking for MYC if it wasn’t done in the frontline. This is because that could potentially inform what I would do next with aggressive salvage.

Andre Goy, MD, MS: Sure.

Peter Martin, MD: That’s a great point, I think. Sometimes you find things that are totally unexpected. We did a biopsy of somebody who had a diffuse large B-cell lymphoma. One area wasn’t getting better, and he had a Merkel cell cancer. I think it’s absolutely an excellent point that if something is not responding, make sure it’s what you think it is.

Andre Goy, MD, MS: In general, we always biopsy all relapse. But in general probably this is not done enough.

Transcript Edited for Clarity

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Transcript: 

Andre Goy, MD, MS: We’re going to switch now into the relapsed/refractory setting. Obviously, this is something that is very important because 80% of the relapse…will occur within the first 18 months, and it’s really challenging.

Salvage and high-dose therapy as well as auto was the standard of care. We know that patients who fail early do very poorly. One of the questions that comes up is regarding how we are starting to understand better the molecular diversity at baseline. What becomes this molecular diversity, and what molecular factors matter to predict the outcome in the relapsed setting? Grzeg?

Grzegorz S. Nowakowski, MD: It’s a very interesting question. What we found, for example, that cell of origin that is predictive of the outcome of the initial diagnosis appears to be not as prognostic at the time of relapse. Relapse seems to be an equalizer of the outcome, at least for cell of origin. There are more data emerging in terms of the molecular clusters and how they look at the time of relapse. As you would expect, some of them are enriched in certain mutations. But at this point, apart from maybe double-hit lymphoma, there is no clear-cut evidence, to my knowledge, that any of those particular subtypes would have worse outcome in the relapsed/refractory setting. All those patients relapsed early, unfortunately.

Andre Goy, MD, MS: Peter, what’s your take on how you manage those patients in relapsed large-cell lymphoma? Obviously, it depends when it happened. How do you manage them?

Peter Martin, MD: I think Grzeg is on the money, and that’s the old victim that the proof of the pudding is in the eating. If somebody has chemotherapy-refractory lymphoma, the fact is chemotherapy didn’t work, and we have to look outside the standard toolbox. I think historically, standard second-line therapy has been R-ICE [rituximab, ifosfamide, carboplatin, etoposide] at our institution. The CORAL study suggested that potentially R-DHAP [rituximab, dexamethasone, high-dose cytarabine, cisplatin] would be better in the germinal center subtype. Occasionally, I’ve done that. I admit that anecdotally I don’t feel like there’s a huge difference.

We have, at our institution, a clinical trial with selinexor and R-ICE, and I think other institutions have done similar trials in that space. We’ll hear more about CAR [chimeric antigen receptor] T cells in that space. Clearly there’s a need for improvement.

Andre Goy, MD, MS: This is definitely a population that is a challenge still, right? Then it depends if the early failure, primary-refractory early failure within 12 months do very poorly, even if they go in to… after salvage, typically they soon…auto. But this is not the majority definitely of the patients. Dr Chavez, how do you manage the patients when they have an early relapse?

Julio Chavez, MD: An early relapse?

Andre Goy, MD, MS: Early relapse.

Julio Chavez, MD: Your early relapser is very challenging. This CORAL study data show that the overall response rate is about 25%, 26% CR [complete response] is less than 10%, and the overall survival is about 6 months. This is a very poor prognosis for the patient, so what we usually recommend is to consider a clinical trial. One of the important clinical trials actually recently completed was the ZUMA-7, and they were looking at seeing if we can improve the outcomes. But in the absence of a trial, unfortunately there is nothing other than the standard of care.

Andre Goy, MD, MS: ZUMA-7, for our audience we should mention that this is a CAR T-cell approach versus a salvage therapy. In order to go to an auto and then obviously if they fail the salvage, they’re going to go into a CAR T commercial for the ZUMA-7 and other studies that cross over.

Julio Chavez, MD: It’s a very challenging population. In the absence of trials, we recommend the approach of a standard salvage chemotherapy. If the patient had that chemotherapy-sensitive disease, as soon as possible we can send them to autologous transplant. That’s probably not the case for double-hit lymphoma because double-hit lymphoma is early relapse, and we had remission after salvage chemotherapy. We typically consider an allogeneic transplant.

Andre Goy, MD, MS: Sorry, go ahead.

Nathan H. Fowler, MD: I just want to add 1 thing to that. In early relapses, especially patients who are primary refractory, I always try to repeat a biopsy. Sometimes you can learn additional things, especially if their first biopsy was needle only. These patients, as you mentioned, they don’t do well. So I’m looking for things like CD30 positivity. I’m looking for ALK status and obviously checking for MYC if it wasn’t done in the frontline. This is because that could potentially inform what I would do next with aggressive salvage.

Andre Goy, MD, MS: Sure.

Peter Martin, MD: That’s a great point, I think. Sometimes you find things that are totally unexpected. We did a biopsy of somebody who had a diffuse large B-cell lymphoma. One area wasn’t getting better, and he had a Merkel cell cancer. I think it’s absolutely an excellent point that if something is not responding, make sure it’s what you think it is.

Andre Goy, MD, MS: In general, we always biopsy all relapse. But in general probably this is not done enough.

Transcript Edited for Clarity
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