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Relapsed/Refractory DLBCL

Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center; John Byrd, MD, Ohio State University; Michael Keating, MB, BS, University of Texas MD Anderson Cancer Center; John Leonard, MD, New York-Presbyterian Hospital
Published: Thursday, Mar 09, 2017


Transcript:

John Byrd, MD:
Leo or John, I have a question for you related to relapsed/refractory large-cell lymphoma patients. Ibrutinib clearly works in the ABC lymphoma group, but there’s a variety of different ways you can get to that phenotype. For instance, the patients that have CARD11 mutations, you wouldn’t expect them to respond to ibrutinib. So, in that multiple refractory patient, or where you’re making a treatment decision, where does personalized medicine, in terms of tumor sequencing, come into the management of these patients?

Leo I. Gordon, MD: Well, I think it’s the future. I think it’s where we need to go. The clinical trials that we’re doing are going to have to begin looking at those kinds of mutations—A20, CARD11—mutations that are probably going to be important in predicting outcomes, and we’ll be avoiding drugs like ibrutinib in people with CARD11 mutations. I don’t think we’re there yet, but I think the technology is certainly there. And I think one of the things that people have begun to do is the so-called “liquid biopsy,” where they’re looking for circulating DNA. You can refine that so that you not only looking for just immunoglobulin DNA, but you’re looking also for certain genes that you’re interested in, like in blood, but certainly in the tumor initially.

John P. Leonard, MD: One of the challenges in the relapsed large-cell lymphoma setting is that you don’t have a lot of time. These patients are sick. If you don’t respond to your second-line therapy in large-cell lymphoma, your overall survival is 4 months. So, to biopsy that patient and send off a panel to wait to treat that patient is not a practical thing today at most centers, probably very many centers at all. Then you have to start thinking ahead and ask, “Well, can we biopsy the tumor earlier, start the process, and then if the patient relapses, have that available to use?” I think it’s what we have to be doing. Beyond the timing, you get into all the issues of, is what you’re sampling representative of the tumor and clones and all those things we do in CLL. I think we are going to figure out long before anyone else because you can monitor the clonal dynamics much better and mutational dynamics much better. But, clearly, that’s the direction we have to move in and see if it works.

One of the other hard things is that to do this, you have to biopsy the patients rigorously, routinely on clinical trials of all of these drugs. And while you can get biopsies in second- and third-line patients—for clinical reasons and even for studies—you’re going to likely need, for instance, a 100-patient study, with 100 biopsies, to get enough mutational diversity to be able to say, “Well, on this subgroup, this worked or this didn’t work.” And that’s just a tall order now, but I think it is really where we have to be heading to make that work.

Krishna V. Komanduri, MD: You addressed the issue of relapsed disease, and in the patient who is not a double-hit patient, I think we may be equally still looking for guidance about what exactly to do there. Do you have a preferred regimen in that situation? And if the patient fails—and you talked about how dismal the prognosis is—what do you do next?

John P. Leonard, MD: So, I think for second-line treatment, we are typically using one of the second-line regimens. From my perspective, they’re pretty similar as far as the outcomes. Now, there are some data out there, that you’re no doubt familiar with, suggesting that the cell of origin may correlate with response to DHAP (dihydroxyacetone phosphate), as an example, or one of the regimens that might be preferred over another. But that being said, at the end of the day, I think the results are largely similar. We try to get those patients to transplant. Certainly, most of those patients will not get into a PET-negative CR, which is our goal to get to an autologous transplant.

Krishna V. Komanduri, MD: What about those who don’t get to?

John P. Leonard, MD: And those that don’t, the question is, how good is the PR? Is it close enough to do an autologous transplant? Is it good enough to do an allotransplant? I will take the chance to highlight an Alliance Intergroup Bone Marrow Clinical Trials Network study that is looking at ibrutinib as part of the transplant regimen and as a maintenance in the activated B-cell subtype. So, hopefully, that patient’s going to register at first relapse, get their second-line regimen, and then get ibrutinib as part of the transplant and follow-up there. And that will ask the question: does ibrutinib help the transplant population do better in that subset? But, clearly, there are a lot of other people. I think it depends on the age of the patient and a lot of other factors as to how aggressive you want to be and what trials you have available.

Leo I. Gordon, MD: When I talk to transplant patients with recurrent diffuse large B-cell lymphoma, some of the risk factors, are they recurring within a few months? Greater than a year? Those are all obviously important factors that predict whether they’re going to do well or how they’re going to do with the transplant. And our goal for autologous transplant—and I remind patients it’s the main benefit of an autologous transplant—is dose of chemotherapy. What you’re getting is a bigger dose. And for some patients, that’s going to make a difference because it is probably curative in some patients. But as we get closer to the transplant, if those patients are not in a PET CR or near a PET CR, I’m thinking about an allogeneic transplant. And because of the added benefit, I explain to them that we have seen now that this is an immunologic treatment, that we’re getting donor T cells that are attacking the lymphoma. The risk, of course, is graft-versus-host disease. And as patients get older and the median age of diffuse large B-cell lymphoma is 60, people over 50, 55 who have an allogeneic transplant have a much higher risk of fairly significant graft-versus-host disease.

Michael J. Keating, MB, BS: One of the interesting things was, in the early stages of the nonablated transplants in CLL, John Gribben was trying to maximize the cell reduction with CHOP and not using any fludarabine. We were using a lot of fludarabine, and we were not getting the acute graft-versus-host disease and John was. All of the nonablated transplants have required fludarabine to be part of the mix, whether it’s with radiation or busulfan or something else like that. And there seems to be something in the fludarabine pretreatment that minimizes the acute graft-versus-host disease. I don’t think any of the large-cell lymphoma regimens would pretreat…

Krishna V. Komanduri, MD: As an immunologist who thinks about this, I think, in one way, it’s because these are very well-tolerated regimens with very little cytokine storm, very little toxicity, and you get the cells then basically without all the tissue injury that probably fields graft-versus-host disease in the early posttransplant period.

Transcript Edited for Clarity
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Transcript:

John Byrd, MD:
Leo or John, I have a question for you related to relapsed/refractory large-cell lymphoma patients. Ibrutinib clearly works in the ABC lymphoma group, but there’s a variety of different ways you can get to that phenotype. For instance, the patients that have CARD11 mutations, you wouldn’t expect them to respond to ibrutinib. So, in that multiple refractory patient, or where you’re making a treatment decision, where does personalized medicine, in terms of tumor sequencing, come into the management of these patients?

Leo I. Gordon, MD: Well, I think it’s the future. I think it’s where we need to go. The clinical trials that we’re doing are going to have to begin looking at those kinds of mutations—A20, CARD11—mutations that are probably going to be important in predicting outcomes, and we’ll be avoiding drugs like ibrutinib in people with CARD11 mutations. I don’t think we’re there yet, but I think the technology is certainly there. And I think one of the things that people have begun to do is the so-called “liquid biopsy,” where they’re looking for circulating DNA. You can refine that so that you not only looking for just immunoglobulin DNA, but you’re looking also for certain genes that you’re interested in, like in blood, but certainly in the tumor initially.

John P. Leonard, MD: One of the challenges in the relapsed large-cell lymphoma setting is that you don’t have a lot of time. These patients are sick. If you don’t respond to your second-line therapy in large-cell lymphoma, your overall survival is 4 months. So, to biopsy that patient and send off a panel to wait to treat that patient is not a practical thing today at most centers, probably very many centers at all. Then you have to start thinking ahead and ask, “Well, can we biopsy the tumor earlier, start the process, and then if the patient relapses, have that available to use?” I think it’s what we have to be doing. Beyond the timing, you get into all the issues of, is what you’re sampling representative of the tumor and clones and all those things we do in CLL. I think we are going to figure out long before anyone else because you can monitor the clonal dynamics much better and mutational dynamics much better. But, clearly, that’s the direction we have to move in and see if it works.

One of the other hard things is that to do this, you have to biopsy the patients rigorously, routinely on clinical trials of all of these drugs. And while you can get biopsies in second- and third-line patients—for clinical reasons and even for studies—you’re going to likely need, for instance, a 100-patient study, with 100 biopsies, to get enough mutational diversity to be able to say, “Well, on this subgroup, this worked or this didn’t work.” And that’s just a tall order now, but I think it is really where we have to be heading to make that work.

Krishna V. Komanduri, MD: You addressed the issue of relapsed disease, and in the patient who is not a double-hit patient, I think we may be equally still looking for guidance about what exactly to do there. Do you have a preferred regimen in that situation? And if the patient fails—and you talked about how dismal the prognosis is—what do you do next?

John P. Leonard, MD: So, I think for second-line treatment, we are typically using one of the second-line regimens. From my perspective, they’re pretty similar as far as the outcomes. Now, there are some data out there, that you’re no doubt familiar with, suggesting that the cell of origin may correlate with response to DHAP (dihydroxyacetone phosphate), as an example, or one of the regimens that might be preferred over another. But that being said, at the end of the day, I think the results are largely similar. We try to get those patients to transplant. Certainly, most of those patients will not get into a PET-negative CR, which is our goal to get to an autologous transplant.

Krishna V. Komanduri, MD: What about those who don’t get to?

John P. Leonard, MD: And those that don’t, the question is, how good is the PR? Is it close enough to do an autologous transplant? Is it good enough to do an allotransplant? I will take the chance to highlight an Alliance Intergroup Bone Marrow Clinical Trials Network study that is looking at ibrutinib as part of the transplant regimen and as a maintenance in the activated B-cell subtype. So, hopefully, that patient’s going to register at first relapse, get their second-line regimen, and then get ibrutinib as part of the transplant and follow-up there. And that will ask the question: does ibrutinib help the transplant population do better in that subset? But, clearly, there are a lot of other people. I think it depends on the age of the patient and a lot of other factors as to how aggressive you want to be and what trials you have available.

Leo I. Gordon, MD: When I talk to transplant patients with recurrent diffuse large B-cell lymphoma, some of the risk factors, are they recurring within a few months? Greater than a year? Those are all obviously important factors that predict whether they’re going to do well or how they’re going to do with the transplant. And our goal for autologous transplant—and I remind patients it’s the main benefit of an autologous transplant—is dose of chemotherapy. What you’re getting is a bigger dose. And for some patients, that’s going to make a difference because it is probably curative in some patients. But as we get closer to the transplant, if those patients are not in a PET CR or near a PET CR, I’m thinking about an allogeneic transplant. And because of the added benefit, I explain to them that we have seen now that this is an immunologic treatment, that we’re getting donor T cells that are attacking the lymphoma. The risk, of course, is graft-versus-host disease. And as patients get older and the median age of diffuse large B-cell lymphoma is 60, people over 50, 55 who have an allogeneic transplant have a much higher risk of fairly significant graft-versus-host disease.

Michael J. Keating, MB, BS: One of the interesting things was, in the early stages of the nonablated transplants in CLL, John Gribben was trying to maximize the cell reduction with CHOP and not using any fludarabine. We were using a lot of fludarabine, and we were not getting the acute graft-versus-host disease and John was. All of the nonablated transplants have required fludarabine to be part of the mix, whether it’s with radiation or busulfan or something else like that. And there seems to be something in the fludarabine pretreatment that minimizes the acute graft-versus-host disease. I don’t think any of the large-cell lymphoma regimens would pretreat…

Krishna V. Komanduri, MD: As an immunologist who thinks about this, I think, in one way, it’s because these are very well-tolerated regimens with very little cytokine storm, very little toxicity, and you get the cells then basically without all the tissue injury that probably fields graft-versus-host disease in the early posttransplant period.

Transcript Edited for Clarity
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