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Treating High-Grade Lymphoma

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 02, 2017



Transcript:

Krishna V. Komanduri, MD:
Leo, you alluded to the fact that we think we know a lot about a double-hit group, but we don’t really know what to do about it. But I think it’s worth talking about now despite those limitations. There are people who use R-EPOCH as therapy rather than R-CHOP. There has been a suggestion that adding lenalidomide, and in the form of R2-CHOP, can improve outcomes. What is your practice?

Leo I. Gordon, MD: Well, I think, first of all, there’s a group of these high-grade lymphomas that, under the microscope, were high-grade. So, there’s Burkitt lymphoma and large cell lymphomas with the very high proliferative index, which is somewhere between diffuse large B-cell and Burkitt. We’ve traditionally called those “high-grade lymphomas.” They tend to have high LDHs; they tend to have a more aggressive course. I don’t think we know what to do with those. Burkitt lymphoma has been treated with a more aggressive regimen with central nervous system prophylaxis: CODOX-M or Hyper-CVAD from the MD Anderson group. I’ve tended to use Hyper-CVAD in that group of patients just because I grew up with it; it was developed at Children’s Memorial Hospital locally by Sharon Murphy. And so I’ve been used to using that regimen. So, we’ve tended to use it for that.

And then we look at the double-hit lymphomas, and if you look at the WHO 2016 classification, they are now, by definition, considered to be high-grade lymphomas. Now, all the double-hit lymphomas are going to be high-grade. I think the problem is we don’t know how to treat them. There are clinical trials ongoing. We’re looking at ixazomib, a proteasome inhibitor. There were some preclinical data suggesting that it might influence c-MYC, so we’re combining that with dose-suggested EPOCH-R. That became a regimen that we use, that we tended to use that or Hyper-CVAD, because there was a sense that it was more aggressive or a better regimen. Although there are data going to be presented at this meeting, from the Alliance Group, comparing—in a group of unselected, diffuse large B-cell lymphoma patients—R-CHOP versus dose-adjusted EPOCH-R, with no apparent differences in outcome, not enough data yet to ask, is there a subgroup advantage to the more aggressive patients?

I think the key message is that these are patients—the high-grade lymphomas, including the double-hit—that tend to recur in the central nervous system. So, some central nervous system prophylaxis I think is warranted. The question of whether that central nervous system recurrence is leptomeningeal, where maybe intrathecal methotrexate might be beneficial, or is it parenchymal, as we sometimes see in lymphomas and extra nodal sites, such as testes or breasts, so that we should maybe be thinking about high-dose methotrexate instead of intrathecal therapy? So, I think that’s the up-front treatment.

The question always is, should we be transplanting these patients? And should we be thinking about an autologous transplant or should we be thinking an allogeneic transplant? And I alluded to this earlier. I think as we now check c-MYC by FISH in everybody, we’re going to see that maybe they’re not quite as bad as we thought they were—not all of them anyway—because we were looking at c-MYC and FISH in patients who had characteristics that we thought might predict that they were positive, so they looked aggressive.

But now if we look in everybody, there are some that might behave in a better way. I’ll say that we have at our institution, in general, moved toward a consolidation in transplant in these patients. It’s something that I don’t tend…

Krishna V. Komanduri, MD: With an auto?

Leo I. Gordon, MD: With an auto.

Krishna V. Komanduri, MD: With mantle cell, for example?

Leo I. Gordon, MD: Well, it’s interesting. Many people do it in mantle cell. I have not been convinced in the data in mantle cell, as we’ve heard at this meeting, that maintenance might be as good.

Krishna V. Komanduri, MD: So, you’re talking about consolidative auto, but not an allogeneic transplant?

Leo I. Gordon, MD: Thinking about consolidative auto. But certainly, in people that relapse quickly after initial therapy even before you get to the auto, then either an allogeneic transplant or perhaps a CAR-T approach might be the thing that we’re thinking about.

Transcript Edited for Clarity

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Transcript:

Krishna V. Komanduri, MD:
Leo, you alluded to the fact that we think we know a lot about a double-hit group, but we don’t really know what to do about it. But I think it’s worth talking about now despite those limitations. There are people who use R-EPOCH as therapy rather than R-CHOP. There has been a suggestion that adding lenalidomide, and in the form of R2-CHOP, can improve outcomes. What is your practice?

Leo I. Gordon, MD: Well, I think, first of all, there’s a group of these high-grade lymphomas that, under the microscope, were high-grade. So, there’s Burkitt lymphoma and large cell lymphomas with the very high proliferative index, which is somewhere between diffuse large B-cell and Burkitt. We’ve traditionally called those “high-grade lymphomas.” They tend to have high LDHs; they tend to have a more aggressive course. I don’t think we know what to do with those. Burkitt lymphoma has been treated with a more aggressive regimen with central nervous system prophylaxis: CODOX-M or Hyper-CVAD from the MD Anderson group. I’ve tended to use Hyper-CVAD in that group of patients just because I grew up with it; it was developed at Children’s Memorial Hospital locally by Sharon Murphy. And so I’ve been used to using that regimen. So, we’ve tended to use it for that.

And then we look at the double-hit lymphomas, and if you look at the WHO 2016 classification, they are now, by definition, considered to be high-grade lymphomas. Now, all the double-hit lymphomas are going to be high-grade. I think the problem is we don’t know how to treat them. There are clinical trials ongoing. We’re looking at ixazomib, a proteasome inhibitor. There were some preclinical data suggesting that it might influence c-MYC, so we’re combining that with dose-suggested EPOCH-R. That became a regimen that we use, that we tended to use that or Hyper-CVAD, because there was a sense that it was more aggressive or a better regimen. Although there are data going to be presented at this meeting, from the Alliance Group, comparing—in a group of unselected, diffuse large B-cell lymphoma patients—R-CHOP versus dose-adjusted EPOCH-R, with no apparent differences in outcome, not enough data yet to ask, is there a subgroup advantage to the more aggressive patients?

I think the key message is that these are patients—the high-grade lymphomas, including the double-hit—that tend to recur in the central nervous system. So, some central nervous system prophylaxis I think is warranted. The question of whether that central nervous system recurrence is leptomeningeal, where maybe intrathecal methotrexate might be beneficial, or is it parenchymal, as we sometimes see in lymphomas and extra nodal sites, such as testes or breasts, so that we should maybe be thinking about high-dose methotrexate instead of intrathecal therapy? So, I think that’s the up-front treatment.

The question always is, should we be transplanting these patients? And should we be thinking about an autologous transplant or should we be thinking an allogeneic transplant? And I alluded to this earlier. I think as we now check c-MYC by FISH in everybody, we’re going to see that maybe they’re not quite as bad as we thought they were—not all of them anyway—because we were looking at c-MYC and FISH in patients who had characteristics that we thought might predict that they were positive, so they looked aggressive.

But now if we look in everybody, there are some that might behave in a better way. I’ll say that we have at our institution, in general, moved toward a consolidation in transplant in these patients. It’s something that I don’t tend…

Krishna V. Komanduri, MD: With an auto?

Leo I. Gordon, MD: With an auto.

Krishna V. Komanduri, MD: With mantle cell, for example?

Leo I. Gordon, MD: Well, it’s interesting. Many people do it in mantle cell. I have not been convinced in the data in mantle cell, as we’ve heard at this meeting, that maintenance might be as good.

Krishna V. Komanduri, MD: So, you’re talking about consolidative auto, but not an allogeneic transplant?

Leo I. Gordon, MD: Thinking about consolidative auto. But certainly, in people that relapse quickly after initial therapy even before you get to the auto, then either an allogeneic transplant or perhaps a CAR-T approach might be the thing that we’re thinking about.

Transcript Edited for Clarity
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