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Understanding the Heterogeneity of Mantle Cell Lymphoma

Insights From: Bijal D. Shah, MD, H. Lee Moffitt Cancer Center & Research Institute; Lauren C. Pinter-Brown, MD, UCI Health; Eduardo Sotomayor, MD, GW Cancer Center
Published: Friday, Jan 18, 2019



Transcript:

Bijal D. Shah, MD:
To answer your question about the heterogeneity of mantle cell lymphoma, I think first you have to go back to what we’ve seen clinically over the years. And this is what first inspired the idea that mantle cell is going to behave differently. There’s data that came out of Peter Martin’s group, the Cornell group I should say, looking at those patients that could undergo watchful waiting. And I think that was the first, one of the first efforts to show indeed there are some mantle cell lymphomas that don’t behave aggressively, at least not at presentation. And so we, at this point in time, now developed clinically the notion there may be an indolent variant of mantle cell lymphoma.

As we moved over the years, I think we were always familiar with the very, very highly aggressive variant of mantle cell lymphoma, the blastoid or pleomorphic variants where there was considerable, either variation in cell size in the case of pleomorphic mantle cell lymphoma or just uniformly enlarged cells, in the case of blastoid variant. And these tended to have a very high growth rate or Ki-67 associated with them. And so now we have two extremes. And what ended up filling the middle was what we call classical mantle cell lymphoma. And, within that, again, there’s going to be some good players, some bad players. And that really feeds into now the biological subtyping. And this is work that I think has really been perhaps best well developed by our European colleagues, looking at the role specifically of proliferation.

So it’s amazing, you look at proliferation of follicular lymphoma, you see a Ki-67 of 20, 30%. At least I don’t bat an eye. That’s fine. That doesn’t really worry me too much. In mantle cell lymphoma, seeing an elevated Ki-67 as high as, again, 30% has consistently fallen out as a high-risk feature in this disease. And I think that has informed the biology on that level. So now we’re going from clinical features looking now more specifically at behavior, and now we’re going to go a step deeper.

We’re going to start asking about molecular heterogeneity and how that informs mantle cell lymphoma. We’re now seeing subtypes that include p53 mutants. It’s interesting that this group is, I shouldn’t say it’s interesting, it is important to recognize that this group is an extraordinarily poor performer. These p53 mutant mantle cell lymphomas tend to be, perhaps not surprisingly, unresponsive to chemotherapy. Early relapses in spite of high-dose cytarabine and stem cell transplant. And even in the context of novel therapies, we can run into some challenges. Part of the reason for that is the p53 also tend to be more proliferative. There does seem to be some overlap.

Transcript edited for clarity.
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Transcript:

Bijal D. Shah, MD:
To answer your question about the heterogeneity of mantle cell lymphoma, I think first you have to go back to what we’ve seen clinically over the years. And this is what first inspired the idea that mantle cell is going to behave differently. There’s data that came out of Peter Martin’s group, the Cornell group I should say, looking at those patients that could undergo watchful waiting. And I think that was the first, one of the first efforts to show indeed there are some mantle cell lymphomas that don’t behave aggressively, at least not at presentation. And so we, at this point in time, now developed clinically the notion there may be an indolent variant of mantle cell lymphoma.

As we moved over the years, I think we were always familiar with the very, very highly aggressive variant of mantle cell lymphoma, the blastoid or pleomorphic variants where there was considerable, either variation in cell size in the case of pleomorphic mantle cell lymphoma or just uniformly enlarged cells, in the case of blastoid variant. And these tended to have a very high growth rate or Ki-67 associated with them. And so now we have two extremes. And what ended up filling the middle was what we call classical mantle cell lymphoma. And, within that, again, there’s going to be some good players, some bad players. And that really feeds into now the biological subtyping. And this is work that I think has really been perhaps best well developed by our European colleagues, looking at the role specifically of proliferation.

So it’s amazing, you look at proliferation of follicular lymphoma, you see a Ki-67 of 20, 30%. At least I don’t bat an eye. That’s fine. That doesn’t really worry me too much. In mantle cell lymphoma, seeing an elevated Ki-67 as high as, again, 30% has consistently fallen out as a high-risk feature in this disease. And I think that has informed the biology on that level. So now we’re going from clinical features looking now more specifically at behavior, and now we’re going to go a step deeper.

We’re going to start asking about molecular heterogeneity and how that informs mantle cell lymphoma. We’re now seeing subtypes that include p53 mutants. It’s interesting that this group is, I shouldn’t say it’s interesting, it is important to recognize that this group is an extraordinarily poor performer. These p53 mutant mantle cell lymphomas tend to be, perhaps not surprisingly, unresponsive to chemotherapy. Early relapses in spite of high-dose cytarabine and stem cell transplant. And even in the context of novel therapies, we can run into some challenges. Part of the reason for that is the p53 also tend to be more proliferative. There does seem to be some overlap.

Transcript edited for clarity.
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