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Mantle Cell Lymphoma: Impact of Genetic Variants

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:
Regarding the genetic variants of mantle cell lymphoma, it’s critical that I highlight p53. I want to, because we’re talking about genetic variants, take a moment just to say that 17p deletion and p53 mutation are not the same thing. And it really seems that p53 mutations are those players that behave worse, and that’s important to keep in mind. We’ve been screening for many, many years for these p53 variants or p53 mutations using FISH [fluorescence in situ hybridization]. You have to exercise some caution there. And so if you see an entire 17p deletion, you’re really missing a good portion of chromosome 17. Those mantle cells may not behave as poorly. In contrast, at least interrogation of our data suggests that those with true p53 point mutations, frameshift mutations, really influence more specifically the behavior of p53 independent of large genomic losses on chromosome 17. Those patients seem to be doing worse. Again, I don’t want to speak definitively about our data sets because this is more preliminary, but what we’re seeing is that the point mutations and mutations specifically involving p53 may be worse players.

Talking about other genomic subsets, when we think about mantle cell lymphoma, ATM is perhaps the most commonly mutated gene. It is interesting that although you can see some overlap with p53 mutations along with ATM, at least by and large, these 2 seem to be discrete groups. Again, I should make sure I communicate that mantle cell can evolve over time to acquire p53 mutations. And so certainly an ATM-mutated mantle cell lymphoma may go on to develop this. But what you’re really hearing me say is that by and large, mantle cell lymphoma seems to be defined not just by cyclin D1 mutations, which affect the cell cycle, but also by mutations that impair DNA damage response. And so with the subclasses now of ATM and p53, at least thinking about them in that context makes a little bit more sense.

In terms of other genomic subsets, I think that’s a harder call to make. There are some interesting data looking at specific classes of mutations, such as those involving noncanonical NF [nuclear factor] kappa B and their impact on ibrutinib resistance. There are newer data looking at SWI/SNF [switch/sucrose nonfermenting] mutations and their potential to impact ibrutinib/venetoclax given together in combination in mantle cell lymphoma. And so I think there are a lot of emerging data asking, “OK, how do we personalize therapy?” I think that’s a slightly different question from what we’re getting at, which is broadly, “Are there genomic subsets of mantle cell lymphoma?” Really, I think beyond the p53 mutation, which carries the worse outcome, we can’t say too much more about it except that probably the majority of our p53 mutations will carry ATM mutations.

Lauren C. Pinter-Brown, MD: Probably the 2 big divisions in the molecular subtypes would be those patients who are SOX11 negative and mutated versus unmutated. So patients who are SOX11 negative and mutated tend to have a very indolent course. They tend to present with circulating cells and splenomegaly, and that would be a patient population in which you might watch them for prolonged periods of time before treating versus the classical presentation of mantle cell lymphoma.

Transcript edited for clarity.
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Transcript:

Bijal D. Shah, MD:
Regarding the genetic variants of mantle cell lymphoma, it’s critical that I highlight p53. I want to, because we’re talking about genetic variants, take a moment just to say that 17p deletion and p53 mutation are not the same thing. And it really seems that p53 mutations are those players that behave worse, and that’s important to keep in mind. We’ve been screening for many, many years for these p53 variants or p53 mutations using FISH [fluorescence in situ hybridization]. You have to exercise some caution there. And so if you see an entire 17p deletion, you’re really missing a good portion of chromosome 17. Those mantle cells may not behave as poorly. In contrast, at least interrogation of our data suggests that those with true p53 point mutations, frameshift mutations, really influence more specifically the behavior of p53 independent of large genomic losses on chromosome 17. Those patients seem to be doing worse. Again, I don’t want to speak definitively about our data sets because this is more preliminary, but what we’re seeing is that the point mutations and mutations specifically involving p53 may be worse players.

Talking about other genomic subsets, when we think about mantle cell lymphoma, ATM is perhaps the most commonly mutated gene. It is interesting that although you can see some overlap with p53 mutations along with ATM, at least by and large, these 2 seem to be discrete groups. Again, I should make sure I communicate that mantle cell can evolve over time to acquire p53 mutations. And so certainly an ATM-mutated mantle cell lymphoma may go on to develop this. But what you’re really hearing me say is that by and large, mantle cell lymphoma seems to be defined not just by cyclin D1 mutations, which affect the cell cycle, but also by mutations that impair DNA damage response. And so with the subclasses now of ATM and p53, at least thinking about them in that context makes a little bit more sense.

In terms of other genomic subsets, I think that’s a harder call to make. There are some interesting data looking at specific classes of mutations, such as those involving noncanonical NF [nuclear factor] kappa B and their impact on ibrutinib resistance. There are newer data looking at SWI/SNF [switch/sucrose nonfermenting] mutations and their potential to impact ibrutinib/venetoclax given together in combination in mantle cell lymphoma. And so I think there are a lot of emerging data asking, “OK, how do we personalize therapy?” I think that’s a slightly different question from what we’re getting at, which is broadly, “Are there genomic subsets of mantle cell lymphoma?” Really, I think beyond the p53 mutation, which carries the worse outcome, we can’t say too much more about it except that probably the majority of our p53 mutations will carry ATM mutations.

Lauren C. Pinter-Brown, MD: Probably the 2 big divisions in the molecular subtypes would be those patients who are SOX11 negative and mutated versus unmutated. So patients who are SOX11 negative and mutated tend to have a very indolent course. They tend to present with circulating cells and splenomegaly, and that would be a patient population in which you might watch them for prolonged periods of time before treating versus the classical presentation of mantle cell lymphoma.

Transcript edited for clarity.
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