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CLL: The Risk of Richter's Transformation

Panelists: William G. Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center; Steven Coutre, MD, Stanford University Medical Center; Matthew S. Davids, MD, MMSc, Dana-Farber Cancer Institute; Nicole Lamanna, MD, Columbia University Medical Center; Shuo Ma, MD, PhD, Robert H. Lurie Comprehensive Cancer Center
Published: Wednesday, Jan 17, 2018



Transcript: 

William G. Wierda, MD, PhD: Dr. Ma, we’ve heard about FISH and 17p deletion, less discussion about mutation and TP53. So, is that a test that you think is important as 17p and looking for 17p by FISH? Maybe you can comment on that.

Shuo Ma, MD, PhD: Right. So, we know that by FISH analysis, the 17p deletion is the highest risk category amongst CLL patients, which predicts shorter time to treatment, less responsiveness to the conventional immunochemotherapy, and also shorter duration of response that translates into shorter overall survival.

The TP53 mutation analysis has not been commonly used, but there are several studies that have demonstrated the equal importance of TP53 mutation similar to 17p deletion. Most of the 17p deletion patients actually also have the p15 mutation on the other allele, but there are also patients who only have the TP53 mutation without a 17p deletion. So, you’re going to miss those groups of patients if you only do the FISH analysis. I do think it would be very beneficial to do the TP53 mutation at diagnosis.

Steven Coutre, MD: I think we have to be a little bit careful though with that because as we see, those tests are much more sensitive, typically, than the FISH test. And so, you’ll see a wide range of percentages. It’s one thing if somebody is 50%, it’s another thing if they’re 4%. We don’t really know what that means.

Shuo Ma, MD, PhD: Right. So, not all 17p deletions are the same. If we have a patient who has a very low percentage, then their prognosis is very similar to patients who do not have the 17p deletion. So, the percentage does matter.

Nicole Lamanna, MD: I agree.

William G. Wierda, MD, PhD: Maybe you can also comment on the prevalence of these higher risk features among patients who are newly diagnosed, or prior to their first therapy, versus in the relapsed setting.

Shuo Ma, MD, PhD: Right. That’s a very good point. So, 17p deletion is relatively less common among newly diagnosed patients, so only about 5% to 10% of patients with newly diagnosed CLL have the 17p deletion. However, as the disease relapses, especially after the patient has gone through prior treatment, the percentage of patients who acquired this mutation can really increase. So, the study has shown that it can be up to 40% to 50% of patients in relapsed setting who can have the 17p deletion. And that really affects their treatment options, so that’s why it’s so important to repeat FISH analysis prior to each line of therapy.

William G. Wierda, MD, PhD: So, there’s a lot of discussion right now on transformation and what’s referred to as Richter’s transformation. Maybe, Matt, you can comment a little bit on—we’re not going to cover it extensively—Richter’s transformation. When do we see it? When should we be worried about it?

Matthew S. Davids, MD, MMSc: Just to define Richter’s transformation, this is when the usually indolent CLL transforms into an aggressive lymphoma, most commonly a diffused large B-cell lymphoma. Rarely, we can also see Hodgkin’s lymphoma transformation events. And Richter’s transformation is relatively rare. It occurs in about 1% to 2% of CLL patients per year. However, this is a cumulative risk. So, as patients live with the disease for long periods of time, the risk of Richter’s can go up. And we’ve seen a number of cases of Richter’s in patients on novel agent-based therapies. I think that’s an interesting question as to why that’s happening. As we’ll talk about, the novel agents can really extend the life of CLL patients who are otherwise very refractory to treatments. That might be allowing them to then go on to develop Richter’s.

In terms of risk factors for Richter’s, some of the things that have been identified, there’s a group of patients with trisomy 12 who also have NOTCH1 mutations. This is not a mutation we’ve talked about yet. It’s not one that all patients are having done certainly at diagnosis, but it’s a risk factor that we’ve identified in the research setting. Similarly, there are certain subtypes, what we call stereotypes, of IGVH status. One in particular, if you come back to the 439 group, does seem to also increase the risk of Richter’s.

So, in general, if patients are developing Richter’s, we start to see some significant symptoms that are a change from what we’d expect from CLL. Things like abnormal lymph node growth that’s asymptomatic but may be asymmetric, symptoms such as drenching night sweats and even fevers, these sorts of things.

William G. Wierda, MD, PhD: Maybe Steve, you can comment on Richter’s in the form of DLBCO versus Hodgkin’s and when we see those, and also clonally related versus clonally unrelated.

Steven Coutre, MD: Yes, I think it’s interesting. As we start seeing this certainly in the context of our novel therapy trials, because those were very, very heavily treated patients on chemoimmunotherapy, I think that’s where you start seeing this phenomenon more. And so, when we first started using the novel agents like ibrutinib, then rather early on in their treatment, you would get some of the transformation events. Of course, some concern initially. But I think looking back, perhaps we’re really selecting a group of patients where we’ve used now an effective new therapy to control their CLL, but we also know that our novel agents aren’t particularly effective against this Richter’s transformation. So, I’m a little more comfortable in thinking that we’re not causing big problems down the line as they stay on these drugs.

Hodgkin’s is interesting. I had a flurry of those a couple years ago with CLL. And some of them vary. Of course, I think some of them do arise perhaps from the preexisting disease, but I think most of them can be a separate coexisting feature. So, we’ve always, in the few cases, approached it by what was our best therapy that we should use for the Hodgkin’s. And then, how do we deal with whether or not we actually have to treat the CLL in that context and look at it that way? So, I think, to me at least, it has been a very different experience in dealing with somebody with a true large cell transformation. And then, of course, we occasionally get the prolymphocytic leukemia transformation. So, again, one of these more aggressive diseases.

Nicole Lamanna, MD: I just want to make one comment. I think there are 2 distinctions that we have to discuss and Matt really highlighted this. Obviously, you have the patients who transform. Majority of those patients are patients who have had prior therapy. So, what Steve was referring to was a lot of those patients who got on to the initial ibrutinib studies probably might have had transformed disease and we just saw that come out because we didn’t look as carefully on those initial studies and then subsequent studies where we were imaging and petting patients and so on and so forth. So, probably a lot of those had multiple relapsed disease, and this would have happened regardless of the treatment that they go on from a study with ibrutinib or any other novel agent.

But then you get a smaller group of patients, about 10% of folks, who have never had any therapy for their CLL and who transformed, that’s a completely different category. Obviously, I think this is one area we’re all very interested in because we have such a lack of therapy for our Richter’s patients that we would hope that when we talk about giving them lymphoma-based therapy, the lymphoma-based therapy just doesn’t cut it for our Richter’s transformed patients. Now, in the frontline setting, if they’ve never had treatment for their CLL, absolutely, because those patients can still be cured of their large-cell lymphoma. But in the relapsed setting that’s not the case, and we still need new therapies.

Steven Coutre, MD: That brings up one other point I wanted to make. We’ve talked about maybe CAT scans. See, a lot of people use PET scans, and we should really try to dissuade individuals from doing that. This isn’t lymphoma...

Nicole Lamanna, MD: With the exception of looking for that.

Steven Coutre, MD: Yes. If somebody is going to get a scan, sometimes you see patients come and they’ve had PET scans. And if you’re going to get a scan, if you need a scan, getting a good CT scan is much more useful. And the other issue is at this meeting, there’s an abstract from the venetoclax trials. In those trials, all patients in a relapsed setting were required to have a PET scan to try to screen out Richter’s patients and to aggressively biopsy, etc. And the message actually is that it’s not sufficiently sensitive or specific to be the only way of excluding a potential transformation. It does help guide us as someone mentioned. You have an asymmetric adenopathy, and an SUV is high.

Matthew S. Davids, MD, MMSc: That’s right. And in that study, even patients who had SUV above 10, some of these patients actually did not have Richter’s. I think the other key message is you have to biopsy. You want to use the PET scan to help direct you to the most FDG-avid node that’s successful.

Steven Coutre, MD: It has such huge implications in the relapsed setting, that diagnosis.

Shuo Ma, MD, PhD: So, one other thing just to add is the LDH. It is a very good marker for monitoring for Richter transformation. Typically, if you have a patient who has a sudden increase in the LDH, and along with immune symptoms or new asymmetric adenopathy, those are the patients who are highly suspicious for Richter’s transformation. But of course, you have to biopsy to confirm, and PET scan can really be a way to help you to identify what is the best place to biopsy, because you really want to biopsy the most PET-avid site to give you the highest yield.

Matthew S. Davids, MD, MMSc: And just to take it back briefly to Bill’s original question about clonality, most of the cases of Richter’s are clonally related to the antecedent CLL. There’s the smaller percentage that are clonally unrelated, and actually those patients with clonally-unrelated Richter’s can do quite well, even with standard DLBCL treatment.

Transcript Edited for Clarity 

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Transcript: 

William G. Wierda, MD, PhD: Dr. Ma, we’ve heard about FISH and 17p deletion, less discussion about mutation and TP53. So, is that a test that you think is important as 17p and looking for 17p by FISH? Maybe you can comment on that.

Shuo Ma, MD, PhD: Right. So, we know that by FISH analysis, the 17p deletion is the highest risk category amongst CLL patients, which predicts shorter time to treatment, less responsiveness to the conventional immunochemotherapy, and also shorter duration of response that translates into shorter overall survival.

The TP53 mutation analysis has not been commonly used, but there are several studies that have demonstrated the equal importance of TP53 mutation similar to 17p deletion. Most of the 17p deletion patients actually also have the p15 mutation on the other allele, but there are also patients who only have the TP53 mutation without a 17p deletion. So, you’re going to miss those groups of patients if you only do the FISH analysis. I do think it would be very beneficial to do the TP53 mutation at diagnosis.

Steven Coutre, MD: I think we have to be a little bit careful though with that because as we see, those tests are much more sensitive, typically, than the FISH test. And so, you’ll see a wide range of percentages. It’s one thing if somebody is 50%, it’s another thing if they’re 4%. We don’t really know what that means.

Shuo Ma, MD, PhD: Right. So, not all 17p deletions are the same. If we have a patient who has a very low percentage, then their prognosis is very similar to patients who do not have the 17p deletion. So, the percentage does matter.

Nicole Lamanna, MD: I agree.

William G. Wierda, MD, PhD: Maybe you can also comment on the prevalence of these higher risk features among patients who are newly diagnosed, or prior to their first therapy, versus in the relapsed setting.

Shuo Ma, MD, PhD: Right. That’s a very good point. So, 17p deletion is relatively less common among newly diagnosed patients, so only about 5% to 10% of patients with newly diagnosed CLL have the 17p deletion. However, as the disease relapses, especially after the patient has gone through prior treatment, the percentage of patients who acquired this mutation can really increase. So, the study has shown that it can be up to 40% to 50% of patients in relapsed setting who can have the 17p deletion. And that really affects their treatment options, so that’s why it’s so important to repeat FISH analysis prior to each line of therapy.

William G. Wierda, MD, PhD: So, there’s a lot of discussion right now on transformation and what’s referred to as Richter’s transformation. Maybe, Matt, you can comment a little bit on—we’re not going to cover it extensively—Richter’s transformation. When do we see it? When should we be worried about it?

Matthew S. Davids, MD, MMSc: Just to define Richter’s transformation, this is when the usually indolent CLL transforms into an aggressive lymphoma, most commonly a diffused large B-cell lymphoma. Rarely, we can also see Hodgkin’s lymphoma transformation events. And Richter’s transformation is relatively rare. It occurs in about 1% to 2% of CLL patients per year. However, this is a cumulative risk. So, as patients live with the disease for long periods of time, the risk of Richter’s can go up. And we’ve seen a number of cases of Richter’s in patients on novel agent-based therapies. I think that’s an interesting question as to why that’s happening. As we’ll talk about, the novel agents can really extend the life of CLL patients who are otherwise very refractory to treatments. That might be allowing them to then go on to develop Richter’s.

In terms of risk factors for Richter’s, some of the things that have been identified, there’s a group of patients with trisomy 12 who also have NOTCH1 mutations. This is not a mutation we’ve talked about yet. It’s not one that all patients are having done certainly at diagnosis, but it’s a risk factor that we’ve identified in the research setting. Similarly, there are certain subtypes, what we call stereotypes, of IGVH status. One in particular, if you come back to the 439 group, does seem to also increase the risk of Richter’s.

So, in general, if patients are developing Richter’s, we start to see some significant symptoms that are a change from what we’d expect from CLL. Things like abnormal lymph node growth that’s asymptomatic but may be asymmetric, symptoms such as drenching night sweats and even fevers, these sorts of things.

William G. Wierda, MD, PhD: Maybe Steve, you can comment on Richter’s in the form of DLBCO versus Hodgkin’s and when we see those, and also clonally related versus clonally unrelated.

Steven Coutre, MD: Yes, I think it’s interesting. As we start seeing this certainly in the context of our novel therapy trials, because those were very, very heavily treated patients on chemoimmunotherapy, I think that’s where you start seeing this phenomenon more. And so, when we first started using the novel agents like ibrutinib, then rather early on in their treatment, you would get some of the transformation events. Of course, some concern initially. But I think looking back, perhaps we’re really selecting a group of patients where we’ve used now an effective new therapy to control their CLL, but we also know that our novel agents aren’t particularly effective against this Richter’s transformation. So, I’m a little more comfortable in thinking that we’re not causing big problems down the line as they stay on these drugs.

Hodgkin’s is interesting. I had a flurry of those a couple years ago with CLL. And some of them vary. Of course, I think some of them do arise perhaps from the preexisting disease, but I think most of them can be a separate coexisting feature. So, we’ve always, in the few cases, approached it by what was our best therapy that we should use for the Hodgkin’s. And then, how do we deal with whether or not we actually have to treat the CLL in that context and look at it that way? So, I think, to me at least, it has been a very different experience in dealing with somebody with a true large cell transformation. And then, of course, we occasionally get the prolymphocytic leukemia transformation. So, again, one of these more aggressive diseases.

Nicole Lamanna, MD: I just want to make one comment. I think there are 2 distinctions that we have to discuss and Matt really highlighted this. Obviously, you have the patients who transform. Majority of those patients are patients who have had prior therapy. So, what Steve was referring to was a lot of those patients who got on to the initial ibrutinib studies probably might have had transformed disease and we just saw that come out because we didn’t look as carefully on those initial studies and then subsequent studies where we were imaging and petting patients and so on and so forth. So, probably a lot of those had multiple relapsed disease, and this would have happened regardless of the treatment that they go on from a study with ibrutinib or any other novel agent.

But then you get a smaller group of patients, about 10% of folks, who have never had any therapy for their CLL and who transformed, that’s a completely different category. Obviously, I think this is one area we’re all very interested in because we have such a lack of therapy for our Richter’s patients that we would hope that when we talk about giving them lymphoma-based therapy, the lymphoma-based therapy just doesn’t cut it for our Richter’s transformed patients. Now, in the frontline setting, if they’ve never had treatment for their CLL, absolutely, because those patients can still be cured of their large-cell lymphoma. But in the relapsed setting that’s not the case, and we still need new therapies.

Steven Coutre, MD: That brings up one other point I wanted to make. We’ve talked about maybe CAT scans. See, a lot of people use PET scans, and we should really try to dissuade individuals from doing that. This isn’t lymphoma...

Nicole Lamanna, MD: With the exception of looking for that.

Steven Coutre, MD: Yes. If somebody is going to get a scan, sometimes you see patients come and they’ve had PET scans. And if you’re going to get a scan, if you need a scan, getting a good CT scan is much more useful. And the other issue is at this meeting, there’s an abstract from the venetoclax trials. In those trials, all patients in a relapsed setting were required to have a PET scan to try to screen out Richter’s patients and to aggressively biopsy, etc. And the message actually is that it’s not sufficiently sensitive or specific to be the only way of excluding a potential transformation. It does help guide us as someone mentioned. You have an asymmetric adenopathy, and an SUV is high.

Matthew S. Davids, MD, MMSc: That’s right. And in that study, even patients who had SUV above 10, some of these patients actually did not have Richter’s. I think the other key message is you have to biopsy. You want to use the PET scan to help direct you to the most FDG-avid node that’s successful.

Steven Coutre, MD: It has such huge implications in the relapsed setting, that diagnosis.

Shuo Ma, MD, PhD: So, one other thing just to add is the LDH. It is a very good marker for monitoring for Richter transformation. Typically, if you have a patient who has a sudden increase in the LDH, and along with immune symptoms or new asymmetric adenopathy, those are the patients who are highly suspicious for Richter’s transformation. But of course, you have to biopsy to confirm, and PET scan can really be a way to help you to identify what is the best place to biopsy, because you really want to biopsy the most PET-avid site to give you the highest yield.

Matthew S. Davids, MD, MMSc: And just to take it back briefly to Bill’s original question about clonality, most of the cases of Richter’s are clonally related to the antecedent CLL. There’s the smaller percentage that are clonally unrelated, and actually those patients with clonally-unrelated Richter’s can do quite well, even with standard DLBCL treatment.

Transcript Edited for Clarity 
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