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Detecting Chromosomal Abnormalities in CLL

Panelists:Alessandra Ferrajoli, MD, The University of Texas MD Anderson Cancer Center; Richard R. Furman, MD, Weill Cornell Medical College; Thomas J. Kipps, MD, PhD, UC San Diego Moores Cancer Center; Shuo Ma, MD, PhD, Northwestern University Feinberg School of Medicine, Susan M. O’Brien, MD, UC Irvine Health; William G. Wierda, MD, PhD, University of Texas MD Anderson Cancer Center
Published: Wednesday, Jan 27, 2016


Transcript:

William G. Wierda, MD, PhD:
Well, we're still using the IWCLL criteria to initiate therapy. I'm interested to hear from Susan. What are the factors or features that you evaluate clinically and prognostic factor-wise when you're seeing a patient who meets those criteria to start first-line therapy, and where do you go from there?

Susan M. O’Brien, MD: Well, I think we all pretty much approach it the same way, which is, looking at age because age is relevant. It's not relevant by itself in a bubble, but it's certainly relevant. Comorbidities; that's where it adds something to age. You know you can have a 75-year-old that plays tennis every week and a 75-year-old that can barely walk into your office. And so it's clearly not just age; it's other comorbidities. And then also, what's the aim of therapy?

So if I have a younger, fit patient, I really want to get that patient to be MRD-negative because that's going to provide the longest and best progression-free survival. If I have a 79-year-old patient with a lot of comorbidities, maybe I want to take a more palliative approach.

I'm not worried about what's going to happen 10 years from now. So, I think it's a combination of the age, the comorbidities, and then the goal. What is the goal that you have discussed with the patient that you have in mind for going forward?

William G. Wierda, MD, PhD: What are the essential prognostic factors that you get for a patient who's going on for treatment?

Susan M. O’Brien, MD: Certainly, we'll look at FISH in terms of the chromosome abnormalities. And to this day, that's highly relevant because the only frontline approval that ibrutinib has—and that will most likely change soon based on the randomized trial we're going to hear about—is in front-line 17p deleted. And you don't want to waste your time giving those people chemotherapy because they don't respond very well, whereas they respond very well to ibrutinib. So that's crucial to know. So have a FISH panel to look at that.

Obviously, all of us are at research institutions so we get a wider array of prognostic factors. If you're asking me, well, in the community, what would I tell somebody that they really have to get? I would certainly say that they have to get the FISH to look at whether there are trisomy 12, 13q deletion in particular, and 17p or 11q deletions.

Thomas J. Kipps, MD, PhD: Yeah, I actually agree with Susan. I'm actually of the opinion that patients with deletion in the short arm, or chromosome 17, may actually be made worse off with chemotherapy, because oftentimes patients have refractory disease and that affects the hematopoietic stem cell. And it's not good to affect that in the setting of persistent disease because then you get persistent myelosuppression.

That's been one of the biggest problems in treating patients with this disease. There may be a small fraction of patients with deletion in 17p that could benefit from chemotherapy, but in the absence of knowledge of what that means in terms of the resistance to the therapy, it's probably better with the advent of these newer agents to use agents such as ibrutinib. And I think that's very important. So this is clearly a very important take-home message.

William G. Wierda, MD, PhD: In terms of prognostic factors for relapsed patients, you have a patient who's been treated with a standard frontline regimen; they've had a remission that's lasted several years and their disease has recurred, and they're progressing and they fulfill the IWCLL criteria again for retreatment. Are there prognostic factors that you recheck at that point, and are they essential to recheck at that point, etc?

Thomas J. Kipps, MD, PhD: Well, it's actually not fixed in stone. If you have a patient with a FISH abnormality, that could change over time. We know that it can change with therapy, particularly with chemoimmunotherapy, where you may have selection for cells which have deletion in 17p. And so it's very important to get the FISH analysis prior to starting any therapy, initial therapy, or second-line therapy, so that you can identify those patients who might be harmed by your therapy. And I think it's very important.

We're also, I think a number of centers are as well, trying to stimulate the cells with CpG-ODN. This allows us to look at the metaphase nuclei, and we actually have a karyotype analysis. It is becoming increasingly more recognized that it's important to look at the complexity of the genetics. And it's a rule of thumb that if your genetics are complicated, it's not a good thing. So a simple genetics test is good.

Absence of translocations or the like is actually a very good thing. And some patients will harbor multiple translocations and aberrancies in their chromosomes that cannot be identified by FISH. They can only be identified by the metaphase analysis. So I would encourage people to seek that out, too, because I think there's going to be relevance to complex genetics to how patients may do over time for some of these newer treatments.

Susan M. O’Brien, MD: What about something that's done very commonly in Europe but not so commonly in the United States: analyzing for p53 mutations?

Thomas J. Kipps, MD, PhD: Well, it's interesting. The p53 mutation is, of course, the important gene that encodes proteins that are important for the response to chemotherapy. And so without that, you are not able to respond well. You're relatively resistant. And I would say two-thirds of the time, patients with 17p deletion will have mutations in p53.

That means about one-third to a quarter of patients will have wild-type p53. And it's a question of whether you can select further for absence of p53 by loss of the gene on the other chromosome. So I think that looking for p53 is important. However, I think this ipilimumab study that you mentioned before identified a prognostic indicator deletion in 17p as being worse than just the mutations in p53. So go figure.

In other words, there are other genes we know that map close to p53 in this area that may help to govern progression and also genomic complexity. And so it's a bad sign to have 17p—but it is a little bit heterogeneous there. If we focus only on p53, I think we're missing some of the things that might be also altered in those patients in the leukemic cells.

Richard R. Furman, MD: How many patients do you think you might actually catch who are not 17p-deleted but do have p53 mutation?

Thomas J. Kipps, MD, PhD: I think it's a very good point because you can have absence of 17p deletion and still have loss of p53 function. And that's difficult. I would say this, it's a rule of thumb to know your patients, know when they're progressing, and follow them very closely when you start, particularly chemoimmunotherapy.

I, frankly, get a little bit concerned if, after starting a fairly effective course of chemoimmunotherapy, I'm not seeing a fairly decent turnaround within a short order within the first two cycles. And I know, for example, that you are actually looking, after just three cycles of FCR chemoimmunotherapy, to see if you have had clearance of the cells from the marrow.

If you're not seeing a response after two or three cycles, it’s unlikely you'll see it after six cycles. So that may be a poor man's way of trying to assess the situation, short of going after trying to identify p53 mutations up front in everyone. It's only a small minority of patients that have p53 mutations without 17p deletion.

Richard R. Furman, MD: And also, what about the variability in terms of the mutations? So p53 sequencing is available commercially now. And the question, of course, is whether the mutation that's seen on the report is going to be of clinical significance or not. And do you tell a patient who is 17p-mutated that that really is something of consequence, not knowing whether or not it really is?

Thomas J. Kipps, MD, PhD: I think you raise a very important question. Obviously, you find mutations with deep sequencing. It may not have the practical clinical relevance that you're talking about. So, I think we need to gather more information about this and how to best incorporate it into standard practice algorithms. But it's a real problem. It's not cut and dried; it's not easy. It's not a very easy question.

Shuo Ma, MD, PhD: While we're on the topic of FISH for CLL, not only is it an important prognostic factor and also predictive factor, but I also want to remind physicians that it's important to include translocation 11;14 at the initial diagnosis of CLL to rule out mantle cell lymphoma—because mantle cell lymphoma can have lymphocytosis and a very similar presentation as CLL.

Richard R. Furman, MD: And that's all the more important with the complications that have been seen with ibrutinib in the mantle cell lymphoma patients. So, with the lymphocytosis, we've not seen any negative sequelae in CLL patients. But we certainly have seen leukostasis in mantle cell patients. So, making sure you have the correct diagnosis so that you know how to handle the lymphocytosis is exceedingly important.

William G. Wierda, MD, PhD: So what I've heard is that FISH is important to evaluate when patients go on their first-line therapy. We want to know if patients have a 17p deletion. Mutations in p53 are also probably important. And if you can get that test, that might be something important to consider. Metaphase karyotyping gives us some information, and that would be potentially of value. And the patients can acquire new changes in abnormalities, so FISH testing at relapse and retreatment might be important to evaluate at that time, as well.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity


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Transcript:

William G. Wierda, MD, PhD:
Well, we're still using the IWCLL criteria to initiate therapy. I'm interested to hear from Susan. What are the factors or features that you evaluate clinically and prognostic factor-wise when you're seeing a patient who meets those criteria to start first-line therapy, and where do you go from there?

Susan M. O’Brien, MD: Well, I think we all pretty much approach it the same way, which is, looking at age because age is relevant. It's not relevant by itself in a bubble, but it's certainly relevant. Comorbidities; that's where it adds something to age. You know you can have a 75-year-old that plays tennis every week and a 75-year-old that can barely walk into your office. And so it's clearly not just age; it's other comorbidities. And then also, what's the aim of therapy?

So if I have a younger, fit patient, I really want to get that patient to be MRD-negative because that's going to provide the longest and best progression-free survival. If I have a 79-year-old patient with a lot of comorbidities, maybe I want to take a more palliative approach.

I'm not worried about what's going to happen 10 years from now. So, I think it's a combination of the age, the comorbidities, and then the goal. What is the goal that you have discussed with the patient that you have in mind for going forward?

William G. Wierda, MD, PhD: What are the essential prognostic factors that you get for a patient who's going on for treatment?

Susan M. O’Brien, MD: Certainly, we'll look at FISH in terms of the chromosome abnormalities. And to this day, that's highly relevant because the only frontline approval that ibrutinib has—and that will most likely change soon based on the randomized trial we're going to hear about—is in front-line 17p deleted. And you don't want to waste your time giving those people chemotherapy because they don't respond very well, whereas they respond very well to ibrutinib. So that's crucial to know. So have a FISH panel to look at that.

Obviously, all of us are at research institutions so we get a wider array of prognostic factors. If you're asking me, well, in the community, what would I tell somebody that they really have to get? I would certainly say that they have to get the FISH to look at whether there are trisomy 12, 13q deletion in particular, and 17p or 11q deletions.

Thomas J. Kipps, MD, PhD: Yeah, I actually agree with Susan. I'm actually of the opinion that patients with deletion in the short arm, or chromosome 17, may actually be made worse off with chemotherapy, because oftentimes patients have refractory disease and that affects the hematopoietic stem cell. And it's not good to affect that in the setting of persistent disease because then you get persistent myelosuppression.

That's been one of the biggest problems in treating patients with this disease. There may be a small fraction of patients with deletion in 17p that could benefit from chemotherapy, but in the absence of knowledge of what that means in terms of the resistance to the therapy, it's probably better with the advent of these newer agents to use agents such as ibrutinib. And I think that's very important. So this is clearly a very important take-home message.

William G. Wierda, MD, PhD: In terms of prognostic factors for relapsed patients, you have a patient who's been treated with a standard frontline regimen; they've had a remission that's lasted several years and their disease has recurred, and they're progressing and they fulfill the IWCLL criteria again for retreatment. Are there prognostic factors that you recheck at that point, and are they essential to recheck at that point, etc?

Thomas J. Kipps, MD, PhD: Well, it's actually not fixed in stone. If you have a patient with a FISH abnormality, that could change over time. We know that it can change with therapy, particularly with chemoimmunotherapy, where you may have selection for cells which have deletion in 17p. And so it's very important to get the FISH analysis prior to starting any therapy, initial therapy, or second-line therapy, so that you can identify those patients who might be harmed by your therapy. And I think it's very important.

We're also, I think a number of centers are as well, trying to stimulate the cells with CpG-ODN. This allows us to look at the metaphase nuclei, and we actually have a karyotype analysis. It is becoming increasingly more recognized that it's important to look at the complexity of the genetics. And it's a rule of thumb that if your genetics are complicated, it's not a good thing. So a simple genetics test is good.

Absence of translocations or the like is actually a very good thing. And some patients will harbor multiple translocations and aberrancies in their chromosomes that cannot be identified by FISH. They can only be identified by the metaphase analysis. So I would encourage people to seek that out, too, because I think there's going to be relevance to complex genetics to how patients may do over time for some of these newer treatments.

Susan M. O’Brien, MD: What about something that's done very commonly in Europe but not so commonly in the United States: analyzing for p53 mutations?

Thomas J. Kipps, MD, PhD: Well, it's interesting. The p53 mutation is, of course, the important gene that encodes proteins that are important for the response to chemotherapy. And so without that, you are not able to respond well. You're relatively resistant. And I would say two-thirds of the time, patients with 17p deletion will have mutations in p53.

That means about one-third to a quarter of patients will have wild-type p53. And it's a question of whether you can select further for absence of p53 by loss of the gene on the other chromosome. So I think that looking for p53 is important. However, I think this ipilimumab study that you mentioned before identified a prognostic indicator deletion in 17p as being worse than just the mutations in p53. So go figure.

In other words, there are other genes we know that map close to p53 in this area that may help to govern progression and also genomic complexity. And so it's a bad sign to have 17p—but it is a little bit heterogeneous there. If we focus only on p53, I think we're missing some of the things that might be also altered in those patients in the leukemic cells.

Richard R. Furman, MD: How many patients do you think you might actually catch who are not 17p-deleted but do have p53 mutation?

Thomas J. Kipps, MD, PhD: I think it's a very good point because you can have absence of 17p deletion and still have loss of p53 function. And that's difficult. I would say this, it's a rule of thumb to know your patients, know when they're progressing, and follow them very closely when you start, particularly chemoimmunotherapy.

I, frankly, get a little bit concerned if, after starting a fairly effective course of chemoimmunotherapy, I'm not seeing a fairly decent turnaround within a short order within the first two cycles. And I know, for example, that you are actually looking, after just three cycles of FCR chemoimmunotherapy, to see if you have had clearance of the cells from the marrow.

If you're not seeing a response after two or three cycles, it’s unlikely you'll see it after six cycles. So that may be a poor man's way of trying to assess the situation, short of going after trying to identify p53 mutations up front in everyone. It's only a small minority of patients that have p53 mutations without 17p deletion.

Richard R. Furman, MD: And also, what about the variability in terms of the mutations? So p53 sequencing is available commercially now. And the question, of course, is whether the mutation that's seen on the report is going to be of clinical significance or not. And do you tell a patient who is 17p-mutated that that really is something of consequence, not knowing whether or not it really is?

Thomas J. Kipps, MD, PhD: I think you raise a very important question. Obviously, you find mutations with deep sequencing. It may not have the practical clinical relevance that you're talking about. So, I think we need to gather more information about this and how to best incorporate it into standard practice algorithms. But it's a real problem. It's not cut and dried; it's not easy. It's not a very easy question.

Shuo Ma, MD, PhD: While we're on the topic of FISH for CLL, not only is it an important prognostic factor and also predictive factor, but I also want to remind physicians that it's important to include translocation 11;14 at the initial diagnosis of CLL to rule out mantle cell lymphoma—because mantle cell lymphoma can have lymphocytosis and a very similar presentation as CLL.

Richard R. Furman, MD: And that's all the more important with the complications that have been seen with ibrutinib in the mantle cell lymphoma patients. So, with the lymphocytosis, we've not seen any negative sequelae in CLL patients. But we certainly have seen leukostasis in mantle cell patients. So, making sure you have the correct diagnosis so that you know how to handle the lymphocytosis is exceedingly important.

William G. Wierda, MD, PhD: So what I've heard is that FISH is important to evaluate when patients go on their first-line therapy. We want to know if patients have a 17p deletion. Mutations in p53 are also probably important. And if you can get that test, that might be something important to consider. Metaphase karyotyping gives us some information, and that would be potentially of value. And the patients can acquire new changes in abnormalities, so FISH testing at relapse and retreatment might be important to evaluate at that time, as well.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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