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Stratifying Patients With CLL to Frontline Therapy

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Matthew S. Davids, MD, MMSc, Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute; Brad Kahl, MD, Washington University School of Medicine; John Pagel, MD, PhD, Swedish Cancer Institute
Published: Friday, Jul 26, 2019



Transcript: 

John Pagel, MD, PhD: Is chemotherapy dead? I think largely it is in CLL [chronic lymphocytic leukemia]. I think there are some patients, perhaps those very favorably mutated patients, in which we can still think about FCR [fludarabine/cyclophosphamide/rituximab] because of the potential for that long-term survival advantage. Right now, I’m not sure that even those patients will be very prevalent. You have to be younger. You have to be able to tolerate the regimen. We’ll see how that plays out over a little bit more time.

We still worry, of course, about the most aggressive patients, and for some reason, we are not getting enough FISH [fluorescence in situ hybridization] studies done to look for 17p deletions. That needs to be done very frequently and routinely. When we see those patients, they’re not candidates for chemoimmunotherapy. We should be really thinking about targeted therapies for those patients.

Ian W. Flinn, MD, PhD: I agree with you on the need to get all those prognostic factors, and I routinely get them in my patients, including the FISH, next-generation sequencing, and mutational status. However, you could make an argument that if all roads lead to ibrutinib, why bother? Brad, what are your thoughts?

Brad Kahl, MD: I think it’s an interesting conversation to have with a newly diagnosed patient, particularly the mutated patients. We heard from Matt that the results comparing ibrutinib to the different chemotherapy regimens demonstrate outcomes that look roughly equivalent for progression-free survival [PFS], if you limit the analysis to the mutated patients. If I have a young, healthy patient who is mutated, I will still offer them the option of FCR [fludarabine/cyclophosphamide/rituximab] and I’ll go through the whole discussion of what that would look like, relative to doing ibrutinib as frontline therapy. Now, if I have an older patient who’s suitable for BR [bendamustine/rituximab], I’ll go through that whole discussion with them about what BR [bendamustine/rituximab] would look like relative to doing ibrutinib. It’s an interesting discussion of pros and cons, time-limited therapy, and chemotherapy versus just taking an oral targeted agent, but that’s indefinite therapy.

Because the outcomes look roughly equivalent for the mutated patients, I let the patient guide me, and if I have a patient who says, “I definitely want to do the oral agent,” I’m fine with that. If I have a patient who says, “I’d rather do the time-limited option,” whether it be [bendamustine/rituximab] or [fludarabine/cyclophosphamide/rituximab], I’m fine with that. I think either option remains appropriate for the mutated patients. If the patients are unmutated, or if they’re 17p, then I will steer them toward a targeted agent rather than chemoimmunotherapy.

Ian W. Flinn, MD, PhD: I have to say, it’s been a while since I put those options out to a patient. I say, “You can get chemotherapy for 6 months or you can stay on the pill.” Everyone in my practice always says they want to take the pill, even when you lay out the potential adverse events of being on ibrutinib or other BTK [Bruton tyrosine kinase] inhibitors for a while. Matt, I think a lot of studies have shown that outcomes are substantially better in the 17p-deleted patients with ibrutinib in frontline. That said, they’re probably not quite the same as they are in other subgroups. Is that reason enough to want to check for 17p deletions? Do you think that’s enough? Do we need to be doing next-generation sequencing, and looking at mutations in that gene?

Matthew S. Davids, MD, MMSc: Yes, absolutely. I think testing for 17p deletion is still relevant, both from a prognostic standpoint and also because it can influence our long-term treatment approach, particularly for younger, fit patients. We know that ibrutinib only has modest durability, in terms of response, for patients who have deletion 17p. We have some evolving 5-year data that we’ve seen from the NCI [National Cancer Institute] group that studied this in a small number of—I think 34—patients with deletion 17p in the frontline setting. About three-quarters of those patients were still in remission at 5 years. That does look promising, especially compared to the relapsed/refractory data where we only see about a 2- to 3-year PFS with ibrutinib in 17p.

If we have younger CLL patients in their 50s or early 60s who are fit, these are not great numbers, and we need to be thinking about the next step. For some of these patients, this could involve cellular therapies. We have CAR [chimeric antigen receptor] T-cell therapy trials now in CLL. We still have allogeneic transplantation, which is a potentially curative therapy. It’s not something we’re using widely right now in CLL, but I think as we use ibrutinib in the frontline setting, we might then use other agents like venetoclax, and these younger patients may run into difficulties down the line. It’s something we might want to start planning for if we know about that 17p status. In terms of the question of mutational screening, I also think it is helpful to look for TP53 mutation. We know that these patients have a similar outcome as 17p-deleted patients, and they should be steered toward novel agent-based approaches, even if they have mutated IGHV.

Ian W. Flinn, MD, PhD: John, are you routinely getting these prognostic factors on the front line for all your patients? I’ve heard some people say, “Well, in your 80-year-old, does it really matter? It’s expensive to get all this testing done.” What do you think?

John Pagel, MD, PhD: I think it’s true that not all 17p deletions are created equal, right? There are some that will behave in a very indolent fashion. It is also accurate to say that you know who these people are in the relapsed setting, based on their prior therapies, how well they’ve done, and what their durations of remission have been like. You can often predict if they’re going to have a very high-risk feature or not. That’s a little less helpful in the frontline setting where you don’t have any of that information to guide you. I think it’s always important to know what the genetic features of a patient’s disease are every time you’re thinking about treating them. I highly recommend doing a FISH test in almost every patient at the time you’re trying to treat them. It does help for planning. I think that was very important to point out. Again, it will also help with understanding the right treatment for each individual patient.

Patients not only with 17p, but also with 11q deletions, are high risk, and we need to know about those patients. It seems they do better, in general, with BTK inhibition, compared to chemoimmunotherapy. Those are the people who tend to have bulky disease, so we might be thinking about getting CT [computed tomography] scans in those patients where we might not otherwise, if they do have an 11q deletion. For sequencing in patients, I think there’s still not a wide need for that, outside of looking for TP53. Assessing for NOTCH1 or some of the other high-risk features isn’t particularly relevant right now, maybe because it’s not directing our therapy. It is important to know in younger patients, perhaps for planning if you’re going to do a cellular therapy or not.

Ian W. Flinn, MD, PhD: John brought up an interesting point that all 17p patients aren’t the same. Do you think it matters whether the relative frequency—there are people who have just above the lower limit of normal cutoff and then there are people who have 60% of their cells. Does that change the way you think of the patient?

Matthew S. Davids, MD, MMSc: It does. I fully agree with that. A lot of laboratories, including our own, use 5% as a cutoff for deletion 17p. We’ll see these cases that have 6% or 7%, and they’re technically deletion 17p, but they don’t tend to behave like an aggressive 17p at that threshold. Usually, we start to see more aggressive disease as it gets closer to 20% or higher. That’s when we’re more concerned. We’re more concerned when we see deletion 17p in the context of a TP53 mutation at the same time. Then, there is this subset of patients who have mutated IGHV with low-level deletion 17p who can have a very indolent prognosis and stay on observation for several years.

Transcript Edited for Clarity

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Transcript: 

John Pagel, MD, PhD: Is chemotherapy dead? I think largely it is in CLL [chronic lymphocytic leukemia]. I think there are some patients, perhaps those very favorably mutated patients, in which we can still think about FCR [fludarabine/cyclophosphamide/rituximab] because of the potential for that long-term survival advantage. Right now, I’m not sure that even those patients will be very prevalent. You have to be younger. You have to be able to tolerate the regimen. We’ll see how that plays out over a little bit more time.

We still worry, of course, about the most aggressive patients, and for some reason, we are not getting enough FISH [fluorescence in situ hybridization] studies done to look for 17p deletions. That needs to be done very frequently and routinely. When we see those patients, they’re not candidates for chemoimmunotherapy. We should be really thinking about targeted therapies for those patients.

Ian W. Flinn, MD, PhD: I agree with you on the need to get all those prognostic factors, and I routinely get them in my patients, including the FISH, next-generation sequencing, and mutational status. However, you could make an argument that if all roads lead to ibrutinib, why bother? Brad, what are your thoughts?

Brad Kahl, MD: I think it’s an interesting conversation to have with a newly diagnosed patient, particularly the mutated patients. We heard from Matt that the results comparing ibrutinib to the different chemotherapy regimens demonstrate outcomes that look roughly equivalent for progression-free survival [PFS], if you limit the analysis to the mutated patients. If I have a young, healthy patient who is mutated, I will still offer them the option of FCR [fludarabine/cyclophosphamide/rituximab] and I’ll go through the whole discussion of what that would look like, relative to doing ibrutinib as frontline therapy. Now, if I have an older patient who’s suitable for BR [bendamustine/rituximab], I’ll go through that whole discussion with them about what BR [bendamustine/rituximab] would look like relative to doing ibrutinib. It’s an interesting discussion of pros and cons, time-limited therapy, and chemotherapy versus just taking an oral targeted agent, but that’s indefinite therapy.

Because the outcomes look roughly equivalent for the mutated patients, I let the patient guide me, and if I have a patient who says, “I definitely want to do the oral agent,” I’m fine with that. If I have a patient who says, “I’d rather do the time-limited option,” whether it be [bendamustine/rituximab] or [fludarabine/cyclophosphamide/rituximab], I’m fine with that. I think either option remains appropriate for the mutated patients. If the patients are unmutated, or if they’re 17p, then I will steer them toward a targeted agent rather than chemoimmunotherapy.

Ian W. Flinn, MD, PhD: I have to say, it’s been a while since I put those options out to a patient. I say, “You can get chemotherapy for 6 months or you can stay on the pill.” Everyone in my practice always says they want to take the pill, even when you lay out the potential adverse events of being on ibrutinib or other BTK [Bruton tyrosine kinase] inhibitors for a while. Matt, I think a lot of studies have shown that outcomes are substantially better in the 17p-deleted patients with ibrutinib in frontline. That said, they’re probably not quite the same as they are in other subgroups. Is that reason enough to want to check for 17p deletions? Do you think that’s enough? Do we need to be doing next-generation sequencing, and looking at mutations in that gene?

Matthew S. Davids, MD, MMSc: Yes, absolutely. I think testing for 17p deletion is still relevant, both from a prognostic standpoint and also because it can influence our long-term treatment approach, particularly for younger, fit patients. We know that ibrutinib only has modest durability, in terms of response, for patients who have deletion 17p. We have some evolving 5-year data that we’ve seen from the NCI [National Cancer Institute] group that studied this in a small number of—I think 34—patients with deletion 17p in the frontline setting. About three-quarters of those patients were still in remission at 5 years. That does look promising, especially compared to the relapsed/refractory data where we only see about a 2- to 3-year PFS with ibrutinib in 17p.

If we have younger CLL patients in their 50s or early 60s who are fit, these are not great numbers, and we need to be thinking about the next step. For some of these patients, this could involve cellular therapies. We have CAR [chimeric antigen receptor] T-cell therapy trials now in CLL. We still have allogeneic transplantation, which is a potentially curative therapy. It’s not something we’re using widely right now in CLL, but I think as we use ibrutinib in the frontline setting, we might then use other agents like venetoclax, and these younger patients may run into difficulties down the line. It’s something we might want to start planning for if we know about that 17p status. In terms of the question of mutational screening, I also think it is helpful to look for TP53 mutation. We know that these patients have a similar outcome as 17p-deleted patients, and they should be steered toward novel agent-based approaches, even if they have mutated IGHV.

Ian W. Flinn, MD, PhD: John, are you routinely getting these prognostic factors on the front line for all your patients? I’ve heard some people say, “Well, in your 80-year-old, does it really matter? It’s expensive to get all this testing done.” What do you think?

John Pagel, MD, PhD: I think it’s true that not all 17p deletions are created equal, right? There are some that will behave in a very indolent fashion. It is also accurate to say that you know who these people are in the relapsed setting, based on their prior therapies, how well they’ve done, and what their durations of remission have been like. You can often predict if they’re going to have a very high-risk feature or not. That’s a little less helpful in the frontline setting where you don’t have any of that information to guide you. I think it’s always important to know what the genetic features of a patient’s disease are every time you’re thinking about treating them. I highly recommend doing a FISH test in almost every patient at the time you’re trying to treat them. It does help for planning. I think that was very important to point out. Again, it will also help with understanding the right treatment for each individual patient.

Patients not only with 17p, but also with 11q deletions, are high risk, and we need to know about those patients. It seems they do better, in general, with BTK inhibition, compared to chemoimmunotherapy. Those are the people who tend to have bulky disease, so we might be thinking about getting CT [computed tomography] scans in those patients where we might not otherwise, if they do have an 11q deletion. For sequencing in patients, I think there’s still not a wide need for that, outside of looking for TP53. Assessing for NOTCH1 or some of the other high-risk features isn’t particularly relevant right now, maybe because it’s not directing our therapy. It is important to know in younger patients, perhaps for planning if you’re going to do a cellular therapy or not.

Ian W. Flinn, MD, PhD: John brought up an interesting point that all 17p patients aren’t the same. Do you think it matters whether the relative frequency—there are people who have just above the lower limit of normal cutoff and then there are people who have 60% of their cells. Does that change the way you think of the patient?

Matthew S. Davids, MD, MMSc: It does. I fully agree with that. A lot of laboratories, including our own, use 5% as a cutoff for deletion 17p. We’ll see these cases that have 6% or 7%, and they’re technically deletion 17p, but they don’t tend to behave like an aggressive 17p at that threshold. Usually, we start to see more aggressive disease as it gets closer to 20% or higher. That’s when we’re more concerned. We’re more concerned when we see deletion 17p in the context of a TP53 mutation at the same time. Then, there is this subset of patients who have mutated IGHV with low-level deletion 17p who can have a very indolent prognosis and stay on observation for several years.

Transcript Edited for Clarity
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