ONCAlert | Upfront Therapy for mRCC

Chronic Lymphocytic Leukemia: Frontline Therapy Selection

Targeted Oncology
Published Online:12:34 PM, Tue July 23, 2019

Harry Erba, MD, PhD: Do you have a preferred regimen for initial therapy?

Javier Pinilla-Ibarz, MD, PhD: That’s a great point. Traditionally, we have a plethora. We used to say, there is a shopping list of really different regimens that we can use. Since the last NCCN [National Comprehensive Cancer Network] Guidelines, I have to say because of the very, very important phase III clinical trial that was reported previously, BTK [Bruton tyrosine kinase] inhibitors—in this case, ibrutinib—have become almost the standard of care in any CLL [chronic lymphocytic leukemia]. We are talking about younger, older, with or without comorbid condition or independently of the stratification. That’s for sure. However, we still have our old chemoimmunotherapy that is fading away but still present. And there are new therapies that we’ll discuss later that were just presented at the ASCO [American Society of Clinical Oncology Annual] Meeting.
 
I think what I really, really try to understand is what are patients’ goals to therapy and their needs and the different adverse-effect profile that new medication and old medication may have, as well as long-term duration of therapy, short-term duration. I have this conversation with my patients who require therapy, to really customize the best therapy for each patient. However, we need to recognize the data, and right now the data are very, very strong for targeted therapies.

Harry Erba, MD, PhD: The Alliance-led Intergroup trial looked at older patients, where patients were randomized between BR [bendamustine-rituximab]-ibrutinib and ibrutinib-rituximab. There was really no difference between the ibrutinib-containing arms.

Javier Pinilla-Ibarz, MD, PhD: Absolutely.

Harry Erba, MD, PhD: But they showed an improvement in progression-free survival. In the younger patients, the ECOG [Eastern Cooperative Oncology Group]-led Intergroup trial was FCR [fludarabine-cyclophosphamide-rituximab] versus ibrutinib-rituximab, again with an improvement in progression-free survival. In a subset of unmutated disease, it looked like they might be a survival benefit as well.

Javier Pinilla-Ibarz, MD, PhD: Well, 5-year survival is in the overall group, right? When you really differentiate the mutated and unmutated, obviously as we predicted, mutated patients still may do well with FCR [fludarabine-cyclophosphamide-rituximab]. However, you expose those patients to chemotherapy, and not all of them are going to do well with FCR [fludarabine-cyclophosphamide-rituximab]. It’s important. The unmutated subset is obviously the 1 that we knew for a long time that they will really much benefit for these new therapies.

Harry Erba, MD, PhD: So let me put you on the spot. You have a young patient who has mutated CLL. How much of a discussion do you have about FCR [fludarabine-cyclophosphamide-rituximab] versus ibrutinib-based regimens?

Javier Pinilla-Ibarz, MD, PhD: It’s a great, great question, and we have been evolving in the last 3 years. I have used ibrutinib in unmutated younger patients for a while because we are already knew the data coming from FCR [fludarabine-cyclophosphamide-rituximab] regimen, that unmutated patients will relapse shortly. And those patients are the ones who may also have clonal evolution induced by chemotherapy over this famous bottleneck that will really be induced by the shrinkage of the cells. And you may have 1 TP53 mutation that will come up. I think it’s important. However, now with the recent approval of frontline venetoclax, we are very fortunate to really discuss even more options for patients, even from younger patients without mutated immunoglobulin.

Harry Erba, MD, PhD: Before we get to that, does the status of TP53 mutation or deletion affect your initial treatment decision?

Javier Pinilla-Ibarz, MD, PhD: Well, what we know for sure—and we’ve known this for a long, long time—is that patients with deletion of 17p or TP53 mutation should not receive any type of chemotherapy agents because chemotherapy doesn’t work and really makes things worse in the long run. In those patients for sure, standard of care has been ibrutinib. Obviously new therapies, such as the 1 that we can discuss later, are going to be introduced and are very, very important. But with those patients, I don’t hesitate to really reinforce the fact that those patients should not receive chemotherapy of any type—no bendamustine, no fludarabine.

Harry Erba, MD, PhD: OK, Javier, I get it. You’re really eager to talk about venetoclax and BCL2 inhibition. Let’s start with the role of BCL2 in the pathogenesis of CLL.

Javier Pinilla-Ibarz, MD, PhD: I think it’s fascinating, and last year we started to understand the official pathology of CLL. We know that in CLL they have these 2 components. One side they probably progress through the BCR signaling, and this is the signaling that we can really block through BTK inhibition or PI3K-delta inhibition. So we block proliferation. But we know that these are not the only mechanisms of CLL that really have to survive. We know that as differentially happens with AML, acute myeloid leukemia, those patients don’t grow slowly over time. But what is happening is that there’s a slow growth of germinal centers, bone marrow. But at the end of the day, what’s happening is these cells grow and don’t die. They don’t die because they upregulate BCL2 that we know is an anti-apoptotic protein that really stops cells from dying. We have these 2 amazing mechanisms in place, and what is really, really exciting is today we have the 2 main mechanisms to really find CLL: the blocking of the proliferative and really the blockade of the anti-apoptotic protein. When we block the anti-apoptotic protein, obviously cells massively go to destruction, and they’re going to die.

Harry Erba, MD, PhD: I think that’s the fascinating clinical observation, right? It’s the rapidity with which you just block BCL2 and then the cells die. How are these cells poised to die? You just blocked BCL2. Why is there just massive apoptosis at that point?

Javier Pinilla-Ibarz, MD, PhD: The reason is because when you block the anti-apoptotic proteins, there is another pro-apoptotic protein that takes its place. There is a disbalance. You disbalance these mechanisms, so cells really will act in this natural way, so that the cells have to go to apoptosis. The BCL2 upregulation is this disbalancing, the fact that those cells should be dying, but they don’t. When you really block these proteins, it allows cells to really continue the normal process of apoptosis.

Transcript edited for clarity.

Harry Erba, MD, PhD: Do you have a preferred regimen for initial therapy?

Javier Pinilla-Ibarz, MD, PhD: That’s a great point. Traditionally, we have a plethora. We used to say, there is a shopping list of really different regimens that we can use. Since the last NCCN [National Comprehensive Cancer Network] Guidelines, I have to say because of the very, very important phase III clinical trial that was reported previously, BTK [Bruton tyrosine kinase] inhibitors—in this case, ibrutinib—have become almost the standard of care in any CLL [chronic lymphocytic leukemia]. We are talking about younger, older, with or without comorbid condition or independently of the stratification. That’s for sure. However, we still have our old chemoimmunotherapy that is fading away but still present. And there are new therapies that we’ll discuss later that were just presented at the ASCO [American Society of Clinical Oncology Annual] Meeting.
 
I think what I really, really try to understand is what are patients’ goals to therapy and their needs and the different adverse-effect profile that new medication and old medication may have, as well as long-term duration of therapy, short-term duration. I have this conversation with my patients who require therapy, to really customize the best therapy for each patient. However, we need to recognize the data, and right now the data are very, very strong for targeted therapies.

Harry Erba, MD, PhD: The Alliance-led Intergroup trial looked at older patients, where patients were randomized between BR [bendamustine-rituximab]-ibrutinib and ibrutinib-rituximab. There was really no difference between the ibrutinib-containing arms.

Javier Pinilla-Ibarz, MD, PhD: Absolutely.

Harry Erba, MD, PhD: But they showed an improvement in progression-free survival. In the younger patients, the ECOG [Eastern Cooperative Oncology Group]-led Intergroup trial was FCR [fludarabine-cyclophosphamide-rituximab] versus ibrutinib-rituximab, again with an improvement in progression-free survival. In a subset of unmutated disease, it looked like they might be a survival benefit as well.

Javier Pinilla-Ibarz, MD, PhD: Well, 5-year survival is in the overall group, right? When you really differentiate the mutated and unmutated, obviously as we predicted, mutated patients still may do well with FCR [fludarabine-cyclophosphamide-rituximab]. However, you expose those patients to chemotherapy, and not all of them are going to do well with FCR [fludarabine-cyclophosphamide-rituximab]. It’s important. The unmutated subset is obviously the 1 that we knew for a long time that they will really much benefit for these new therapies.

Harry Erba, MD, PhD: So let me put you on the spot. You have a young patient who has mutated CLL. How much of a discussion do you have about FCR [fludarabine-cyclophosphamide-rituximab] versus ibrutinib-based regimens?

Javier Pinilla-Ibarz, MD, PhD: It’s a great, great question, and we have been evolving in the last 3 years. I have used ibrutinib in unmutated younger patients for a while because we are already knew the data coming from FCR [fludarabine-cyclophosphamide-rituximab] regimen, that unmutated patients will relapse shortly. And those patients are the ones who may also have clonal evolution induced by chemotherapy over this famous bottleneck that will really be induced by the shrinkage of the cells. And you may have 1 TP53 mutation that will come up. I think it’s important. However, now with the recent approval of frontline venetoclax, we are very fortunate to really discuss even more options for patients, even from younger patients without mutated immunoglobulin.

Harry Erba, MD, PhD: Before we get to that, does the status of TP53 mutation or deletion affect your initial treatment decision?

Javier Pinilla-Ibarz, MD, PhD: Well, what we know for sure—and we’ve known this for a long, long time—is that patients with deletion of 17p or TP53 mutation should not receive any type of chemotherapy agents because chemotherapy doesn’t work and really makes things worse in the long run. In those patients for sure, standard of care has been ibrutinib. Obviously new therapies, such as the 1 that we can discuss later, are going to be introduced and are very, very important. But with those patients, I don’t hesitate to really reinforce the fact that those patients should not receive chemotherapy of any type—no bendamustine, no fludarabine.

Harry Erba, MD, PhD: OK, Javier, I get it. You’re really eager to talk about venetoclax and BCL2 inhibition. Let’s start with the role of BCL2 in the pathogenesis of CLL.

Javier Pinilla-Ibarz, MD, PhD: I think it’s fascinating, and last year we started to understand the official pathology of CLL. We know that in CLL they have these 2 components. One side they probably progress through the BCR signaling, and this is the signaling that we can really block through BTK inhibition or PI3K-delta inhibition. So we block proliferation. But we know that these are not the only mechanisms of CLL that really have to survive. We know that as differentially happens with AML, acute myeloid leukemia, those patients don’t grow slowly over time. But what is happening is that there’s a slow growth of germinal centers, bone marrow. But at the end of the day, what’s happening is these cells grow and don’t die. They don’t die because they upregulate BCL2 that we know is an anti-apoptotic protein that really stops cells from dying. We have these 2 amazing mechanisms in place, and what is really, really exciting is today we have the 2 main mechanisms to really find CLL: the blocking of the proliferative and really the blockade of the anti-apoptotic protein. When we block the anti-apoptotic protein, obviously cells massively go to destruction, and they’re going to die.

Harry Erba, MD, PhD: I think that’s the fascinating clinical observation, right? It’s the rapidity with which you just block BCL2 and then the cells die. How are these cells poised to die? You just blocked BCL2. Why is there just massive apoptosis at that point?

Javier Pinilla-Ibarz, MD, PhD: The reason is because when you block the anti-apoptotic proteins, there is another pro-apoptotic protein that takes its place. There is a disbalance. You disbalance these mechanisms, so cells really will act in this natural way, so that the cells have to go to apoptosis. The BCL2 upregulation is this disbalancing, the fact that those cells should be dying, but they don’t. When you really block these proteins, it allows cells to really continue the normal process of apoptosis.

Transcript edited for clarity.
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